Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.

Autoimmunity arises from the pathologic reaction of B-cell–derived antibodies and/or T cells to self-epitopes. Proof of an autoimmune pathogenesis requires adoptive transfer of disease by either immune cells or antibody.1,2 Transplacental or iatrogenic transfer of autoreactive antibodies may cause disease. This condition was first shown in Harrington's self experimentation using plasma from a patient with idiopathic thrombocytopenic purpura (ITP).3Mothers with ITP, myasthenia gravis, and/or systemic lupus erythematosus (SLE) with SSA-Ro-SSB/La immunity may transfer antibodies to their fetus, resulting in neonatal disease.4-7Allogeneic stem cell transplantation from donors with autoimmune disease may also transfer the disease to recipients.8-13 

Clinical tolerance is failure of an organism to reject an antigen or tissue without use of immune-suppressive medications but with intact normal rejection of third-party or foreign antigens. The oldest theory of tolerance, and now viewed as orthodoxy, is clonal selection of lymphocyte repertoires.14 Self-reactive lymphocytes are deleted and not allowed to mature. Clonal selection as an explanation for tolerance was first proposed by Burnet15 in 1957 in regards to antibody formation and self-recognition and non–self-recognition. Subsequently, this concept was extended to selection of T cells by deletion of autoreactive clones within the thymus.16-21 T-cell precursors emigrate from the marrow to the thymus. In the thymus, if self-antigen of sufficient concentration and affinity for their specific T-cell receptor (TCR) repertoires is present, the T cells undergo apoptosis (deletion) or anergy (functional silencing).22-25 Because lymphocyte progenitors are continually generated from HSCs, clonal selection would have to be an ongoing process occurring throughout life.

Thymic editing includes not only negative selection to delete self-reactive clones but also positive selection to allow maturation of self-reactive clones.17,26 If a particular TCR fails to engage a major histocompatibility complex (MHC) peptide/complex, or binds it too tightly, it undergoes apoptosis. If it recognizes an MHC/peptide complex with moderate avidity, it is positively selected and undergoes further maturation. The avidity (concentration and binding affinity) of an MHC/peptide complex appears to play a role in positive versus negative selection of T lymphocytes.27,28Intrathymic selection and anergy as a mechanism of maintaining tolerance of autoreactive repertoires was, therefore, amended by theories concerning peripheral tolerance.29 30 

Mechanisms of peripheral tolerance revolve, in part, around the 2-signal hypothesis of self-discrimination and non–self-discrimination introduced by Bretscher and Cohn31 in 1970. T cells, positively selected within the thymus, remain anergic unless antigen is presented with a second signal (ie, a costimulatory signal). Basically, antigen presentation to a T cell without costimulation maintains anergy, whereas TCR engagement of antigen combined with costimulation results in T-cell activation.32-35 

The traditional costimulatory molecule for T-cell activation is CD28, a ligand for B7-1 (CD80), and B7-2 (CD86) receptors on T cells.36 CD28 binding increases transcription of interleukin 2 (IL-2).35,37 A variety of other molecules, including CD40L, inducible costimulator (ICOS), and various adhesion molecules, also provide secondary or tertiary signals to facilitate T-cell activation.38-43 Requirement of costimulation for activation may place some constraints on peripheral sites for cellular activation. Antigen-presenting cells (APCs) that express costimulatory molecules are localized within secondary lymphoid tissues (spleen and draining lymph nodes). Transfer of antigen by immune cells to secondary lymphoid regions may be important to induce T-cell activation.44 For example, allogeneic tissue grafts are not rejected in mice that lack secondary lymphoid tissue.45 

Besides the requirement for costimulation, a variety of mechanisms maintain peripheral tolerance. Some of these mechanisms are similar to intrathymic tolerance but occur in the periphery, including peripheral T-cell deletion and/or anergy induced by T-cell interaction with parenchymal cells.46,47 Other checks to maintain peripheral tolerance include activation-induced cell death,48 suppressor or regulatory cells,49-51and peripheral antigen avidity (ie, antigen persistence, concentration, and affinity).52,53 Theories on peripheral tolerance explain how a T-cell repertoire selected intrathymically for reactivity to self maintains peripheral tolerance. A further extension of tolerance to what has been termed the “danger signal” explains the context in which costimulation arises.54 

The danger metaphor proposed by Matzinger54 involves the use of the innate immune system (neutrophils, natural killer cells, and macrophages) to break peripheral tolerance. T-cell–mediated immunity, known as adaptive immunity, is an evolutionary development of vertebrates.55 Adaptive immunity involves the rearrangement of a limited number of germ line genes to produce a highly diversified repertoire of approximately 1014 to 1018 somatically mutated T-cell (immunoglobulinlike) receptors and B-cell immunoglobulin receptors. These T cells undergo deletion and anergy within the thymus. However, the innate immune system does not have pathogen-receptor repertoire diversity.56 Response to infection is intrinsic to a limited number of germ-line receptor genes that recognize pathogen-specific molecular patterns. These patterns include receptors for conserved pathogen structures like lipopolysaccharides, mannans, bacterial DNA, and lipoteichoic acids. Receptor-mediated phagocytosis of pathogens by macrophages leads to release of proinflammatory cytokines and expression of costimulation molecules, along with MHC presentation of pathogen-derived peptides, leading to T-cell activation. Thus, pathogen stimulation of innate immunity can lead to activation of the adaptive immune system.57-59 

In animal models, active immunization with self-epitopes requires an adjuvant (immune stimulant) to break tolerance. Adjuvant is often nothing more than homogenized pathogens such as mycobacterium, which provides the danger signal for activation of innate APCs such as macrophages. Presentation of coinjected self-proteins by adjuvant-activated APCs initiates antigen-specific autoreactive T cells. Once activated to self by innate immunity, how is the adaptive immune system prevented from causing autoimmune disease? This question may be approached by viewing the immune system as dynamic and constantly fluctuating.

In all prior theories of tolerance, lymphocytes are viewed as responding or not responding, like a light switch that is on or off. The perturbation theory postulated by Grossman and Singer60and Grossman and Paul61 62 proposes that lymphocytes are dynamically tuned much like a rheostat dims or brightens a room. Lymphocytes selected intrathymically may maintain a steady tone by repeated interaction with peripheral tissue. It is the sudden change in dynamic homeostasis that is perceived as a perturbation. By analogy, blood is always dynamically fluctuating between clotting and lysis. In steady state, blood may be erroneously perceived as static. The immune system may also be dynamically fluctuating between autoimmunity and tolerance in a dynamic steady state not readily appreciated. A steady state that may be controlled by clonal selection, activation, feedback inhibition, and intracellular receptor and signal transduction tuning. It is conceivable, but unproven, that immune ablation followed by infusion of hematopoietic stem cells (HSCs) may “reset the immune rheostat.”

All processes involving tolerance, even deletion, are ongoing recurring events and may be broken. Both central and peripheral T-cell tolerance may be broken by environmental exposure. Classic agents capable of breaking tolerance include drugs and infections.63-65 

Drug-induced autoimmunity

Numerous drugs may cause autoimmunity by affecting thymic TCR antigen interaction or TCR signal events. A common drug associated with lupuslike manifestations is procainamide.66-68 When the metabolite procainamide-hydroxylamine is injected into the thymus of an animal or added to primary thymic organ cultures, chromatin-reactive T cells emerge.66 Procainamide-hydroxylamine may alter the avidity of TCRs for self-antigen, preventing deletion of some autoreactive T-cell repertoires.68 Cyclosporine is an immunosuppressive medication that inhibits TCR-mediated signaling. By inhibiting peripheral T-cell activation, cyclosporine suppresses autoimmunity but by interference with thymic TCR signaling may also inhibit thymic deletion of autoreactive T cells,69-72causing a T-cell autoimmune sclerodermalike disease termed syngeneic graft versus host disease (GVHD).72 

Drug-induced disruption of central tolerance implies existence of a functional thymus throughout adulthood. By using the membrane protein CD45 to differentiate naive (CD45 RA) from memory (CD45RO) T cells, thymic-dependent T-cell production appears to diminish markedly after puberty, presumably because of thymic atrophy. If the thymus involutes, new adult T cells would then be derived exclusively from peripheral expansion of existing memory cells. However, with the advent of newer DNA assays, the accuracy of differentiation between naive and memory T cells by CD45 has been questioned.73-75 

During TCR thymic development, rearrangement of TCR genes leads to excision of circular DNA termed T-cell receptor rearrangement excision circles (TRECs).73 TRECs are episomal, unique to T cells, and do not duplicate during mitosis. Because TCR rearrangement occurs during thymic development, TRECs may be used as a marker for recent thymic emigrants. In the early post–hematopoietic stem cell transplantation (HSCT) period, there is a substantial increase in peripheral blood TREC-positive T cells.74 Although an inverse correlation exists between age and TREC production after HSCT, TREC numbers increased in all age groups. Therefore, thymic-dependent generation of T cells occurs in all ages. A drug or environmental-related disruption of thymic tolerance, which alters TCR antigen avidity or TCR cytoplasmic or nuclear signaling events, may allow escape of autoreactive lymphocytes. Once in the periphery, long-lived autoreactive cells could cause a persistent autoimmune disease.

Infection-induced autoimmunity

An infectious agent has been associated with virtually every autoimmune disease, including diabetes mellitus,76-79ankylosing spondylitis,80 multiple sclerosis (MS),81-86 myocarditis,87-89 rheumatoid arthritis (RA),90-96 and SLE.97 These associations are suggested by epidemiologic studies and serology that connect disease onset or flare to various infectious agents, cross-reaction of virus or pathogen epitopes and self-proteins, and occasional isolation of an infectious agent in affected tissue.

An infection could precipitate an autoimmune disease by breaking self-tolerance through molecular mimicry,98,99 determinant or epitope spreading,100,101 or bystander activation.102 Molecular mimicry is the capacity of a lymphocyte activated to an infectious pathogen to cross-react with a similar host determinant. Because memory lymphocytes are long lived, the infectious agent that initiated molecular mimicry to self does not need to persist for autoimmunity to occur. This situation may be one reason for difficulty in proving an infectious etiology for autoimmune disorders. Bystander activation arises when activation of T cells specific for antigen X occurs during an immune response against a nonhomologous antigen Y. In contrast, molecular mimicry is targeted toward self-peptides homologous to the initiating determinant on a viral or other infectious agent. Immunization with adjuvant and peptide is an example of bystander activation to the coinjected nonhomologous peptide.103 

Infection-related inflammation is associated with tissue destruction and presentation of self-epitopes, as well as up-regulation of APC costimulatory molecules that may also lead to bystander activation of T cells to self-determinants. Theiler murine encephalomyelitis virus (TMEV)–induced demyelination, an autoimmune demyelinating disease that mimics MS, is an example of viral-induced bystander activation.104 TMEV is a picornavirus (small RNA virus) that infects gray matter neurons but, through bystander activation of the immune system, leads to an autoimmune-demyelinating white matter disease.105 

Superantigens may also cause bystander activation. Superantigens are bacterial, mycoplasma, or viral proteins that activate polyclonal groups of T cells.106-112 Polyclonal activation arises by cross-linking the side of a MHC molecule to the Vβ portion of a TCR. Superantigen binding occurs outside the MHC peptide–binding groove and outside the TCR CDR3 antigen-specific recognition site. Activation by superantigen results in overexpansion and/or deletion of entire Vβ families, resulting in skewing of the T-cell repertoire. Superantigen activation of T cells has been suggested to initiate or cause a flare of various autoimmune diseases, including myocarditis, diabetes, MS, and psoriasis.107 

Once molecular mimicry, bystander activation, or superantigens initiate an autoimmune disease, the immune response spreads over time to epitopes that are distinct and non–cross-reactive to the inducing epitope, a phenomenon termed determinant or epitope spreading.113 Epitope spreading has been documented for both T- and B-cell immune responses. A hierarchical order of epitope spreading occurs according to immune dominance of the epitope. Determinant spreading may occur to different regions on the same protein (intramolecular epitope spread) or to a protein distinct from the protein containing the disease-initiating epitope (intermolecular epitope spreading). Temporal spreading of immune responses to other epitopes has been demonstrated in numerous animal autoimmune disorders, including experimental autoimmune encephalomyelitis (EAE),114 diabetes in nonobese diabetic (NOD) mice,115 and experimental autoimmune myasthenia gravis.116 Determinant spreading is suspected to be associated with several human autoimmune diseases, including MS,117 SLE,118 bullous skin diseases,119 myasthenia gravis,120diabetes,121,122 and chronic rejection of organ allografts.123-125 

The mechanism of epitope spreading may be related to costimulation, because in some models blocking CD28/B7 costimulation may prevent epitope spreading.100 Whatever the mechanism, epitope spreading makes it difficult to retrospectively determine the inducing epitope or antigen. Effectiveness of targeted immune interventions directed against one TCR or epitope may be limited by the phenomenon of epitope spreading.

MHC autoimmune-associated genes

MHC antigens were initially referred to as tissue transplantation antigens. They were discovered, as the name implies (major histocompatability complex), to have a major role in rejection of transplanted organs. As later discovered by Zinkernagel and Doherty,126 the MHCs are peptide-presenting molecules resulting in MHC/peptide restriction for T-cell recognition.127 It is not, therefore, surprising that many autoimmune diseases are associated with particular MHC genotypes.

Numerous suspected autoimmune disorders (such as MS, RA, spondyloarthropathies, diabetes, myasthenia gravis, Crohn disease, primary biliary cirrhosis, autoimmune hepatitis, SLE, vasculitis, pemphigus vulgaris, and Sjögren syndrome) are associated with MHC alleles.128 Because combined MHC/peptide presentation is essential for T-cell activation, a MHC association may be indirect evidence for an immune pathogenesis. RA-prone MHC alleles, their frequencies vary for different ethnic groups, share a similar amino acid epitope sequence (LLEQKRAA or LLEQRRAA) encoded by codons 67 to 74.129-131 The HLA sequence 67 to 74 is a HLA contact site for both peptide and TCR binding. This finding suggests HLA presentation of a common infectious or self-antigen to T cells is involved in the pathogenesis of RA. Spondyloarthropathies are linked with only some molecular subtypes of HLA-B27.132 Similar to RA, peptide-binding differences may explain differences in disease susceptibility. HLA-B27 may even present its own B27-derived peptides. In which case, the putative arthritogenic peptide may be a component of the HLA-B27 molecule.

The autoimmune etiology for scleroderma is questionable because of poor response to immune suppressive medications. Similarly, scleroderma also has a relatively weak MHC association that may indicate only partial immune pathogenesis or weak linkage of scleroderma genes to MHC alleles or the absence of an autoimmune etiology.133 Although MHC genes correlate with autoimmune disease susceptibility, most patients with disease-associated MHC genes remain disease free throughout their lifespan. Environment and/or non-MHC genes must, therefore, contribute toward development of disease.

Non-MHC autoimmune genes

Multiple non-MHC genes that regulate cell proliferation (oncogenes), cell signaling (tyrosinases), immune response (costimulatory molecules, interleukins, and cytokines), and apoptosis (fas) may play a role in development of autoimmunity.134Analysis of the diabetic-prone NOD mouse has revealed at least 18 insulin-dependent diabetes prone genes.135 SLE occurs in various strains of mice, including Murthy Roth lymphoproliferative (MRL/lpr) mice and New Zealand Black X New Zealand White F1 hybrid (NZB/NZW) mice.136 Various mating crosses of lupus-prone mice, as well as backcrosses to normal mice, have linked murine lupus to 38 different genomic loci.137 Some loci are associated with glomerulonephritis, others with vasculitis, some with anti-ds DNA, some with antichromatin antibody, some with lymphoproliferation, and others with splenomegaly. No single gene is sufficient to cause disease. Various combinations of SLE-prone genes among different patients may explain why patients with SLE can have highly variable organ involvement and clinical symptoms. Collagen-induced arthritis in rats is a model for RA and is induced by injection of collagen and adjuvant.138,139 At least 14 genomic intervals or collagen-induced arthritis (CIA) loci are associated with collagen-induced arthritis.140 141 

Although autoimmunity involves MHC and numerous non-MHC genes, environmental interactions with these genes are essential to manifest disease. Approximately two thirds of syngeneic twins with MS, RA, SLE, or type I diabetes are discordant for clinical disease.142Although a concordance rate of 33% is much higher than the general population, it remains significantly below a predetermined dominant Mendelian penetrance of 100% and suggests that environmental factors continue to have a significant role in polygenic autoimmune diseases.

Animal models and anecdotal case reports

Animal autoimmune diseases that are induced by immunization with adjuvant or self-peptide and adjuvant may be ameliorated by syngeneic or pseudo-autologous HSCT.143-155 

Immunization with adjuvant and either myelin basic protein or proteolipid protein peptides induces a T-cell–mediated demyelinating disease, EAE, that, depending on the animal model, may be monophasic, relapsing-remitting with secondary progression, or progressive from onset. EAE in Swiss Jackson Laboratory/Jackson (SJL/J) mice is a relapsing, remitting, and secondarily progressive disease. Several investigators have demonstrated cure, decreased relapse rates, or decreased disease severity in EAE animals undergoing syngeneic HSCT.146,149-151 Because of the expense of long-term animal housing, most experiments in EAE are performed before disease onset to abort disease initiation or shortly after disease onset to ameliorate its course. It is unlikely that such experiments are applicable to patients with a long duration of MS with accumulated disease burden and tissue damage. Syngeneic HSCT performed in mice with chronic EAE, unlike the results in acute EAE, failed to demonstrate neurologic improvement.146 Histologic analysis revealed chronic scarring with glial proliferation that is unaffected by HSCT.146 To be effective as therapy for EAE, HSCT needs to be performed early in the disease course during its inflammatory stage and before accumulation of disease burden. A principle that may also be important for MS.

Murine bone marrow transplantations are performed by killing and removing the femur from the donor and using a syringe to flush out the marrow cells. It is technically difficult and inhumane to perform a murine autologous transplantation because the surviving recipient's legs would have to be amputated. However, marrow could be harvested from a syngeneic donor in the same active stage of EAE as the recipient, referred to as a pseudoautologous transplant. HSCT of EAE using pseudoautologous donors suggests that infused lymphocytes contaminating the graft may contribute to relapse.147 This suggestion indicates that lymphocyte depletion of grafts may be important in decreasing posttransplantation relapse after autologous HSCT.

Besides immunization with myelin peptides, demyelinating central nervous system disease may be induced with viruses such as TMEV.156 Autologous HSCT of TMEV-induced demyelinating disease causes a high mortality from viral superinfection of the central nervous system during the postconditioning pancytopenic period.156 Autoimmune disease mediated by an infectious agent can be rapidly fatal after autologous HSCT but only if the infectious agent is still present at the time of transplantation.

Several other environmentally induced animal autoimmune diseases are improved or cured by syngeneic HSCT. These diseases include experimental autoimmune myasthenia gravis,153 adjuvant arthritis 154,155 and collagen-induced arthritis.145 Encouraging results of syngeneic and pseudoautologous HSCT in animal-induced autoimmunity supported the design of autologous and syngeneic HSCT trials in patients with severe autoimmune disorders.

Anecdotal case reports of patients with a coincidental autoimmune disease and a malignancy provided further support and rationale for trial design.157-166 Refractory autoimmune diseases entered remission sometimes for several years. Because the indication for transplantation was a malignancy, and the outcome was reported retrospectively, in most cases a detailed pretransplantation evaluation by a rheumatologist or neurologist is missing. The autografts were usually not purged of lymphocytes, and the transplantations were not tailored as therapy for an autoimmune disease. Duration of response appeared shorter for RA compared with SLE. Too few patients have been reported for other autoimmune diseases, and long-term results of response to treatment in those that relapse, as well as duration of remission in those who had not relapsed, remain unknown.

Mobilization of HSCs

Collection of stem cells from patients with autoimmune diseases is based on methods already established for patients with nonautoimmune disorders. The complications and risks of the procedure appear greater in patients with autoimmune disease and are specific for the autoimmune disease and involved organ system.167 The most common peripheral blood stem cell (PBSC) mobilization regimens are single-agent granulocyte colony-stimulating factor (G-CSF) or cyclophosphamide and G-CSF.

Flares of MS and RA have occurred while patients were taking G-CSF for mobilization.167,168 MS flares have resulted in serious and irreversible neurologic deterioration. G-CSF–related flares of RA are relatively mild, being manifest as a transient increase in the number of swollen or tender joints that resolves with or without an increase in corticosteroid dose.167 The only complications of G-CSF PBSC mobilization in patients with scleroderma are transient telangiectasia that spontaneously resolves.167 In other diseases, such as SLE, there exists virtually no data on PBSC with G-CSF as a single agent. The simultaneous administration of G-CSF and steroids has been used in a limited number of patients without disease exacerbation.169 

To prevent G-CSF–related disease flare, combined cyclophosphamide and G-CSF (Cy/G-CSF) may be used for mobilization. However, combined Cy/G-CSF PBSC mobilization has been complicated by neutropenic-related infection and disease-specific fatal visceral organ toxicity.167 Infections with opportunistic organisms may be more common in patients who have been on high-dose corticosteroids for prolonged intervals, such as patients with refractory SLE. Scleroderma patients with cardiac and/or pulmonary involvement undergoing PBSC with 4.0 g/m2 cyclophosphamide have succumbed to cardiac arrest and/or pulmonary alveolar hemorrhage.167 No significant regimen-related organ damage has been reported at doses of 2.0 g/m2 or for doses of 4.0 g/m2 in nonscleroderma patients. This finding emphasizes the importance of adjusting the mobilization regimen based on disease and organ involvement for the minimum mobilization-related morbidity.

Although cyclophosphamide-based mobilization is generally associated with more toxicity from infection or organ damage, autoimmune diseases are generally ameliorated by the immune suppressive effects of cyclophosphamide.167 The duration of improvement from cyclophosphamide-based PBSC mobilization is unknown because most patients proceed within a relatively short time interval from mobilization to HSCT. As an exception, in at least one autoimmune disease (Evans syndrome), cyclophosphamide-based PBSC resulted in rapid and fatal acceleration of disease activity.170 This acceleration was attributed to a rapid cyclophosphamide-induced suppression of otherwise compensatory and accelerated hematopoiesis in the presence of persistent peripheral destruction from residual immunoglobulins against red blood cells and platelets.

There is no single optimal mobilization regimen for PBSC in patients with autoimmune disease. The PBSC method should be individualized for the disease and organ system involved. Newer mobilizing agents such as stem cell factor, thrombopoietin, chemokines, and/or high-dose corticosteroids and G-CSF need to be evaluated to collect progenitor stem cells with minimum mobilization-related morbidity.

After collection of progenitor cells, most but not all centers perform ex vivo lymphocyte depletion.167 Because the existence or identity of suppressor cells remains vague, graft depletion techniques are nonspecific without attempts at conserving regulatory cells. Positive enrichment for CD34+ cells has been performed by using either CEPRATE (CellPro, Bothel, WA), Isolex (Nexel, Irvine, CA), or CliniMACS (Miltenyi, Bergish Gladbach, Germany) cell separation systems. Negative selection was performed with T-cell antibodies by e-rosette or Nexel Isolex CD4/CD8 selection.

Insufficient clinical data are currently available to compare an unmanipulated versus a T-cell–depleted graft in terms of disease response or relapse. Aggressive lymphocyte depletion may adversely affect immune reconstitution against pathogens, increasing the risk of serious posttransplantation opportunistic infections such as cytomegalovirus, fungemia, Pneumocystis carinii pneumonia, or Epstein-Barr virus posttransplantation lymphoproliferative disease (PTLD).

Conditioning regimens and the role of immunosuppressive versus myeloablative conditioning for reinduction of self-tolerance

The first convincing evidence that intense immunosuppression may cure life-threatening autoimmune diseases was obtained in a patient with mixed cryoglobulinemia in end-stage renal failure with a cryocrit level of 60%.171 In the early 1970s, a patient with monoclonal immunoglobulin (Ig)M and polyclonal IgG was treated with a combination of cyclophosphamide and azathioprine. Treatment was complicated by lymphocytopenia and sepsis because of neutropenia, but the patient recovered with no stem cell support. After recovery, renal function normalized in parallel with elimination of the cryoglobulinemia, and the patient is alive and disease free for more than 25 years.171 This case represents the longest observation of a patient with reinduced self-tolerance after elimination of self-reactive lymphocytes and reestablishment of immunity from uncommitted stem cells.

Brodsky et al172 extended this early observation by treating a variety of autoimmune diseases with high-dose cyclophosphamide (200 mg/kg) without HSC infusion.172 For some autoimmune diseases such as SLE, early results from high-dose cyclophosphamide without stem cell support are encouraging. Although the response rate is high, depending on disease, relapse is common. With the exception of some diseases such as SLE, a more intense and myeloablative regimen with stem cell support may be required for durable responses. Infusion of mobilized HSCs shortens the duration of neutropenia by 5 to 7 days, theoretically decreasing the risk of serious infections. Ex vivo expansion of HSCs before infusion may completely eliminate neutropenic-related infections. For these reasons, a trial that randomized between cyclophosphamide with or without stem cell support is not currently being planned, and the rest of this review will be devoted to immune suppression with HSC support.

Ideally, the conditioning regimen should be able to eliminate immune cells without neutropenia. Such a regimen does not exist. The more immune ablative a regimen becomes, the more likely it is to be myeloablative and require stem cell support for reconstituting hematopoiesis. The conditioning regimens being used in autoimmune transplantations were empirically developed for use in malignancies. Autoimmune conditioning regimens include cyclophosphamide (Cy)173-177; cyclophosphamide and polyclonal antilymphocyte antibodies such as antithymocyte globulin (ATG) or humanized monoclonal rat antihuman CD52 (Campath-1H) antibodies (Cy/ATG or Cy/Campath-1H, respectively)178-188; carmustine, etoposide, cytarabine, and melphalan (BEAM) 189-192; cyclophosphamide and total body irradiation (Cy/TBI)193; cyclophosphamide, TBI, and antithymocyte globulin (Cy/TBI/ATG)194,195; busulfan and cyclophosphamide (Bu/Cy)196,197; busulfan, cyclophosphamide, and ATG (Bu/Cy/ATG)198; cyclophosphamide and thiotepa (Cy/TT)199 200; and fludarabine-based regimens.

Cy or Cy/ATG is the most common conditioning regimen used for HSCT of SLE.181-184,188 Pulse cyclophosphamide (500-1000 mg/m2) is a standard treatment for SLE. It is, therefore, reasonable to escalate cyclophosphamide to transplantation doses as the conditioning regimen for SLE. To avoid cardiac injury, transplantation doses of cyclophosphamide are limited to 200 mg/kg usually divided into 50 mg/kg per day. Cyclophosphamide is often used to mobilize stem cells before HSCT at doses of 2.0 to 4.0 g/m2. If cyclophosphamide is used in both the mobilizing and conditioning regimen, either the conditioning regimen dose may be decreased or the time interval between mobilization and HSCT may be delayed by several weeks to minimize the risk of cardiac toxicity from total cyclophosphamide dose. When the conditioning dose of cyclophosphamide is decreased, some centers add another agent such as thiotepa.199 200 Most patients with SLE eligible for HSCT are corticosteroid dependent and markedly cushingoid. There is a marked discrepancy between ideal and actual weight in terms of calculating cyclophosphamide dose. For safety reasons, in cushingoid patients, the dose is generally based on ideal or an adjusted ideal rather than actual weight.

Cy and Cy/ATG are conditioning regimens for scleroderma176,187,188 and RA.173-175,180High-dose cyclophosphamide may be associated with high cardiopulmonary mortality in patients with scleroderma.167 Volume shifts and infections that stress cardiovascular reserve are the likely culprit of HSCT-related cardiopulmonary collapse in scleroderma-associated pulmonary artery hypertension. In RA, organ function is generally normal, and cyclophosphamide-related toxicity is less problematic. The toxicity of a conditioning regimen, therefore, depends on the disease and disease-related organ dysfunction.

Bu/Cy regimens have been used in a limited number of HSCTs for MS197 and RA.196 Busulfan is fat soluble and readily crosses the blood-brain barrier to the site of MS plaques. Busulfan is administered orally with variability in absorption and first-pass hepatic metabolism. Busulfex is an intravenous formulation that gives more uniform and less toxic serum levels. For RA, it may be equally important for efficacy that the conditioning regimen target not only lymphocytes but also synovial macrophages. Theoretically, HSCT results may be improved in RA by adding a more effective antimacrophage agent such as busulfan to a cyclophosphamide-based regimen.201 There are special concerns about the use of Bu/Cy in RA and MS. Patients with RA may have disease-related interstitial pneumonitis with little reserve for busulfan-related lung injury. The effects of alkylating agents on demyelinated neurons are unknown. In MS, the neurotoxicity of high-dose alkylating-based conditioning regimens remains unknown.

BEAM and Cy/TBI are common lymphoma regimens being used to treat MS.189-191,193 TBI was selected because, unlike most agents, radiation readily crosses the blood-brain barrier. To avoid TBI-related pulmonary injury, radiation is generally given in the anteroposterior and posteroanterior position with 50% lung blocks with full dose to the mediastinal lymph nodes and spinal cord. A comparison of BEAM versus Cy/TBI regimen-related toxicity has not been performed. In general, TBI regimens are not used in RA because trials of nonmyeloablative total nodal irradiation in RA were associated with unexpected late complications such as myelodysplasia.202 

Cy/TBI/ATG has been used as a conditioning regimen in the United States for scleroderma195 and MS,169 and in Europe for juvenile chronic arthritis (JCA).194 For patients with pulmonary scleroderma, TBI without lung shielding has been associated with lethal pulmonary deterioration.195 If attenuated with partial lung shields, TBI-related scleroderma lung injury appears less likely. Cy/TBI/ATG has been associated with lethal PTLD.358 The investigators attributed PTLD to use of high-dose rabbit ATG. Lower and less immune-suppressive doses of rabbit ATG or the use of horse ATG has not been reported to cause PTLD in autoimmune diseases.

Independent of the conditioning regimen (Cy or Cy/TBI/ATG), when combined with aggressive T-cell depletion, HSCT in JCA has been complicated by lethal macrophage activation syndrome (MAS), manifesting as fever, lymphadenopathy, hepatosplenomegaly, and disseminated intravascular coagulation.186 MAS is a reactive hematophagocytic lymphohistiocytosis and has been associated with JCA independent of HSCT.203 The diagnosis is confirmed on bone marrow aspirate by macrophages (or histiocytes) actively phagocytosing hematopoietic cells and may arise from immune dysregulation perhaps in response to viral infections. To date, posttransplantation MAS appears to be a complication unique to JCA.

No reports exist of late regimen-related organ toxicity from HSCT in autoimmune diseases. All patients need to be warned of infertility and of regimen-specific late toxicities such as cataracts from TBI. Late malignancies are also possible.204 Similar to mobilization regimens, conditioning regimens must be uniquely designed for the disease, organ impairment, disease-specific infection susceptibility, and extent of prior immune suppressive medication–related infectious risk to ensure minimum regimen-related mortality.

Mortality

Transplantation-related mortality (TRM) for all autoimmune diseases has been reported to be 8.6%.205 TRM is disease specific, in order of highest to lowest TRM: scleroderma, SLE, MS, and RA. This mortality is higher than expected because of phase 1 trials that selected patients with advanced end-organ dysfunction and/or active and refractory disease. Judicious selection of patients earlier in disease or in remission, but with a high risk of relapse or further progression, will diminish TRM. Variability in TRM based on the center performing the transplant, also known as the center effect,206 may be occurring for autoimmune diseases. Many factors affect TRM, including patient selection, supportive care, conditioning regimen, degree of lymphocyte depletion of the graft, use of disease-specific versus generic protocols, and so forth. A lower mortality in centers dedicated to autoimmune HSCTs may be obscured within the variability of multicenter registry data.

Posttransplantation immunization

After HSCT, a patient's titer from prior immunizations (eg, diphtheria, measles, tetanus, hepatitis B, etc) is often low or undetectable. As discussed in the “Breaking tolerance by environmental exposure” section, immunization could, theoretically, reinduce autoimmune disease. The risk of relapse may vary according to the type of immunization. For example, there was concern that onset and flare of MS may be associated with hepatitis B vaccination, although recent studies have shown no association.207 Although the risk of infection-related mortality or infection-induced autoimmunity in a nonimmunized individual probably outweighs any theoretical risk of immunization-induced disease relapse, guidelines on posttransplantation vaccination in autoimmunity have yet to be written.

MS, SLE, RA, and scleroderma will be discussed further because phase 3 autologous HSCT trials are being prepared in these diseases. In Europe, the European Bone Marrow Transplant/European League Against Rheumatism (EBMT/EULAR) autoimmune committee is designing these trials. In the United States, the trials are funded by the National Institutes of Health and are being designed by disease-specific working groups composed of transplant physicians, rheumatologists, and neurologists.

Autologous HSCT for MS

MS is a relatively common North American and European disease with a prevalence of approximately 1 in 1000 people.208 It is at onset an immune-mediated disease confined to the central nervous system. The disease is characterized by a variable course.209-211 Patterns are (1) relapsing-remitting MS defined as relapsing disease without progression between relapses with or without residual neurologic deficits from each relapse, (2) secondary progressive MS defined as continuous (often insidious and steady) neurologic deterioration with or without superimposed relapses after an initial relapsing-remitting course, and (3) primary progressive MS defined as steady continuous deterioration from onset. At onset, approximately 15% of the cases are primary progressive and 85% are relapsing-remitting.209-211 Within 10 years, 50% of relapsing-remitting cases become secondary progressive, and by 25 years, 90% have progressive disease. Relapse frequency in the first year of diagnosis influences time interval to disability.209-211 The median time to difficulty ambulating without unilateral assistance (an extended disability status score [EDSS] of 6.0) is 7 years for 5 or more relapses; 13 years for 2 to 4 relapses; and 18 years for 1 to 2 relapses.

Accepted immune-modulating agents for MS are interferon beta (Avonex, Betaseron)212-216 or Copaxone (copolymer 1 or glatiramar acetate)217,218 known as ABC therapy. Avonex and Betaseron are different formulations of interferon-β and Copaxone is an oral mixture of random peptide sequences containing L-glutamate, L-lysine, L-alanine, and L-tyrosine, thought to mimic myelin peptides. The ABCs of MS therapy are approved for relapsing-remitting disease and, although not approved by the U.S. Food and Drug Administration (FDA), are often used for progressive forms of MS. The immune suppressive chemotherapy drug mitoxantrone received FDA approval for secondary progressive and progressive-relapsing MS.219,220 The need for new interventions in MS is evident from the desperation of patients who in some studies have a higher suicide rate compared with the general population.221 

Natural history magnetic resonance imaging (MRI) studies have demonstrated that neurologic progression can continue despite lack of new demyelinating events on MRI.222,223 Although early relapse frequency within the first year of diagnosis appears to correlate with onset of late disability, Confavreux et al224 reported that relapse frequency in disease of longer duration and EDSS scores more than 4.0 do not correlate with disability. This finding indicates that treatment designed to prevent relapses (ie, immune-modulating therapy) used late in disease is probably not adequate to prevent progressive disability. Demyelination alone does not adequately explain the progressive disability that occurs in patients with progressive MS. Yet, the most important therapeutic goal is to prevent disability and maintain neurologic function. An evolving amount of literature on MS supports the concept that, although initially an inflammatory demyelinating disease, MS transitions into or is also an axonal degenerative disease.225-228 

HSCT for MS was suggested in 1995.229 In general, initial HSCTs were phase 1 studies and captured patients with progressive disease and high disability (EDSS) scores189-191,230-233(Table 1). The Thessaloniki group has reported a 3-year progression-free survival for primary progressive MS (39%), which appears significantly lower than for secondary progressive (92%).190 In an Italian study, Mancardi et al231 reported 10 subjects undergoing HSCT followed with a frequent MRI protocol who demonstrated lack of enhancing lesions and accumulation of T2 burden of disease over an observation period of 4 to 30 months. A second study with a 5-year follow-up has noted a discordant response between MRI and clinical results.230Some patients had clinical progression of disability, defined as an increase in the EDSS by one or more points but no new attacks or change on MRI in terms of T2 disease burden. The patients whose EDSS increased despite lack of MRI changes had significant pretransplantation disabilities (EDSS of 7.0 to 8.5). Although longer follow-up is necessary, it appears that HSCT slows or halts acute attacks and further immune-mediated demyelination but not progressive disability, especially in disease of increasing duration or higher disability scores.

Table 1.

Results of autologous/syngeneic hematopoietic stem cell transplantation in patients with multiple sclerosis

GroupNo. of patients*EDSS baselineRegimenProgressedFollow-up, mo, median (range)Treatment-related deaths
Fassas et al190 191  24 6.0  (4.5-8.0) BEAM + ATG 5/23 40  (21-51) 1  
Burt et al179,193 230  27 7.0  (3.0-8.5) Cy/TBI 4/25 14  (2-58) 0  
Nash et al169 20 7.0  (5.0-8.0) Cy/TBI/ATG 2/13 5  (3-24) 1  
Carreras et al232 10 6.2  (5.0-6.5) BEAM + ATG 2/10 18  (16-32) 0  
Kozak et al189 6.5  (6.5-7.5) BEAM + ATG 1/8 8.5  (1-16) 0  
Openshaw et al197 6.5  (5.5-7.5) BU/Cy + ATG 1/4 18  (17-30) 2  
Mandalfino et al233 1 (identical twin) 6.5 Cy/TBI 0/1 26 
GroupNo. of patients*EDSS baselineRegimenProgressedFollow-up, mo, median (range)Treatment-related deaths
Fassas et al190 191  24 6.0  (4.5-8.0) BEAM + ATG 5/23 40  (21-51) 1  
Burt et al179,193 230  27 7.0  (3.0-8.5) Cy/TBI 4/25 14  (2-58) 0  
Nash et al169 20 7.0  (5.0-8.0) Cy/TBI/ATG 2/13 5  (3-24) 1  
Carreras et al232 10 6.2  (5.0-6.5) BEAM + ATG 2/10 18  (16-32) 0  
Kozak et al189 6.5  (6.5-7.5) BEAM + ATG 1/8 8.5  (1-16) 0  
Openshaw et al197 6.5  (5.5-7.5) BU/Cy + ATG 1/4 18  (17-30) 2  
Mandalfino et al233 1 (identical twin) 6.5 Cy/TBI 0/1 26 

EDSS indicates extended disability status score; BEAM, carmustine, etoposide, cytarabine, melphalan; ATG, antithymocyte globulin; Cy/TBI, cyclophosphamide and total body irradiation; and BU/Cy, busulfan and cyclophosphamide.

*

Actual patient number is based on updated communication with the author and may be higher than the number reported in the reference.

Two possible phase 3 MS trial designs are being proposed to run simultaneously. For secondary progressive MS, the trial would be aimed at suppressing relapses in patients with progressive disability. Patients with accumulated baseline deficits, but still inflammatory disease, could be considered candidates. This group could include ambulatory patients with an EDSS of 3.5 to 6.0 and continued relapses (or MRI evidence of active disease) randomized between a TBI and Cy regimen with or without low-dose ATG and CD34-selected HSCs versus mitoxantrone every 3 months for 2 years. However, suppression of relapses may be insufficient to halt progressive neurologic impairment, particularly as the duration of disease and the level of disability increase.

For relapsing-remitting MS, the protocol would be aimed at suppressing relapses in patients at risk for progressive disability. Patients with relapsing-remitting disease who have failed interferon may be randomized between cyclophosphamide (200 mg/kg, with or without low-dose ATG) with CD34-selected HSC support versus best standard therapy (ie, continued interferon or interferon and adjuvant immunotherapy) (azathioprine, methotrexate, mitoxantrone, or cyclophosphamide). Because patients in this study would be earlier in the disease course, a safer conditioning regimen that does not include TBI would be indicated. Efficacy of earlier intervention in MS is supported by the Controlled High-risk Subjects Avenox Multiple Sclerosis Prevention Study (CHAMPS), in which over a 3-year interval treatment with interferon after the first clinical event significantly lowered the probability of developing clinically definite MS.234 If early intervention before onset of progressive disease is important in preventing late disability, a safe but intense immune suppressive regimen might be indicated in patients with relapsing-remitting MS who have failed interferon.

Although the primary outcome of these trials would be progressive disability defined by the EDSS, other outcome measures would include clinical status by the Neurologic Rating Scale and Multiple Sclerosis Functional Composite, measurement of accumulated atrophy on MRI of the brain and cervical spinal cord, and potentially measures of whole brain N-acetyl-aspartate on magnetic resonance spectroscopy that reflects neuronal and axonal integrity.

Autologous HSCT for SLE

Although studies have suggested that SLE encompasses several genetic diseases with some clinical commonalties,235,236the disease will be considered here as a single entity with protean clinical expressivity.237,238 SLE has an overall prevalence that has varied from 12 to 50.8 cases per 100 000 persons.239 Survival has improved dramatically, reaching a 90% 10-year survival and a 70% 20-year survival in the 1990s. Within the first 5 years, the main cause of death is active disease (neurologic, renal, systemic) or infection. Thereafter, causes of death tend to be infectious or cardiovascular events (strokes and/or myocardial infarction) related to hypertension and hyperglycemia/hypercholesterinemia because of chronic corticotherapy.

Three consecutive but separable levels of etiology, ethiopathogenesis, and pathogenesis have been considered for SLE.240 It has been thought imperative to identify the specific molecular defects as the only way to design and use any novel and rational treatments.241 In practice, however, SLE is treated with a variety of drugs, mainly immunosuppressive, that have been discussed recently.242 Along with corticosteroids, intravenous pulse cyclophosphamide has been used in a National Institutes of Health–developed protocol specifically directed toward lupus nephropathy.243 

At the pinnacle of the lupus iceberg, however, there are cases of refractory-relapsing (“intractable”)244 disease. For such patients, following the considerable experimental evidence discussed formerly and also on the basis of serendipitous case reports of coincidental diseases, HSCT was proposed in 1993.245Several cases of concomitant SLE and malignancy have been treated with HSCT and published. They include chronic myeloid leukemia/SLE,166 non-Hodgkin lymphoma (NHL)/SLE,157 and Hodgkin disease/SLE.160 The first patient eventually died of his leukemia without any evidence of active SLE. In another case, the NHL did not relapse, but ITP supervened in conjunction with an anticentromere antibody.163 

The first patient with SLE received a transplantation of her own T-cell–depleted marrow in 1996.199 The first report on HSCT for SLE in the United States was published 1 year later in 1997.183 There are now several fully published case reports of nonconcomitant SLE patients having undergone HSCT (Table2).181-184,192,199,246 All received transplantations of cyclophosphamide and G-CSF–mobilized CD34+ cells, and conditioning regimens varied from Cy/TT to Cy/ATG (200 mg) to BEAM. All patients reached complete remission, but in several there was a serologic antinuclear antibody (ANA) relapse after 2 to 3 years from transplantation. In the patient with the longest posttransplantation follow-up, after 3 years of corticoid-free remission, there was a reappearance of ANA/DNA antibodies, and, after another year, there was also a mild proteinuria, which is currently being treated with a combination of corticosteroids and mycophenolate mofetil.247 

Table 2.

Results of autologous hematopoietic stem cell transplantation in patients with systemic lupus erythematosus

ReferenceNo. of patients receiving transplantsRegimenResultsMortality
Marmont et al199 TT/Cy Clinical remission for more than 3 y, serologic relapse 0  
Burt et al179 183 
Traynor et al181 
Cy/ATG Clinical remission for up to 4 y, 2 relapsed at 3 y and 3.5 y, respectively 1/12 mobilized 
Fouillard et al192 BEAM Clinical remission for 1 y; ANA negative at 6 mo but positive at 9 mo 0  
Rosen et al188 Cy/ATG Complete remission of active disease 0  
Musso et al185 Cy/ATG Posttransplantation low ANA titer and low Coombs positive at 8 mo but anti-ds DNA negative and anticardiolipin antibody negative 
ReferenceNo. of patients receiving transplantsRegimenResultsMortality
Marmont et al199 TT/Cy Clinical remission for more than 3 y, serologic relapse 0  
Burt et al179 183 
Traynor et al181 
Cy/ATG Clinical remission for up to 4 y, 2 relapsed at 3 y and 3.5 y, respectively 1/12 mobilized 
Fouillard et al192 BEAM Clinical remission for 1 y; ANA negative at 6 mo but positive at 9 mo 0  
Rosen et al188 Cy/ATG Complete remission of active disease 0  
Musso et al185 Cy/ATG Posttransplantation low ANA titer and low Coombs positive at 8 mo but anti-ds DNA negative and anticardiolipin antibody negative 

TT/Cy indicates thiotepa and cyclophosphamide; Cy/ATG, cyclophosphamide and antithymocyte globulin; BEAM, carmustine, etoposide, cytarabine, melphalan; ANA, antinuclear antibody; and anti-ds, anti–double strand DNA antibody.

In the most extensive single-center clinical study published to date,181 9 patients underwent stem cell mobilization with cyclophosphamide 2.0 g/m2 and G-CSF 10 μg/kg. Two patients were excluded from transplantation because of infection (one death from disseminated mucormycosis), and 7 received autotransplantations after conditioning with cyclophosphamide (200 mg/kg), 3.0 g methylprednisolone, and 90 mg/kg equine antithymocyte globulin. All patients were seriously ill, with SLE disease activity indices of 17 to 37, including 1 case with alveolar hemorrhage and 4 with World Health Organization class III-IV glomerulonephritis and nephrotic syndrome. Lupus remained in clinical remission, and ANA became negative in all patients with 1 to 3 years of posttransplantation follow-up.

Phase 3 trials are being designed in the United States to compare autologous HSCT with a control arm. The standard of care for the control arm has generated a great deal of discussion and controversy within the working group. Potential controls could be intravenous pulse cyclophosphamide, oral cyclophosphamide, mycophenolate mofetil, or an open control of best available care. American experience with oral cyclophosphamide or mycophenolate mofetil in SLE is limited. Pulse cyclophosphamide (500-1000mg/m2) has a long track record and is generally considered the standard of care. If HSCT candidates are selected for failure to pulse cyclophosphamide, it is difficult to continue failed therapy as on the control arm. One solution is to offer HSCT earlier in disease. Eligible patients with nonrenal visceral involvement need only fail corticosteroids and 3 months of pulse cyclophosphamide. For patients in whom the indication is nephritis, active disease must be present despite at least 6 cycles of monthly pulse cyclophosphamide. Enrolling patients earlier in disease who are less ill would also decrease the morbidity and mortality of HSCT. A second solution is to allow patients enrolled on the pulse cyclophosphamide arm who continue to fail to crossover to HSCT.

Numerous SLE disease activity indices exist to measure disease activity including the British Isles Lupus Assessment Group scale (BILAG),248 Systemic Lupus Erythematosus Disease Activity Index,249 Systemic Lupus Activity Measure,250and the Lupus Activity Index.251 The index used depends on institutional and investigator familiarity. In the American phase 3 trial of HSCT for SLE, the disease activity instrument will be the BILAG. BILAG is one of the more useful instruments for characterizing disease stage because BILAG score correlates with necessity to treat and has been validated as an instrument to measure disease activity.252 253 The evaluation is based on a 5-category classification, characterizing the degree of symptoms attributed to active lupus for 86 questions based on the patient's history, examination, and laboratory results. The 5 categories of response are the following: not present, improving, same, worse, and new. The 86 questions are grouped into the following 8 systems: general, mucocutaneous, neurologic, musculoskeletal, cardiovascular and respiratory, vasculitis, renal, and hematologic. For each of the 8 systems, a severity grade (A to E) is calculated according to the scores. The following list indicates interpretation of each of the grades for each system: A, disease is active enough to need treatment; B, disease has the potential to need treatment soon; C, disease currently does not meet grade A or B criteria; D, disease has satisfactorily resolved; and E, disease has never been involved. Because a crossover arm is tentatively planned in the American phase 3 trial, the primary endpoint will be need to treat as defined by a BILAG grade A.

Autologous HSCT for RA

RA affects 1% of the North American population.254It is an immune-mediated disease that involves joint synovium with formation of an inflammatory pannus that erodes cartilage and bone.255 The characteristic joint lesion in RA includes an increase in the numbers of both fibroblastlike and macrophagelike synoviocytes in the synovial intimal lining, infiltrating lymphocytes, plasma cells, monocytes, and macrophages. T cells comprise about 30% to 50% of synovial tissue cells. Synovial T cells have been demonstrated to have a restricted repertoire256,257 and to react to a variety of microbial antigens258 and self-antigens such as type II collagen epitopes.259Synovial macrophages produce IL-1 and tumor necrosis factor α (TNF-α).260 RA fibroblastlike synoviocytes can proliferate in an anchorage-independent manner, escape contact inhibition,261 aggressively invade into cartilage when coimplanted into severe combined immune deficient mice,262and have somatic mutations of the p53 tumor suppressor gene.263 These complexities underscore the shortcomings of previous approaches designed to eliminate only one set of immune cells.

The most common rheumatoid symptoms are joint pain, swelling or deformity, morning stiffness, elevated sedimentation rate, and a positive rheumatoid factor. Extra-articular symptoms may occur, including rheumatoid nodules, vasculitis, and pulmonary interstitial fibrosis.264,265 Patients with more than 20 to 30 involved joints have a 5-year mortality of 40% to 60%.266-275Despite newer therapeutic agents like anti-TNF drugs, about 5% to 10% of patients with RA continue to have a desperate need for better and more definitive therapies.276 Because RA may be associated with significant morbidity, oncogene mutation, loss of synoviocyte growth inhibition, and, in some patients, high mortality, it is perhaps surprising that it was not until 1997 that the first HSCT for RA was reported from Australia173 and the first American HSCT for RA reported in 1998.180 

In general, the procedure has been well tolerated without mortality (Table 3). HSCT offers an almost immediate relief of symptoms. Patients become pain free, sometimes for the first time in years. Activities required for daily living, such as buttoning a shirt or combing hair, rapidly return to normal. Morning stiffness resolves, rheumatoid nodules disappear, sedimentation rate normalizes, and rheumatoid factor may disappear. Although these studies demonstrated that high-dose cyclophosphamide was well tolerated with marked improvements (American College of Rheumatology [ACR] 50 or ACR 70), a complete remission was unusual and relapse within 1 to 2 years is common.173,175,180,277,278 There are suggestions of a dose-response effect. A dose escalation study of cyclophosphamide at 100 mg/kg revealed transient 1- to 2-month responses but at 200 mg/kg response duration increased to 18 to 20 months.174 Too few myeloablative transplantations, for example a busulfan and cyclophosphamide regimen, have been performed to determine if durable remissions are feasible.

Table 3.

Results of autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis

ReferenceNo. of patientsConditioningCommentMortality
Joske et al173 Cy Marked improvement at 6 mo follow-up 0  
Snowden et al174 Cy Cohort I, cyclophosphamide 100 mg/kg-response for 1-2 mo 0  
   Cohort II, cyclophosphamide 200 mg/kg, improved for 17-19 mo  
Burt et al179 180  Cy/ATG Marked improvement up to 18 mo but 2 relapsed 0  
Pavletic et al178 Cy/ATG Relapsed at 5 and 7 mo 
Durez et al196 BU/Cy Remission > 10 mo 0  
McColl et al175 Cy/ATG (identical twin) Remission > 24 mo 0  
Munro et al278 N/A Marked improvement for 1 y 0  
Verburg et al277 12 Cy Marked improvement in 8/12 patients with follow-up, ranging from 7-21 mo 
ReferenceNo. of patientsConditioningCommentMortality
Joske et al173 Cy Marked improvement at 6 mo follow-up 0  
Snowden et al174 Cy Cohort I, cyclophosphamide 100 mg/kg-response for 1-2 mo 0  
   Cohort II, cyclophosphamide 200 mg/kg, improved for 17-19 mo  
Burt et al179 180  Cy/ATG Marked improvement up to 18 mo but 2 relapsed 0  
Pavletic et al178 Cy/ATG Relapsed at 5 and 7 mo 
Durez et al196 BU/Cy Remission > 10 mo 0  
McColl et al175 Cy/ATG (identical twin) Remission > 24 mo 0  
Munro et al278 N/A Marked improvement for 1 y 0  
Verburg et al277 12 Cy Marked improvement in 8/12 patients with follow-up, ranging from 7-21 mo 

Cy indicates cyclophosphamide; Cy/ATG, cyclophosphamide and antithymocyte globulin; BU/Cy, busulfan and cyclophosphamide, and N/A, not applicable.

For an intense and expensive treatment such as HSCT to be considered for RA, sustained complete remissions or 70% improvement as defined by the ACR (ACR 70) must be achieved.279 Several modifications are being considered, including the use of the current easily tolerated nonmyeloablative yet highly immunosuppressive regimen with posttransplantation immune modulation, eg, a TNF inhibitor, cyclosporine A, and/or methotrexate; or the use of a more intense myeloablative regimen such as busulfan and cyclophosphamide.

A European approach being proposed for phase 3 trials uses the current cyclophosphamide mobilization (2.0 to 4.0 g/m2) and cyclophosphamide conditioning (200 mg/kg) with posttransplantation immune modulation. The nontransplant arm will be cyclophosphamide mobilization only followed by maintenance methotrexate (John Snowden, verbal communication, May 2001). This approach assumes that RA is not curable but is more easily controlled with conventional therapies after HSCT. Continued posttransplantation immune suppression may increase the risk of posttransplantation opportunistic infections. The Australians, rather than comparing HSCT with another therapy, are randomizing patients with RA to HSCT with or without T-cell depletion of the autograft. The American and Israeli approach is to pilot phase 1/2 autologous HSCT studies by using more intense myeloablative regimens (fludarabine plus oral busulfan or intravenous Busulfex and cyclophosphamide) in the hope of inducing more durable remissions, while simultaneously developing mini-allogeneic HSCT protocols for patients with HLA-matched siblings.

Autologous HSCT for scleroderma

Scleroderma is a rare disorder with a prevalence of anywhere from 2 to 100 per one million people.280 Two subsets of scleroderma are generally recognized, limited and extensive cutaneous scleroderma. Limited cutaneous scleroderma is characterized by cutaneous involvement of acral areas (hands, face, feet, forearms) but not the trunk. Limited scleroderma generally has a good prognosis. Diffuse cutaneous scleroderma is characterized by truncal and acral skin involvement and early visceral (lung, renal, cardiac, gastrointestinal) involvement. For all patients with diffuse scleroderma, 5-year mortality is 25% to 30%.281 High skin scores,282 pulmonary, renal, or cardiac involvement is associated with a higher mortality of 40% to 50% within 5 years.282-286 

Scleroderma is characterized by fibrosis (ie, excessive deposition of collagen in skin and visceral organs). The etiology of scleroderma is unclear, and an autoimmune pathogenesis remains controversial. Unlike MS, RA, and SLE, the MHC association is weak.287,288Randomized trials of D-penicillamine, interferon-α, or methotrexate either are no better than placebo or improve skin score with little beneficial effect on visceral organ function.289-291 An exception is pulse intravenous cyclophosphamide, which appears to ameliorate scleroderma-related pulmonary alveolitis.292Scleroderma may be a vasculopathy, connective tissue disorder, and/or immune-mediated disease. Raynaud phenomena, nail fold capillary abnormalities, and elevated plasma von Willebrand antigen are indications of a vasculopathy with endothelial injury that may secondarily lead to ischemia and fibrosis.293-295Scleroderma may be a connective tissue disease. The tight skin mouse, which is an animal model for scleroderma, is a genetic connective tissue disease because of a defect in the fibrillin 1 gene.296-298 

Support for an immune-mediated etiology include a variety of autoantibodies, including antitopoisomerase (Scl-70) antibodies,299,300 and anticentromere antibodies.301 Chronic GVHD is an immune-mediated disorder that is clinically and histologically similar to scleroderma.302-304 Similar to scleroderma, chronic GVHD is associated with tissue fibrosis and is slow to respond to immune suppression. GVHD is caused by allogeneic lymphocytes, and patients with scleroderma have been reported to have an increased incidence of allogeneic hematopoietic cellular microchimerism.305Transplacental transfer of fetal lymphocytes to the mother may lead to mixed chimerism in postpartum females.306 Transplacental transfer of maternal lymphocytes to the fetus may cause mixed chimerism in males and nonparous females. Similar to scleroderma, GVHD is also associated with endothelial damage and elevated von Willebrand antigen.307 The perceived failure of immune therapies in both chronic GVHD and scleroderma may be due to neglect in recognizing or effectively treating an early inflammatory phase. Late fibrotic processes may progress and regress more slowly.

Regardless of etiology, because of its poor prognosis and lack of effective therapies, patients with scleroderma are being enrolled in HSCT protocols.176,195 Early results indicate improved skin scores and activities of daily living but unchanged renal, cardiac, and pulmonary function. In a study of mostly European patients by using a variety of conditioning regimens, skin score generally improved with stabilization of lung function. Overall mortality was 27% because of 10% disease progression and 17% transplantation-related mortality.308 These results suggest that more careful selection of patients earlier in disease is necessary in the design of phase 3 trials. Phase 3 randomized trials of HSCT versus monthly pulse cyclophosphamide are accruing in Europe and are being designed in the United States. The primary endpoint of these trials is overall survival.

Animal models

Animal autoimmunelike diseases that occur spontaneously (without known precipitating infection or immunization) are not cured by a syngeneic HSCT. In fact, disease may be transferred to a normal strain of mice by HSCT from the autoimmune-prone donor.309Syngeneic HSCT in spontaneous-onset lupuslike disease of MRL/lpr mice resulted in only transient disease amelioration.310 Curing a spontaneous-onset autoimmunelike disease requires allogeneic HSCT from a nonautoimmune-prone donor.311-321 Murine spontaneous-onset lupuslike disease is cured by allogeneic HSCT from a normal donor strain.311,314,315,317 Spontaneous-onset diabetes in NOD mice is prevented by allogeneic HSCT from a nondiabetic prone strain316,319,321 and cured by combined pancreas and allogeneic HSCT from the same donor.318 In fact, the “tolerizing” effect322 323 of HSCs is best demonstrated by donor-specific organ tolerance when combining solid organ and marrow transplant from the same donor.

Donor-specific organ tolerance was initially performed by lethally irradiating animals to ablate their marrow followed by allogeneic donor bone marrow transplantation.324-326 Although donor-specific tolerance is associated with hematopoietic chimerism, the cellular mechanism by which donor-specific tolerance arises is not fully understood.327 Fas ligand is a surface protein that can signal other cells expressing Fas to undergo apoptosis. Fas ligand expression appears to be necessary for donor marrow to induce donor organ tolerance, because hematopoietic-induced donor-specific tolerance does not occur in Fas knockout mice.328 Therefore, the mechanism of allogeneic HSCT-induced tolerance to solid organ grafts may be in part explained by donor-induced apoptotic deletion of graft reactive cells. It has been postulated that allogeneic HSCT may induce tolerance to autoimmune epitopes by a similar deletion of autoreactive repertoires, a phenomena termed graft versus autoimmunity (GVA).329,330 A graft-versus-disease effect has already been established as the mechanism of remission for several hematologic malignancies, first discovered in 1981 and termed graft versus leukemia.331 332 

A putative GVA effect is supported by experiments showing that allogeneic chimerism by using a sublethal conditioning regimen followed by allogeneic transplantation can prevent the onset of diabetes and even reverse preexisting insulitis in NOD mice, whereas the same radiation protocol without allogeneic HSC is insufficient.333 With nonmyeloablative-conditioning regimens, spontaneous animal models of autoimmunity have been cured in the setting of mixed chimerism.333-336 These experimental findings support low-conditioning preparative regimens for allogeneic transplantations in human autoimmune diseases.

Although in theory a GVA effect may be beneficial, the most significant toxicity of allogeneic HSCT is an immunologic reaction of donor cells against normal host tissues, a complication known as GVHD. Mini-conditioning may be associated with less GVHD compared with the more hazardous high-dose transplantation regimens. A lower GVHD risk may be due to reduced regimen-related tissue damage, decreased inflammatory cytokine release, decreased exposure of hidden tissue epitopes, and veto of alloreactive donor lymphocytes by hematopoietic cells of host origin, particularly CD8+cells.337,338 Mini-transplantations are less likely to provide the danger signal hypothesized by Matzinger54 that is necessary to break peripheral tolerance.

Allogeneic HSCT in patients with autoimmune diseases

Anecdotal case reports of patients undergoing allogeneic HSCT for malignancy or aplastic anemia and a coincidental autoimmune disease have in most cases resulted in long-term remission of the autoimmune disease.339-353 Most patients maintain remission indefinitely after discontinuation of immune-suppressive prophylaxis for GVHD. An occasional patient has relapsed despite being chimeric (ie, 100% donor hematopoiesis). Chimeric analysis of peripheral blood for residual host hematopoiesis may, however, be falsely negative. Separation and analysis of lineage-specific subsets, such as only T cells, may reveal mixed chimerism (both donor and host cells) in only the T-cell lineage. The clinically asymptomatic donor may also have subclinical disease, such as rheumatoid factor positive, that could adoptively transfer the same disease for which the recipient received a transplant. Alternatively, because the patients are MHC matched, the donor and recipient may have similar non-MHC autoimmune genes that in the presence of host “factors,” such as a persistent latent infectious agent or recurrent environmental exposure, may initiate de novo disease.

HLA-matched sibling allogeneic transplantations have already been successfully performed for some hematologic autoimmune diseases, including a case of hemolytic anemia,354 pure red cell aplasia,355 and Evans syndrome.356 357 Phase 1 allogeneic HSCT trials using mini-conditioning regimens with and without lymphocyte-depleted grafts are being suggested and designed for autoimmune diseases. Just as in autologous HSCT, protocols will need to be tailored for each disease.

HSCT of autoimmune disorders has raised new expectations, opportunities, and questions. What is the best mobilization regimen? What is the optimal conditioning regimen? Does T-cell depletion of the graft result in self-tolerance and decreased relapse, or rather result in an increased risk of infections? Can we predict candidates likely to relapse after autologous HSCT? Is relapsed disease responsive to previously refractory therapy and easier to control? Is HSCT cost effective? What is the mechanism(s) of posttransplantation remission? Which, if any, diseases may be cured by an autologous graft and which will require an allograft? Encouraging phase 1 trials have propelled this field to phase 3 trials in MS, SLE, RA, and scleroderma. Completion of these trials should determine if autologous HSCT is better than current standards of care. Nonmyeloablative or reduced-intensity allogeneic transplantation protocols are being written, and advances in ex vivo stem cell expansion will soon be applied to autoimmune diseases to eliminate regimen-related neutropenia.

Historically, most autoimmune diseases are incurable, and it was impractical to define complete remission. HSCT, whether allogeneic or even autologous, may change this axiom. Initial results suggest that clinical tolerance, that is no evidence of disease off all immune-suppressive medications with normal third-party immune responsiveness, is being achieved in at least some patients. However, further improvement of the efficacy and safety of both autologous and allogeneic stem cell transplantation procedures need to be developed, and larger cohorts of patients need to be studied to assess the full benefits of stem cell transplantation as a most promising new armamentarium for the treatment of autoimmune diseases.

1
Rose
NR
Bona
C
Defining criteria for autoimmune diseases.
Immunol Today.
14
1993
426
430
2
Marmont
AM
Defining criteria for autoimmune diseases.
Immunol Today.
15
1994
388
3
Harrington
WJ
Minnich
V
Hollinsworth
JW
Moore
CV
Demonstration of a thrombocytopenic factor in the blood of patients with thriombocytopenic purpura.
J Lab Clin Med.
38
1951
1
10
4
Gardnerova
M
Eymard
B
Morel
E
et al
The fetal/adult acetylcholine receptor antibody ratio in mothers with myasthenia gravis as a marker for transfer of the disease to the newborn.
Neurology.
48
1997
50
54
5
Keesey
K
Lindstrom
J
Cokely
H
Hermann
C
Antiacetylcholine receptor antibody in neonatal myasthenia gravis.
N Engl J Med.
296
1977
55
6
Yamada
H
Kato
EH
Kobashi
G
et al
Passive immune thrombocytopenia in neonates of mothers with idiopathic thrombocytopenic purpura: incidence and risk factors.
Semin Thromb Hemost.
25
1999
491
496
7
Burrows
RF
Kelton
JG
Fetal thrombocytopenia and its relation to maternal thrombocytopenia.
N Engl J Med.
329
1993
1463
1466
8
Snowden
JA
Heaton
DC
Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity.
Br J Dermatol.
137
1997
130
132
9
Neumeister
P
Strunk
D
Apfelbeck
U
Sill
H
Linkesch
W
Adoptive transfer of vitiligo after allogeneic bone marrow transplantation for non-Hodgkin's lymphoma
Lancet.
355
2000
1334
1335
10
Berisso
GA
van Lint
MT
Bacigalupo
A
Marmont
AM
Adoptive autoimmune hyperthyroidism following allogeneic stem cell transplantation from an HLA-identical sibling with Graves' disease.
Bone Marrow Transplant.
23
1999
1091
1092
11
Kishimoto
Y
Yamamoto
Y
Ito
T
et al
Transfer of autoimmune thyroiditis and resolution of palmoplantar pustular psoriasis following allogeneic bone marrow transplantation.
Bone Marrow Transplant.
19
1997
1041
1043
12
Thomson
JA
Wilson
RM
Franklin
IM
Transmission of thyrotoxicosis of autoimmune type by sibling allogeneic bone marrow transplant.
Eur J Endocrinol.
133
1995
564
566
13
Aldouri
MA
Ruggier
R
Epstein
O
Prentice
HG
Adoptive transfer of hyperthyroidism and autoimmune thyroiditis following allogeneic bone marrow transplantation for chronic myeloid leukaemia.
Br J Haematol.
74
1990
118
119
14
Cohen
IR
Discrimination and dialogue in the immune system.
Semin Immunol.
12
2000
269
271
15
Burnet
FM
A modification of Jerne's theory of antibody production using the concept of clonal selection.
Aust J Sci.
20
1957
67
16
Schwartz
RH
A clonal deletion model for Ir gene control of the immune response.
Scand J Immunol.
7
1978
3
10
17
Blackman
M
Kappler
J
Marrack
P
The role of the T cell receptor in positive and negative selection of developing T cells.
Science.
248
1990
1335
1341
18
Smith
H
Chen
IM
Kubo
R
Tung
KS
Neonatal thymectomy results in a repertoire enriched in T cells deleted in adult thymus.
Science.
245
1989
749
752
19
Lafferty
KJ
Gazda
LS
Tolerance: a case of self/not-self discrimination maintained by clonal deletion?
Hum Immunol.
52
1997
119
126
20
Fry
AM
Jones
LA
Kruisbeek
AM
Matis
LA
Thymic requirement for clonal deletion during T cell development.
Science.
246
1989
1044
1046
21
Kappler
JW
Roehm
N
Marrack
P
T cell tolerance by clonal elimination in the thymus.
Cell.
49
1987
273
280
22
Ramsdell
F
Fowlkes
BJ
Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance.
Science.
248
1990
1342
1348
23
Schwarz
RH
A cell culture model for T lymphocyte clonal anergy.
Science.
248
1990
1349
1356
24
Malvey
EN
Telander
DG
Vanasek
TL
Mueller
DL
The role of clonal anergy in the avoidance of autoimmunity: inactivation of autocrine growth without loss of effector function.
Immunol Rev.
165
1998
301
318
25
Ramsdell
F
Lantz
T
Fowlkes
BJ
A nondeletional mechanism of thymic self tolerance.
Science.
246
1989
1038
1041
26
Bevan
MJ
Hogquist
KA
Jameson
SC
Selecting the T cell receptor repertoire.
Science.
264
1994
796
797
27
Ashton-Rickardt
PG
Tonegawa
S
A differential-avidity model for T-cell selection.
Immunol Today.
15
1994
362
366
28
Sebzda
E
Wallace
VA
Mayer
J
Yeung
RS
Mak
TW
Ohashi
PS
Positive and negative thymocyte selection induced by different concentrations of a single peptide.
Science.
263
1994
1615
1618
29
Miller
JF
Morahan
G
Peripheral T cell tolerance.
Annu Rev Immunol.
10
1992
51
69
30
Bretscher
P
Contemporary models for peripheral tolerance and the classical “historical postulate.”
Semin Immunol.
12
2000
221
229
discussion 257-344.
31
Bretscher
P
Cohn
M
A theory of self-nonself discrimination.
Science.
169
1970
1042
1049
32
Freeman
GJ
Gribben
JG
Boussiotis
VA
et al
Cloning of B7–2: a CTLA-4 counter-receptor that costimulates human T cell proliferation.
Science.
262
1993
909
911
33
Azuma
M
Ito
D
Yagita
H
et al
B70 antigen is a second ligand for CTLA-4 and CD28.
Nature.
366
1993
76
79
34
June
CH
Bluestone
JA
Nadler
LM
Thompson
CB
The B7 and CD28 receptor families.
Immunol Today.
15
1994
321
331
35
Fraser
JD
Irving
BA
Crabtree
GR
Weiss
A
Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28.
Science.
251
1991
313
316
36
Harding
FA
McArthur
JG
Gross
JA
Raulet
DH
Allison
JP
CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones.
Nature.
356
1992
607
609
37
Lindstein
T
June
CH
Ledbetter
JA
Stella
G
Thompson
CB
Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway.
Science.
244
1989
339
343
38
Hutloff
A
Dittrich
AM
Beier
KC
et al
ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28.
Nature.
97
1999
263
266
39
Cocks
BG
Chang
CC
Carballido
JM
Yssel
H
de Vries
JE
Aversa
G
A novel receptor involved in T-cell activation.
Nature.
376
1995
260
263
40
Shahinian
A
Pfeffer
K
Lee
KP
et al
Differential T cell costimulatory requirements in CD28-deficient mice.
Science.
261
1993
609
612
41
Grewal
IS
Flavell
RA
The role of CD40 ligand in costimulation and T-cell activation.
Immunol Rev.
153
1996
85
106
42
Banchereau
J
Bazan
F
Blanchard
D
et al
The CD40 antigen and its ligand.
Annu Rev Immunol.
12
1994
881
922
43
Grewal
IS
Foellmer
HG
Grewal
KD
et al
Requirement for CD40 ligand costimulation induction, T cell activation, and experimental allergic encephalomyelitis.
Science.
273
1996
1864
1867
44
Zinkernagel
RM
Ehl
S
Aichele
P
Oehen
S
Kundig
T
Hengartner
H
Antigen localisation regulates immune responses in a dose- and time-dependent fashion: a geographical view of immune reactivity.
Immunol Rev.
156
1997
199
209
45
Lakkis
FG
Arakelov
A
Konieczny
BT
Inoue
Y
Immunologic “ignorance” of vascularized organ transplants in the absence of secondary lymphoid tissue.
Nat Med.
6
2000
686
688
46
Jones
LA
Chin
LT
Longo
DL
Kruisbeek
AM
Peripheral clonal elimination of functional T cells.
Science.
250
1990
1726
1729
47
Bertolino
P
Trescol-Biemont
MC
Thomas
J
et al
Death by neglect as a deletional mechanism of peripheral tolerance.
Int Immunol.
11
1999
1225
1238
48
Pender
MP
Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance.
Immunol Cell Biol.
77
1999
216
223
49
Shevach
EM
Suppressor T cells: rebirth, function and homeostasis.
Curr Biol.
10
2000
R572
R575
50
Shevach
EM
Regulatory T cells in autoimmmunity*.
Annu Rev Immunol.
18
2000
423
449
51
Roncarolo
MG
Levings
MK
The role of different subsets of T regulatory cells in controlling autoimmunity.
Curr Opin Immunol.
12
2000
676
683
52
Garza
KM
Agersborg
SS
Baker
E
Tung
KS
Persistence of physiological self antigen is required for the regulation of self tolerance.
J Immunol.
164
2000
3982
3989
53
Critchfield
JM
Racke
MK
Zuniga-Pflucker
JC
et al
T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis.
Science.
263
1994
1139
1143
54
Matzinger
P
Tolerance, danger, and the extended family.
Annu Rev Immunol.
12
1994
991
1045
55
Laird
DJ
De Tomaso
AW
Cooper
MD
Weissman
IL
50 million years of chordate evolution: seeking the origins of adaptive immunity.
Proc Natl Acad Sci U S A.
97
2000
6924
6926
56
Medzhitov
R
Janeway
C
Jr
Innate immunity.
N Engl J Med.
343
2000
338
344
57
Fearon
DT
Locksley
RM
The instructive role of innate immunity in the acquired immune response.
Science.
272
1996
50
53
58
Medzhitov
R
Janeway
CA
Jr
Innate immunity: impact on the adaptive immune response.
Curr Opin Immunol.
9
1997
4
9
59
Lo
D
Feng
L
Li
L
et al
Integrating innate and adaptive immunity in the whole animal.
Immunol Rev.
169
1999
225
239
60
Grossman
Z
Singer
A
Tuning of activation thresholds explains flexibility in the selection and development of T cells in the thymus.
Proc Natl Acad Sci U S A.
93
1996
14747
14752
61
Grossman
Z
Paul
WE
Self-tolerance: context dependent tuning of T cell antigen recognition.
Semin Immunol.
12
2000
197
203
discussion 257-344.
62
Grossman
Z
Paul
WE
Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses.
Proc Natl Acad Sci U S A.
89
1992
10365
10369
63
Uetrecht
JP
Current trends in drug-induced autoimmunity.
Toxicology.
119
1997
37
43
64
Rose
NR
The role of infection in the pathogenesis of autoimmune disease.
Semin Immunol.
10
1998
5
13
65
Steinman
L
Conlon
P
Viral damage and the breakdown of self-tolerance.
Nat Med.
3
1997
1085
1087
66
Kretz-Rommel
A
Rubin
RL
Disruption of positive selection of thymocytes causes autoimmunity.
Nat Med.
6
2000
298
305
67
Rubin
RL
Kretz-Rommel
A
Initiation of autoimmunity by a reactive metabolite of a lupus-inducing drug in the thymus.
Environ Health Perspect.
107(suppl 5)
1999
803
806
68
Rubin
RL
Etiology and mechanisms of drug-induced lupus.
Curr Opin Rheumatol.
11
1999
357
363
69
Jenkins
MK
Schwartz
RH
Pardoll
DM
Effects of cyclosporine A on T cell development and clonal deletion.
Science.
241
1988
1655
1658
70
Chen
W
Thoburn
C
Hess
AD
Characterization of the pathogenic autoreactive T cells in cyclosporine-induced syngeneic graft-versus-host disease.
J Immunol.
161
1998
7040
7046
71
Homma
M
van Breda Vriesman
PJ
Damoiseaux
JG
Defective de novo thymocyte maturation in cyclosporin A (CsA)-induced autoimmunity: expression of costimulatory and activation molecules.
Clin Exp Immunol.
110
1997
79
85
72
Damoiseaux
JG
Beijleveld
LJ
van Breda Vriesman
PJ
Multiple effects of cyclosporin A on the thymus in relation to T-cell development and autoimmunity.
Clin Immunol Immunopathol.
82
1997
197
202
73
Douek
DC
Vescio
RA
Betts
MR
et al
Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution.
Lancet.
355
2000
1875
1881
74
Douek
DC
Koup
RA
Evidence for thymic function in the elderly.
Vaccine.
18
2000
1638
1641
75
Douek
DC
McFarland
RD
Keiser
PH
et al
Changes in thymic function with age and during the treatment of HIV infection.
Nature.
396
1998
690
695
76
Benoist
C
Mathis
D
Autoimmune diabetes. Retrovirus as trigger, precipitator or marker?
Nature.
388
1997
833
834
77
Vague
P
Vialettes
B
Prince
MA
de Micco
P
Coxsackie B viruses and autoimmune diabetes.
N Engl J Med.
305
1981
1157
1158
78
Karam
JH
Grodsky
GM
Forsham
PH
Coxsackie viruses and diabetes.
Lancet.
2
1971
1209
79
Anonymous
Coxsackie viruses and diabetes.
Lancet.
2
1971
804
80
Ringrose
JH
HLA-B27 associated spondyloarthropathy, an autoimmune disease based on crossreactivity between bacteria and HLA-B27?
Ann Rheum Dis.
58
1999
598
610
81
Hafler
DA
The distinction blurs between an autoimmune versus microbial hypothesis in multiple sclerosis.
J Clin Invest.
104
1999
527
529
82
Salmi
AA
Panelius
M
Halonen
P
Rinne
UK
Penttinen
K
Measles virus antibody in cerebrospinal fluids from patients with multiple sclerosis.
Br Med J.
1
1972
477
479
83
Berti
R
Soldan
SS
Akhyani
N
McFarland
HF
Jacobson
S
Extended observations on the association of HHV-6 and multiple sclerosis.
J Neurovirol.
6(suppl 2)
2000
S85
S87
84
Haahr
S
Munch
M
The association between multiple sclerosis and infection with Epstein-Barr virus and retrovirus.
J Neurovirol.
6(suppl 2)
2000
S76
S79
85
Monteyne
P
Bureau
JF
Brahic
M
Viruses and multiple sclerosis.
Curr Opin Neurol.
11
1998
287
291
86
Ferrante
P
Omodeo-Zorini
E
Caldarelli-Stefano
R
et al
Detection of JC virus DNA in cerebrospinal fluid from multiple sclerosis patients.
Mult Scler.
4
1998
49
54
87
Rose
NR
Neumann
DA
Herskowitz
A
Coxsackie virus myocarditis.
Adv Intern Med.
37
1992
411
429
88
Penninger
JM
Bachmaier
K
Review of microbial infections and the immune response to cardiac antigens.
J Inf Dis.
181(suppl 3)
2000
S498
S504
89
Anonymous
Dilated cardiomyopathy and enteroviruses.
Lancet.
336
1990
971
973
90
Rook
G
Lydyard
P
Stanford
J
Mycobacteria and rheumatoid arthritis.
Arthritis Rheum.
33
1990
431
435
91
Hakkarainen
K
Turunen
H
Miettinen
A
Karppelin
M
Kaitila
K
Jansson
E
Mycoplasmas and arthritis.
Ann Rheum Dis.
51
1992
1170
1172
92
Small
P
Rheumatoid arthritis—an infectious disease?
Ann Allergy.
60
1988
377
378
93
Taylor-Robinson
D
Thomas
BJ
Dixey
J
Osborn
MF
Furr
PM
Keat
AC
Evidence that Chlamydia trachomatis causes seronegative arthritis in women.
Ann Rheum Dis.
47
1988
295
299
94
Takeda
T
Mizugaki
Y
Matsubara
L
Imai
S
Koike
T
Takada
K
Lytic Epstein-Barr virus infection in the synovial tissue of patients with rheumatoid arthritis.
Arthritis Rheum.
43
2000
1218
1225
95
Blaschke
S
Schwarz
G
Moneke
D
Binder
L
Muller
G
Reuss-Borst
M
Epstein-Barr virus infection in peripheral blood mononuclear cells, synovial fluid cells, and synovial membranes of patients with rheumatoid arthritis.
J Rheumatol.
27
2000
866
873
96
Zhang
D
Nikkari
S
Vainionpaa
R
Luukkainen
R
Yli-Kerttula
U
Toivanen
P
Detection of rubella, mumps, and measles virus genomic RNA in cells from synovial fluid and peripheral blood in early rheumatoid arthritis.
J Rheumatol.
24
1997
1260
1265
97
Kowal
C
Weinstein
A
Diamond
B
Molecular mimicry between bacterial and self antigen in a patient with systemic lupus erythematosus.
Eur J Immunol.
29
1999
1901
1911
98
Albert
LJ
Inman
RD
Molecular mimicry and autoimmunity.
N Engl J Med.
341
1999
2068
2074
99
Benoist
C
Mathis
D
Autoimmunity. The pathogen connection.
Nature.
394
1998
227
228
100
Vanderlugt
CL
Begolka
WS
Neville
KL
et al
The functional significance of epitope spreading and its regulation by co-stimulatory molecules.
Immunol Rev.
164
1998
63
72
101
Mamula
MJ
Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes.
Immunol Rev.
164
1998
231
239
102
Ehl
S
Hombach
J
Aichele
P
Hengartner
H
Zinkernagel
RM
Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model.
J Exp Med.
185
1997
1241
1251
103
Shoenfeld
Y
Aron-Maor
A
Vaccination and autoimmunity-“vaccinosis”: a dangerous liaison?
J Autoimmun.
14
2000
1
10
104
Miller
SD
Gerety
SJ
Immunologic aspects of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease.
Semin Virol.
1
1990
263
272
105
Miller
SD
Vanderlugt
CL
Begolka
WS
et al
Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading.
Nat Med.
3
1997
1133
1136
106
Posnett
DN
Do superantigens play a role in autoimmunity?
Semin Immunol.
5
1993
65
72
107
Torres
BA
Johnson
HM
Modulation of disease by superantigens.
Curr Opin Immunol.
10
1998
465
470
108
Fraser
J
Arcus
V
Kong
P
Baker
E
Proft
T
Superantigens-powerful modifiers of the immune system.
Mol Med Today.
6
2000
125
132
109
Macphail
S
Superantigens: mechanisms by which they may induce, exacerbate and control autoimmune diseases.
Int Rev Immunol.
18
1999
141
180
110
Li
H
Llera
A
Malchiodi
EL
Mariuzza
RA
The structural basis of T cell activation by superantigens.
Annu Rev Immunol.
17
1999
435
466
111
Brocke
S
Hausmann
S
Steinman
L
Wucherpfennig
KW
Microbial peptides and superantigens in the pathogenesis of autoimmune diseases of the central nervous system.
Semin Immunol.
10
1998
57
67
112
Schiffenbauer
J
Soos
J
Johnson
H
The possible role of bacterial superantigens in the pathogenesis of autoimmune disorders.
Immunol Today.
19
1998
117
120
113
Vanderlugt
CL
Miller
SD
Epitope spreading.
Curr Opin Immunol.
8
1996
831
836
114
Vanderlugt
CL
Neville
KL
Nikcevich
KM
Eagar
TN
Bluestone
JA
Miller
SD
Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis.
J Immunol.
164
2000
670
678
115
Heath
VL
Hutchings
P
Fowell
DJ
Cooke
A
Mason
DW
Peptides derived from murine insulin are diabetogenic in both rats and mice, but the disease-inducing epitopes are different: evidence against a common environmental cross-reactivity in the pathogenicity of type 1 diabetes.
Diabetes.
48
1999
2157
2165
116
Agius
MA
Twaddle
GM
Fairclough
RH
Epitope spreading in experimental autoimmune myasthenia gravis.
Ann N Y Acad Sci.
841
1998
365
367
117
Goebels
N
Hofstetter
H
Schmidt
S
Brunner
C
Wekerle
H
Hohlfeld
R
Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: epitope spreading versus clonal persistence.
Brain.
123
pt 3
2000
508
518
118
Orth
T
Mayet
WJ
Deister
H
Chang
S
Schmitz
M
Bachmann
M
Analysis of epitope spreading over an eleven-year period in a patient with systemic lupus erythematosus.
Scand J Rheumatol.
27
1998
461
464
119
Chan
LS
Epitope spreading in paraneoplastic pemphigus: autoimmune induction in antibody-mediated blistering skin diseases.
Arch Dermatol.
136
2000
663
664
120
Wang
ZY
Okita
DK
Howard
JF
Jr
Conti-Fine
BM
CD4+ epitope spreading and differential T cell recognition of muscle acetylcholine receptor subunits in myasthenia gravis.
Ann N Y Acad Sci.
841
1998
334
337
121
Bonifacio
E
Lampasona
V
Bernasconi
L
Ziegler
AG
Maturation of the humoral autoimmune response to epitopes of GAD in preclinical childhood type 1 diabetes.
Diabetes.
49
2000
202
208
122
Naserke
HE
Ziegler
AG
Lampasona
V
Bonifacio
E
Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes.
J Immunol.
161
1998
6963
6969
123
Yang
L
DuTemple
B
Gorczynski
RM
Levy
G
Zhang
L
Evidence for epitope spreading and active suppression in skin graft tolerance after donor-specific transfusion.
Transplantation.
67
1999
1404
1410
124
Suciu-Foca
N
Ciubotariu
R
Colovai
A
et al
Persistent allopeptide reactivity and epitope spreading in chronic rejection.
Transplant Proc.
31
1999
100
101
125
Ciubotariu
R
Liu
Z
Colovai
AI
et al
Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts.
J Clin Invest.
101
1998
398
405
126
Zinkernagel
RM
Doherty
PC
Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system.
Nature.
248
1974
701
702
127
Zinkernagel
RM
The Nobel Lectures in Immunology. The Nobel Prize for Physiology or Medicine, 1996. Cellular immune recognition and the biological role of major transplantation antigens.
Scand J Immunol.
46
1997
421
436
128
Nepom
GT
Erlich
H
MHC class-II molecules and autoimmunity.
Annu Rev Immunol.
9
1991
493
525
129
Gregersen
PK
Silver
J
Winchester
RJ
The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.
Arthritis Rheum.
30
1987
1205
1213
130
Wordsworth
BP
Lanchbury
JS
Sakkas
LI
Welsh
KI
Panayi
GS
Bell
JI
HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region.
Proc Natl Acad Sci U S A.
86
1989
10049
10053
131
Nepom
GT
HLA and rheumatoid arthritis.
HLA in Health and Disease.
2nd ed.
Lechler
R
Warrens
A
2000
181
185
Academic Press
London, United Kingdom
132
Breur-Vriesendorp
BS
Dekker-Saeys
AJ
Ivanyi
P
Distribution of HLA-B27 subtypes in patients with ankylosing spondylitis: the disease is associated with a common determinant of the various B27 molecules.
Ann Rheum Dis.
46
1987
353
356
133
Arnett
FC
HLA and autoimmunity in scleroderma (systemic sclerosis).
Int Rev Immunol.
12
1995
107
128
134
Theofilopoulos
AN
Genes and Genetics of Autoimmunity.
1999
1
285
Karger
Basel, Switzerland
135
Ghosh
S
Palmer
SM
Rodrigues
NR
et al
Polygenic control of autoimmune diabetes in non-obese diabetic mice.
Nat Genet.
4
1993
404
409
136
Rudofsky
UH
Lawrence
DA
New Zealand mixed mice: a genetic systemic lupus erythematosus model for assessing environmental effects.
Environm Health Perspect.
107(suppl 5)
1999
713
721
137
Wakeland
EK
Wandstrat
AE
Liu
K
Morel
L
Genetic dissection of systemic lupus erythematosus.
Curr Opin Immunol.
11
1999
701
707
138
Wooley
PH
Animal models of rheumatoid arthritis.
Curr Opin Rheumatol.
3
1991
407
420
139
Myers
LK
Rosloniec
EF
Cremer
MA
Kang
AH
Collagen-induced arthritis, an animal model of autoimmunity.
Life Sci.
61
1997
1861
1878
140
Remmers
EF
Longman
RE
Du
Y
et al
A genome scan localizes five non-MHC loci controlling collagen-induced arthritis in rats.
Nat Genet.
14
1996
82
85
141
Griffiths
MM
Wang
J
Joe
B
et al
Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen-induced arthritis.
Arthritis Rheum.
43
2000
1278
1289
142
Hawkes
CH
Twin studies in medicine—what do they tell us?
QJM.
90
1997
311
321
143
van Bekkum
DW
Stem cell transplantation in experimental models of autoimmune disease.
J Clin Immunol.
20
2000
10
16
144
Karussis
D
Vourka-Karussis
U
Mizrachi-Koll
R
Abramsky
O
Acute/relapsing experimental autoimmune encephalomyelitis: induction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation.
Mult Scler.
5
1999
17
21
145
Kamiya
M
Sohen
S
Yamane
T
Tanaka
S
Effective treatment of mice with type II collagen induced arthritis with lethal irradiation and bone marrow transplantation.
J Rheumatol.
20
1993
225
230
146
Burt
RK
Padilla
J
Begolka
WS
Canto
MCD
Miller
SD
Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis.
Blood.
91
1998
2609
2616
147
van Gelder
M
van Bekkum
DW
Effective treatment of relapsing experimental autoimmune encephalomyelitis with pseudoautologous bone marrow transplantation.
Bone Marrow Transplant.
18
1996
1029
1034
148
Blank
M
Tomer
Y
Slavin
S
Shoenfeld
Y
Induction of tolerance to experimental anti-phospholipid syndrome (APS) by syngeneic bone marrow cell transplantation.
Scand J Immunol.
42
1995
226
234
149
Karussis
DM
Vourka-Karussis
U
Lehmann
D
et al
Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation.
J Clin Invest.
92
1993
765
772
150
van Gelder
M
Kinwel-Bohre
EP
van Bekkum
DW
Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT.
Bone Marrow Transplant.
11
1993
233
241
151
Burt
RK
Burns
W
Ruvolo
P
et al
Syngeneic bone marrow transplantation eliminates V beta 8.2 T lymphocytes from the spinal cord of Lewis rats with experimental allergic encephalomyelitis.
J Neurosci Res.
41
1995
526
531
152
Knaan-Shanzer
S
Houben
P
Kinwel-Bohre
EP
van Bekkum
DW
Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation.
Bone Marrow Transplant.
8
1991
333
338
153
Pestronk
A
Drachman
DB
Teoh
R
Adams
RN
Combined short-term immunotherapy for experimental autoimmune myasthenia gravis.
Ann Neurol.
14
1983
235
241
154
van Bekkum
DW
Conditioning regimens for the treatment of experimental arthritis with autologous bone marrow transplantation.
Bone Marrow Transplant.
25
2000
357
364
155
van Bekkum
DW
Bohre
EP
Houben
PF
Knaan-Shanzer
S
Regression of adjuvant-induced arthritis in rats following bone marrow transplantation.
Proc Natl Acad Sci U S A.
86
1989
10090
10094
156
Burt
RK
Padilla
J
Dal Canto
MC
Miller
SD
Viral hyperinfection of the central nervous system and high mortality after hematopoietic stem cell transplantation for treatment of Theiler's murine encephalomyelitis virus-induced demyelinating disease.
Blood.
94
1999
2915
2922
157
Snowden
JA
Patton
WN
O'Donnell
JL
Hannah
EE
Hart
DN
Prolonged remission of longstanding systemic lupus erythematosus after autologous bone marrow transplant for non-Hodgkin's lymphoma.
Bone Marrow Transplant.
19
1997
1247
1250
158
Demirer
T
Celebi
H
Arat
M
et al
Autoimmune thrombocytopenia in a patient with small cell lung cancer developing after chemotherapy and resolving following autologous peripheral blood stem cell transplantation.
Bone Marrow Transplant.
24
1999
335
337
159
Jindra
P
Koza
V
Fiser
J
Vozobulova
V
Svojgrova
M
Autologous CD34+ cells transplantation after FAMP treatment in a patient with CLL and persisting AIHA: complete remission of lymphoma with control of autoimmune complications.
Bone Marrow Transplant.
24
1999
215
217
160
Schachna
L
Ryan
PF
Schwarer
AP
Malignancy-associated remission of systemic lupus erythematosus maintained by autologous peripheral blood stem cell transplantation.
Arthritis Rheum.
41
1998
2271
2272
161
Rosler
W
Manger
B
Repp
R
Kalden
JR
Gramatzki
M
Autologous PBPCT in a patient with lymphoma and Sjogren's syndrome: complete remission of lymphoma without control of the autoimmune disease.
Bone Marrow Transplant.
22
1998
211
213
162
Cooley
HM
Snowden
JA
Grigg
AP
Wicks
IP
Outcome of rheumatoid arthritis and psoriasis following autologous stem cell transplantation for hematologic malignancy.
Arthritis Rheum.
40
1997
1712
1715
163
Euler
HH
Marmont
AM
Bacigalupo
A
et al
Early recurrence or persistence of autoimmune diseases after unmanipulated autologous stem cell transplantation
Blood.
88
1996
3621
3625
164
Musso
M
Porretto
F
Crescimanno
A
Bondi
F
Polizzi
V
Scalone
R
Crohn's disease complicated by relapsed extranodal Hodgkin's lymphoma: prolonged complete remission after unmanipulated PBPC autotransplant.
Bone Marrow Transplant.
26
2000
921
923
165
Meloni
G
Capria
S
Vignetti
M
Mandelli
F
Modena
V
Blast crisis of chronic myelogenous leukemia in long-lasting systemic lupus erythematosus: regression of both diseases after autologous bone marrow transplantation.
Blood.
89
1997
4659
166
Meloni
G
Capria
S
Salvetti
M
Cordone
I
Mancini
M
Mandelli
F
Autologous peripheral blood stem cell transplantation in a patient with multiple sclerosis and concomitant Ph+ acute leukemia.
Haematologica.
84
1999
665
667
167
Burt
RK
Fassas
A
Snowden
J
et al
Collection of hematopoietic stem cells from patients with autoimmune diseases.
Bone Marrow Transplant.
28
2001
1
12
168
Openshaw
H
Stuve
O
Antel
JP
et al
Multiple sclerosis flares associated with recombinant granulocyte colony-stimulating factor.
Neurology.
54
2000
2147
2150
169
Nash
RA
Kraft
GH
Bowen
JD
et al
Treatment of severe multiple sclerosis (MS) with high dose immunosuppressive therapy (HDIT) and autologous stem cell transplantation (SCT) [abstract].
Blood.
96(suppl)
2000
842a
170
Martino
R
Sureda
A
Brunet
S
Peripheral blood stem cell mobilization in refractory autoimmune Evans syndrome: a cautionary case report.
Bone Marrow Transplant.
20
1997
521
171
Slavin
S
Treatment of life-threatening autoimmune diseases with myeloablative doses of immunosuppressive agents: experimental background and rationale for ABMT.
Bone Marrow Transplant.
12
1993
85
88
172
Brodsky
RA
Petri
M
Smith
BD
et al
Immunablative high dose cyclophosphamide without stem cell rescue for refractory severe autoimmune disease.
Ann Intern Med.
129
1998
1031
1035
173
Joske
DJ
Ma
DT
Langlands
DR
Owen
ET
Autologous bone-marrow transplantation for rheumatoid arthritis [letter].
Lancet.
350
1997
337
174
Snowden
JA
Biggs
JC
Milliken
ST
Fuller
A
Brooks
PM
A phase I/II dose escalation study of intensified cyclophosphamide and autologous blood stem cell rescue in severe, active rheumatoid arthritis.
Arthritis Rheum.
42
1999
2286
2292
175
McColl
G
Kohsaka
H
Szer
J
Wicks
I
High-dose chemotherapy and syngeneic hemopoietic stem-cell transplantation for severe, seronegative rheumatoid arthritis.
Ann Int Med.
131
1999
507
509
176
Tyndall
A
Black
C
Finke
J
et al
Treatment of systemic sclerosis with autologous haemopoietic stem cell
Lancet.
349
1997
254
177
Lim
SH
Kell
J
al-Sabah
A
Bashi
W
Bailey-Wood
R
Peripheral blood stem-cell transplantation for refractory autoimmune thrombocytopenic purpura [letter].
Lancet.
349
1997
475
178
Pavletic
S
O'Dell
J
Ursick
M
et al
Autologous blood stem cell transplantation can overcome and modulate therapeutic resistance in severe rheumatoid arthritis [abstract].
Blood.
94
1999
404b
179
Burt
RK
Traynor
AE
Pope
R
et al
Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation.
Blood.
92
1998
3505
3514
180
Burt
RK
Georganas
C
Schroeder
J
et al
Autologous hematopoietic stem cell transplantation in refractory rheumatoid arthritis: sustained response in two of four patients.
Arthritis Rheum.
42
1999
2281
2285
181
Traynor
AE
Schroeder
J
Rosa
RM
et al
Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study.
Lancet.
356
2000
701
707
182
Traynor
A
Burt
RK
Haematopoietic stem cell transplantation for active systemic lupus erythematosus.
Rheumatology (Oxford).
38
1999
767
772
183
Burt
RK
Traynor
A
Ramsey-Goldman
R
Hematopoietic stem-cell transplantation for systemic lupus erythematosus.
N Engl J Med.
337
1997
1777
1778
184
Musso
M
Porretto
F
Crescimanno
A
et al
Autologous peripheral blood stem and progenitor (CD34+) cell transplantation for systemic lupus erythematosus complicated by Evans syndrome.
Lupus.
7
1998
492
494
185
Musso
M
Porretto
F
Crescimanno
A
et al
Successful treatment of resistant thrombotic thrombocytopenic purpura/hemolytic uremic syndrome with autologous peripheral blood stem and progenitor (CD34+) cell transplantation.
Bone Marrow Transplant.
24
1999
207
209
186
Quartier
P
Prieur
AM
Fischer
A
Haemopoietic stem-cell transplantation for juvenile chronic arthritis [letter].
Lancet.
353
1999
1885
1886
187
Martini
A
Maccario
R
Ravelli
A
et al
Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis.
Arthritis Rheum.
42
1999
807
811
188
Rosen
O
Thiel
A
Massenkeil
G
et al
Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells.
Arthritis Res.
2
2000
327
336
189
Kozak
T
Havrdova
E
Pit'ha
J
et al
High-dose immunosuppressive therapy with PBPC support in the treatment of poor risk multiple sclerosis.
Bone Marrow Transplant.
25
2000
525
531
190
Fassas
A
Anagnostopoulos
A
Kazis
A
et al
Autologous stem cell transplantation in progressive multiple sclerosis—an interim analysis of efficacy.
J Clin Immunol.
20
2000
24
30
191
Fassas
A
Anagnostopoulos
A
Kazis
A
et al
Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study.
Bone Marrow Transplant.
20
1997
631
638
192
Fouillard
L
Gorin
NC
Laporte
JP
Leon
A
Brantus
JF
Miossec
P
Control of severe systemic lupus erythematosus after high-dose immunusuppressive therapy and transplantation of CD34+ purified autologous stem cells from peripheral blood.
Lupus.
8
1999
320
323
193
Burt
RK
Traynor
AE
Cohen
B
et al
T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients.
Bone Marrow Transplant.
21
1998
537
541
194
Wulffraat
N
van Royen
A
Bierings
M
Vossen
J
Kuis
W
Autologous haemopoietic stem-cell transplantation in four patients with refractory juvenile chronic arthritis.
Lancet.
353
1999
550
553
195
McSweeney
PA
Furst
DE
Storek
J
et al
High dose immune suppressive therapy (HDIT) using total body irradiation (TBI) cyclophosphamide (CY) and ATG with autologous CD34+ selected peripheral blood stem cell (PBSC) rescue as treatment for severe systemic sclerosis [abstract].
Blood.
92(suppl)
1998
285
196
Durez
P
Toungouz
M
Schandene
L
Lambermont
M
Goldman
M
Remission and immune reconstitution after T-cell-depleted stem-cell transplantation for rheumatoid arthritis.
Lancet.
352
1998
881
197
Openshaw
H
Lund
BT
Kashyap
A
et al
Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: report of toxicity and immunological monitoring.
Biol Blood Marrow Transplant.
6
2000
563
575
198
Baron
F
Ribbens
C
Kaye
O
Fillet
G
Malaise
M
Beguin
Y
Effective treatment of Jo-1-associated polymyositis with T-cell-depleted autologous peripheral blood stem cell transplantation.
Br J Haematol.
110
2000
339
342
199
Marmont
AM
van Lint
MT
Gualandi
F
Bacigalupo
A
Autologous marrow stem cell transplantation for severe systemic lupus erythematosus of long duration.
Lupus.
6
1997
545
548
200
Marmont
AM
van Lint
MT
Occhini
D
Lamparelli
T
Bacigalupo
A
Failure of autologous stem cell transplantation in refractory thrombocytopenic purpura.
Bone Marrow Transplant.
22
1998
827
828
201
Squires
DJ
Lamerton
LF
The effect of various cytotoxic agents on bone marrow progenitor cells as measured by diffusion chamber assays.
Br J Haematol.
29
1975
31
42
202
Urowitz
MB
Rider
WD
Myeloproliferative disorders in patients with rheumatoid arthritis treated with total body irradiation.
Am J Med.
78
1985
60
64
203
Grom
AA
Passo
M
Macrophage activation syndrome in systemic juvenile rheumatoid arthritis.
J Pediatr.
129
1996
630
632
204
Curtis
RE
Rowlings
PA
Deeg
HJ
et al
Solid cancers after bone marrow transplantation.
N Engl J Med.
336
1997
897
904
205
Tyndall
A
Fassas
A
Passweg
J
et al
Autologous haematopoietic stem cell transplants for autoimmune disease—feasibility and transplant-related mortality. Autoimmune Disease and Lymphoma Working Parties of the European Group for Blood and Marrow Transplantation, the European League Against Rheumatism and the International Stem Cell Project for Autoimmune Disease.
Bone Marrow Transplant.
24
1999
729
734
206
Gjertson
DW
Update: center effects.
Clinical Transplants.
1990
375
383
207
Confavreux
C
Suissa
S
Saddier
P
Bourdes
V
Vukusic
S
Vaccinations and the risk of relapse in multiple sclerosis.
N Engl J Med.
344
2001
319
326
208
Noseworthy
JH
Lucchinetti
C
Rodriguez
M
Weinshenker
BG
Multiple sclerosis.
N Engl J Med.
343
2000
938
952
209
Weinshenker
BG
The natural history of multiple sclerosis: update 1998.
Semin Neurol.
18
1998
301
307
210
Weinshenker
BG
The natural history of multiple sclerosis.
Neurol Clin.
13
1995
119
146
211
Weinshenker
BG
Natural history of multiple sclerosis.
Ann Neurol.
36(suppl)
1994
S6
S11
212
Paty
DW
Li
DK
UBC MS/MRI Study Group
IFNB Multiple Sclerosis Study Group
Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial.
Neurology.
43
1993
662
667
213
The IFNB Multiple Sclerosis Study Group, University of British Columbia MS/MRI Analysis Group
Interferon (beta)-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial.
Neurology.
45
1995
1277
1285
214
PRISMS (Prevention of Relapses and Disability by Interferon (beta)-1a Subcutaneously in Multiple Sclerosis) Study Group
Randomised double-blind placebo-controlled study of interferon (beta)-1a in relapsing/remitting multiple sclerosis [erratum in Lancet. 1999;353:678].
Lancet.
352
1998
1498
1504
215
European Study Group on Interferon (beta)-1b in Secondary Progressive MS
Placebo-controlled multicentre randomised trial of interferon (beta)-1b in treatment of secondary progressive multiple sclerosis.
Lancet.
352
1998
1491
1497
216
The IFNB Multiple Sclerosis Study Group
Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial.
Neurology.
43
1993
655
661
217
Johnson
KP
Brooks
BR
Cohen
JA
et al
Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial.
Neurology.
45
1995
1268
1276
218
Johnson
KP
Brooks
BR
Cohen
JA
et al
Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability.
Neurology.
50
1998
701
708
219
Millefiorini
E
Gasperini
C
Pozzilli
C
et al
Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome.
J Neurol.
244
1997
153
159
220
Edan
G
Miller
D
Clanet
M
et al
Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria.
J Neurol Neurosurg Psychiatry.
62
1997
112
118
221
Sadovnick
AD
Eisen
K
Ebers
GC
Paty
DW
Cause of death in patients attending multiple sclerosis clinics.
Neurology
41
1991
1193
1196
222
McFarland
HF
Stone
LA
Calabresi
PA
Maloni
H
Bash
CN
Frank
JA
MRI studies of multiple sclerosis: implications for the natural history of the disease and for monitoring effectiveness of experimental therapies.
Mult Scler.
2
1996
198
205
223
Filippi
M
Rovaris
M
Comi
G
Magnetic resonance in monitoring the natural history of multiple sclerosis and the effects of treatment.
Ital J Neurol Sci.
17
1996
385
391
224
Confavreux
C
Vukusic
S
Moreau
T
Adeleine
P
Relapses and progression of disability in multiple sclerosis.
N Engl J Med.
343
2000
1430
1438
225
Trapp
BD
Peterson
J
Ransohoff
RM
Rudick
R
Mork
S
Bo
L
Axonal transection in the lesions of multiple sclerosis.
N Engl J Med.
338
1998
278
285
226
De Stefano
N
Matthews
PM
Fu
L
et al
Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study.
Brain.
121
pt 8
1998
1469
1477
227
Fu
L
Matthews
PM
De Stefano
N
et al
Imaging axonal damage of normal-appearing white matter in multiple sclerosis.
Brain.
121
pt 1
1998
103
113
228
Ferguson
B
Matyszak
MK
Esiri
MM
Perry
VH
Axonal damage in acute multiple sclerosis lesions.
Brain.
120
pt 3
1997
393
399
229
Burt
RK
Burns
W
Hess
A
Bone marrow transplantation for multiple sclerosis.
Bone Marrow Transplant.
16
1995
1
6
230
Burt
RK
Cohen
BA
Lobeck
LJ
et al
Immune suppressive therapy with autologous hematopoietic stem cell transplantation arrests active CNS inflammation but not axonal atrophy in patients with severe disability and progressive multiple sclerosis [abstract].
Blood.
98
2001
687a
231
Mancardi
GL
Saccardi
R
Filipppi
M
et al
Autologous hempatopoietic stem cell transplantation suppresses gd-enhanced MRI activity in MS.
Neurology.
57
2001
62
68
232
Carreras
E
Saiz
A
Graus
F
et al
Autologous CD34+ selected hematopoietic stem cell transplantation (CD34+/HSCT) for multiple sclerosis: update of a single center experience in 10 patients [abstract].
Biol Blood Marrow Transplant.
7
2001
69
233
Mandalfino
P
Rice
G
Smith
A
Klein
JL
Rystedt
L
Ebers
GC
Bone marrow transplantation in multiple sclerosis.
J Neurol.
247
2000
691
695
234
Jacobs
LD
Beck
RW
Simon
JH
et al
Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
N Engl J Med.
343
2000
898
904
235
Kono
DH
Theophilopoulos
AN
Genetic susceptibility to spontaneous lupus in mice.
Genes and Genetics of Autoimmunity.
Theophilopoulos
AN
1 Current Directions in Autoimmunity
1999
72
98
Karger
Basel, Switzerland
236
Coutinho
A
An outsider's view on SLE research.
Lupus.
8
1999
171
173
237
Wallace
DJ
Hahn
BH
Dubois' Lupus Erythematosus.
1997
1
1227
Williams & Wilkins
Baltimore, MD
238
Lahita
RG
Systemic Lupus Erythematosus.
1999
1
1003
Academic Press
San Diego, CA
239
Hochberg
MC
Epidemiology of systemic lupus erythematosus.
Dubois' Lupus Erythematosus.
Wallace
DJ
Hahn
BH
1997
49
69
Williams & Wilkins
Baltimore, MD
240
Alarcon-Segovia
D
Alarcon-Riquelme
ME
Etiopathogenesis of systemic lupus erythematosus: a tale of three troikas.
Systemic Lupus Erythematosus.
Lahita
RG
1999
56
65
Academic Press
San Diego, CA
241
Liossis
SN
Tsokos
GC
Systemic lupus erythematosus.
Principles of Molecular Rheumatology.
Tsokos
GC
2000
311
323
Humana Press
Totowa, NJ
242
Old treatment-new treatment [special issue].
Lupus.
Shoenfeld
Y
Khamashta
M
10
2001
135
248
243
Takada
K
Illei
GC
Boumpas
DT
Cyclophosphamide for the treatment of systemic lupus erythematosus.
Lupus.
10
2001
154
161
244
Treatment-resistant rheumatic disease.
Rheum Dis Clin N Am.
Cash
JM
Wilder
RL
21
1995
1
18
245
Marmont
AM
Perspective: immunoablation with stem cell rescue: a possible cure for systemic lupus erythematosus.
Lupus.
2
1993
151
156
246
Musso
M
Porretto
F
Crescimanno
A
Bondi
F
Polizzi
V
Scalone
R
Intense immunosuppressive therapy followed by autologous peripheral blood selected progenitor cell infusion for severe autoimmune diseases.
Am J Hematol.
66
2001
75
79
247
Marmont
AM
Eminence-based medicine. Lupus: tinkering with hematopoietic stem cells.
Lupus.
10
2001
1
6
248
Symmons
DPM
Coopock
JS
Bacon
PA
et al
Development and assessment of a computerized index of clinical disease activity in systemic lupus erythematosus.
QJM.
68
1988
927
937
249
Bombardier
C
Gladman
DD
Urowitz
MB
Caron
D
Chang
CH
Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE.
Arthritis Rheum.
35
1992
630
640
250
Liang
MH
Socher
SA
Roberts
WN
Esdaile
JM
Measurement of systemic lupus erythematosus activity in clinical research.
Arthritis Rheum.
31
1988
817
825
251
Petri
M
Bochemstedt
L
Colman
J
et al
Serial assessment of glomerular filtration rate in lupus nephropathy.
Kidney Int.
34
1988
832
839
252
Gladman
DD
Goldsmith
CH
Urowitz
MB
et al
Crosscultural validation and reliability of three disease activity indices in systemic lupus erythematosus.
J Rheum.
19
1992
608
611
253
Gladman
DD
Goldsmith
CH
Urowitz
MB
et al
Sensitivity to change of three SLE disease activity indices: international validation.
J Rheum.
21
1994
1468
1471
254
Abdel-Nasser
AM
Rasker
JJ
Valkenburg
HA
Epidemiological and clinical aspects relating to the variability of rheumatoid arthritis.
Semin Arthritis Rheum.
27
1997
123
140
255
Firestein
GS
Etiology and pathogenesis of rheumatoid arthritis.
Textbook of Rheumatology.
5th ed.
Kelley
WN
et al
1996
851
897
WB Saunders
Philadelphia, PA
256
Goronzy
JJ
Zettl
A
Weyand
CM
T cell receptor repertoire in rheumatoid arthritis.
Int Rev Immunol.
17
1998
339
363
257
Hall
FC
Thomson
K
Procter
J
McMichael
AJ
Wordsworth
BP
TCR beta spectratyping in RA: evidence of clonal expansions in peripheral blood lymphocytes.
Ann Rheum Dis.
57
1998
319
322
258
Lamb
JR
Young
DB
T cell recognition of stress proteins. A link between infectious and autoimmune disease.
Mol Biol Med.
7
1990
311
321
259
He
X
Kang
AH
Stuart
JM
Accumulation of T cells reactive to type II collagen in synovial fluid of patients with rheumatoid arthritis.
J Rheumatol.
27
2000
589
593
260
Weinberg
JB
Wortham
TS
Misukonis
MA
Patton
KL
Chitneni
SR
Synovial mononuclear phagocytes in rheumatoid arthritis and osteoarthritis: quantitative and functional aspects.
Immunol Invest.
22
1993
365
374
261
Lafyatis
R
Remmers
EF
Roberts
AB
Yocum
DE
Sporn
MB
Wilder
RL
Anchorage-independent growth of synoviocytes from arthritic and normal joints: stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids.
J Clin Invest.
83
1989
1267
1276
262
Muller-Ladner
U
Kriegsmann
J
Franklin
BN
et al
Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice.
Am J Pathol.
149
1996
1607
1615
263
Kullmann
F
Judex
M
Neudecker
I
et al
Analysis of the p53 tumor suppressor gene in rheumatoid arthritis synovial fibroblasts.
Arthritis Rheum.
42
1999
1594
1600
264
Hollingsworth
JW
Non-articular complications of rheumatoid arthritis.
Med Times.
98
1970
121
130
265
Hart
FD
Rheumatoid arthritis: extra-articular manifestations. II.
BMJ.
2
1970
747
752
266
Callahan
LF
Pincus
T
Mortality in the rheumatic diseases.
Arthritis Care Res.
8
1995
229
241
267
Pincus
T
Brooks
RH
Callahan
LF
Prediction of long-term mortality in patients with rheumatoid arthritis according to simple questionnaire and joint count measures.
Ann Intern Med.
120
1994
26
34
268
Mitchell
DM
Spitz
PW
Young
DY
Bloch
DA
McShane
DJ
Fries
JF
Survival, prognosis, and causes of death in rheumatoid arthritis.
Arthritis Rheum.
29
1986
706
714
269
Leigh
JP
Fries
JF
Mortality predictors among 263 patients with rheumatoid arthritis.
J Rheumatol.
18
1991
1307
1312
270
Pincus
T
Callahan
LF
Vaughn
WK
Questionnaire, walking time and button test measures of functional capacity as predictive markers for mortality in rheumatoid arthritis.
J Rheumatol.
14
1987
240
251
271
Cobb
S
Anderson
F
Bauer
W
Length of life and cause of death in rheumatoid arthritis.
N Engl J Med.
249
1953
553
556
272
Myllykangas-Luosujarvi
RA
Aho
K
Isomaki
HA
Mortality in rheumatoid arthritis.
Semin Arthritis Rheum.
25
1995
193
202
273
Myllykangas-Luosujarvi
R
Aho
K
Kautiainen
H
Isomaki
H
Shortening of life span and causes of excess mortality in a population-based series of subjects with rheumatoid arthritis.
Clin Exp Rheumatol.
13
1995
149
153
274
Vandenbroucke
J
Hazevoet
HM
Cats A. Survival and cause of death in rheumatoid arthritis: a 25-year prospective followup.
J Rheumatol.
11
1984
158
161
275
Uddin
J
Kraus
AS
Kelly
HG
Survivorship and death in rheumatoid arthritis.
Arthritis Rheum.
13
1970
125
130
276
Klippel
JH
Biologic therapy for rheumatoid arthritis.
N Engl J Med.
343
2000
1640
1641
277
Verburg
RJ
Kruize
AA
van den Hoogan
FHJ
et al
High dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy.
Arthritis Rheum.
44
2001
754
760
278
Munro
R
Madhok
R
T-cell-depleted stem-cell transplantation for rheumatoid.
Lancet.
352
1998
1628
1629
279
Amett
F
Edworthy
S
Bloch
D
et al
The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.
Arthritis Rheum.
31
1988
315
324
280
Silman
AJ
Black
CM
Welsh
KI
Epidemiology, demographics, genetics.
Systemic Sclerosis.
Clements
P
Furst
D
1996
23
50
Williams & Wilkins
Baltimore, MD
281
Bryan
C
Knight
C
Black
CM
Silman
AJ
Prediction of five-year survival following presentation with scleroderma: development of a simple model using three disease factors at first visit.
Arthritis Rheum.
42
1999
2660
2665
282
Clements
PJ
Lachenbruch
PA
Ng
SC
Simmons
M
Sterz
M
Furst
DE
Skin score. A semiquantitative measure of cutaneous involvement that improves prediction of prognosis in systemic sclerosis.
Arthritis Rheum.
33
1990
1256
1263
283
Altman
RD
Medsger
TA
Bloch
DA
Michel
BA
Predictors of survival in systemic sclerosis (scleroderma).
Arthritis Rheum.
34
1991
403
413
284
Jacobsen
S
Halberg
P
Ullman
S
Mortality and causes of death of 344 Danish patients with systemic sclerosis (scleroderma).
Br J Rheumatol.
37
1998
750
755
285
Bryan
C
Howard
Y
Brennan
P
Black
C
Silman
A
Survival following the onset of scleroderma: results from a retrospective inception cohort study of the UK patient population.
Br J Rheumatol.
35
1996
1122
1126
286
Abu-Shakra
M
Lee
P
Mortality in systemic sclerosis: a comparison with the general population.
J Rheumatol.
22
1995
2100
2102
287
Briggs
D
Welsh
KI
Major histocompatibility complex class II genes and systemic sclerosis.
Ann Rheum Dis.
50(suppl 4)
1991
862
865
288
Hietarinta
M
Koskimies
S
Lassila
O
Soppi
E
Toivanen
A
Familial scleroderma: HLA antigens and autoantibodies.
Br J Rheumatol.
32
1993
336
338
289
Clements
PJ
Furst
DE
Wong
WK
et al
High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial.
Arthritis Rheum.
42
1999
1194
1203
290
van den Hoogen
FH
Boerbooms
AM
Swaak
AJ
Rasker
JJ
van Lier
HJ
van de Putte
LB
Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial.
Br J Rheumatol.
35
1996
364
372
291
Grassegger
A
Schuler
G
Hessenberger
G
et al
Interferon-gamma in the treatment of systemic sclerosis: a randomized controlled multicentre trial.
Br J Dermatol.
139
1998
639
648
292
White
B
Moore
WC
Wigley
FM
Xiao
HQ
Wise
RA
Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.
Ann Int Med.
132
2000
947
954
293
Norton
WL
Nardo
JM
Vascular disease in progressive systemic sclerosis (scleroderma).
Ann Int Med.
73
1970
317
324
294
Kahaleh
MB
The role of vascular endothelium in fibroblast activation and tissue fibrosis, particularly in scleroderma (systemic sclerosis) and pachydermoperiostosis (primary hypertrophic osteoarthropathy).
Clin Exp Rheumatol.
10(suppl 7)
1992
51
56
295
Kahaleh
MB
Osborn
I
LeRoy
EC
Increased factor VIII/von Willebrand factor antigen and von Willebrand factor activity in scleroderma and in Raynaud's phenomenon.
Ann Int Med.
94
1981
482
484
296
Siracusa
LD
Sherratt
MJ
Peters
R
Shuttleworth
CA
Jimenez
SA
The Tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils.
J Cell Biol.
140
1998
1159
1166
297
Siracusa
LD
McGrath
R
Ma
Q
et al
A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation.
Genome Res.
6
1996
300
313
298
Gayraud
B
Keene
DR
Sakai
LY
Ramirez
F
New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse.
J Cell Biol.
150
2000
667
680
299
Guldner
HH
Szostecki
C
Vosberg
HP
Lakomek
HJ
Penner
E
Bautz
FA
Scl 70 autoantibodies from scleroderma patients recognize a 95 kDa protein identified as DNA topoisomerase I.
Chromosoma.
94
1986
132
138
300
Maul
GG
French
BT
van Venrooij
WJ
Jimenez
SA
Topoisomerase I identified by scleroderma 70 antisera: enrichment of topoisomerase I at the centromere in mouse mitotic cells before anaphase.
Proc Natl Acad Sci U S A.
83
1986
5145
5149
301
Steen
VD
Ziegler
GL
Rodnan
GP
Medsger
TA
Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis.
Arthritis Rheum.
27
1984
125
131
302
Graham-Brown
RA
Sarkany
I
Scleroderma-like changes due to chronic graft-versus-host disease.
Clin Exp Dermatol.
8
1983
531
538
303
Claman
HN
Graft-versus-host disease and animal models for scleroderma.
Curr Opin Rheumatol.
2
1990
929
931
304
Bos
G
Majoor
G
Slaaf
D
Reneman
R
van Breda Vriesman
P
In vivo demonstration of microvascular pathology by intravital microscopy in experimental chronic graft-versus-host disease: analogy with scleroderma.
J Rheumatol.
15
1988
1339
1345
305
Nelson
JL
Furst
DE
Maloney
S
et al
Microchimerism and HLA-compatible relationships of pregnancy in scleroderma.
Lancet.
351
1998
559
562
306
Maloney
S
Smith
A
Furst
DE
et al
Microchimerism of maternal origin persists into adult life.
J Clin Invest.
104
1999
41
47
307
Shen
N
Ffrench
P
Guyotat
D
et al
Expression of adhesion molecules in endothelial cells during allogeneic bone marrow transplantation.
Eur J Haematol.
52
1994
296
301
308
Binks
M
Passweg
JR
Furst
D
et al
Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease.
Ann Rheum Dis.
60
2001
577
584
309
LaFace
DM
Peck
AB
Reciprocal allogeneic bone marrow transplantation between NOD mice and diabetes-nonsusceptible mice associated with transfer and prevention of autoimmune diabetes.
Diabetes.
38
1989
894
901
310
Karussis
DM
Vourka-Karussis
U
Lehmann
D
Abramsky
O
Ben-Nun
A
Slavin
S
Immunomodulation of autoimmunity in MRL/lpr mice with syngeneic bone marrow transplantation (SBMT).
Clin Exp Immunol.
100
1995
111
117
311
Kushida
T
Inaba
M
Takeuchi
K
Sugiura
K
Ogawa
R
Ikehara
S
Treatment of intractable autoimmune diseases in MRL/lpr mice using a new strategy for allogeneic bone marrow transplantation.
Blood.
5
2000
1862
1868
312
van Gelder
M
Mulder
AH
van Bekkum
DW
Treatment of relapsing experimental autoimmune encephalomyelitis with largely MHC-matched allogeneic bone marrow transplantation.
Transplantation.
62
1996
810
818
313
El-Badri
NS
Wang
BY
Steele
A
et al
Successful prevention of autoimmune disease by transplantation of adequate number of fully allogeneic hematopoietic stem cells.
Transplantation.
70
2000
870
877
314
Kirzner
RP
Engelman
RW
Mizutani
H
Specter
S
Good
RA
Prevention of coronary vascular disease by transplantation of T-cell-depleted bone marrow and hematopoietic stem cell preparation in autoimmune-prone w/BF(1) mice.
Biol Blood Marrow Transplant.
6
2000
513
522
315
Takeuchi
K
Inaba
M
Miyashima
S
Ogawa
R
Ikehara
S
A new strategy for treatment of autoimmune diseases in chimeric resistant MRL/lpr mice.
Blood.
91
1998
4616
4623
316
Li
H
Kaufman
CL
Ildstad
ST
Allogeneic chimerism induces donor-specific tolerance to simultaneous islet allografts in nonobese diabetic mice.
Surgery.
118
1995
192
198
317
Himeno
K
Good
RA
Marrow transplantation from tolerant donors to treat and prevent autoimmune diseases in BXSB mice.
Proc Natl Acad Sci U S A.
85
1988
2235
2239
318
Yasumizu
R
Sugiura
K
Iwai
H
et al
Treatment of type 1 diabetes mellitus in non-obese diabetic mice by transplantation of allogeneic bone marrow and pancreatic tissue.
Proc Natl Acad Sci U S A.
84
1987
6555
6557
319
Ikehara
S
Ohtsuki
H
Good
RA
et al
Prevention of type I diabetes in nonobese diabetic mice by allogenic bone marrow transplantation.
Proc Natl Acad Sci U S A.
82
1985
7743
7747
320
Ikehara
S
Good
RA
Nakamura
T
et al
Rationale for bone marrow transplantation in the treatment of autoimmune diseases.
Proc Natl Acad Sci U S A.
82
1985
2483
2487
321
Ikehara
S
Yasumizu
R
Inaba
M
et al
Long-term observations of autoimmune-prone mice treated for autoimmune disease by allogeneic bone marrow transplantation.
Proc Natl Acad Sci U S A.
86
1989
3306
3310
322
Weissman
IL
Transfer of tolerance.
Transplantation.
15
1973
265
269
323
Sykes
M
Hematopoietic cell transplantation for the induction of allo- and xenotolerance.
Clin Transplant.
10
1996
357
363
324
Nakamura
T
Good
RA
Yasumizu
R
et al
Successful liver allografts in mice by combination with allogeneic bone marrow transplantation.
Proc Natl Acad Sci U S A.
83
1986
4529
4532
325
Gandy
KL
Weissman
IL
Tolerance of allogeneic heart grafts in mice simultaneously reconstituted with purified allogeneic hematopoietic stem cells.
Transplantation.
65
1998
295
304
326
Kawaharada
N
Shears
LL
2nd
Li
S
Pham
SM
Mixed hematopoietic chimerism prevents allograft vasculopathy.
J Heart Lung Transplant.
18
1999
532
541
327
Remuzzi
G
Cellular basis of long-term organ transplant acceptance: pivotal role of intrathymic clonal deletion and thymic dependence of bone marrow microchimerism-associated tolerance.
Am J Kidney Dis.
31
1998
197
212
328
George
JF
Sweeney
SD
Kirklin
JK
Simpson
EM
Goldstein
DR
Thomas
JM
An essential role for Fas ligand in transplantation tolerance induced by donor bone marrow.
Nat Med.
4
1998
333
335
329
Slavin
S
Nagler
A
Varadi
G
Or
R
Graft vs autoimmunity following allogeneic non-myeloablative blood stem cell transplantation in a patient with chronic myelogenous leukemia and severe systemic psoriasis and psoriatic polyarthritis.
Exp Hematol.
28
2000
853
857
330
Burt
RK
Traynor
A
Hematopoietic stem cell therapy of autoimmune diseases.
Curr Opin Hematol.
5
1998
472
477
331
Weiden
PL
Sullivan
KM
Fluornoy
N
et al
Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.
N Engl J Med.
304
1981
1529
1533
332
Horowitz
MM
Gale
RP
Sondel
PM
et al
Graft-versus-leukemia reactions after bone marrow transplantation.
Blood.
75
1990
555
562
333
Li
H
Kaufman
CL
Boggs
SS
Johnson
PC
Patrene
KD
Ildstad
ST
Mixed allogeneic chimerism induced by a sublethal approach prevents autoimmune diabetes and reverses insulitis in nonobese diabetic (NOD) mice.
J Immunol.
156
1996
380
388
334
Wang
B
Yamamoto
Y
El-Badri
NS
Good
RA
Effective treatment of autoimmune disease and progressive renal disease by mixed bone-marrow transplantation that establishes a stable mixed chimerism in BXSB recipient mice.
Proc Natl Acad Sci U S A.
96
1999
3012
3016
335
Wang
BY
Cherry
El-Badri
NS
Good
RA
Prevention of development of autoimmune disease in BXSB mice by mixed bone marrow transplantation.
Proc Natl Acad Sci U S A.
94
1997
12065
12069
336
Delaney
CP
Murase
N
Chen-Woan
M
Fung
JJ
Starzl
TE
Demetris
AJ
Allogeneic hematolymphoid microchimerism and prevention of autoimmune disease in the rat. A relationship between allo- and autoimmunity.
J Clin Invest.
97
1996
217
225
337
Prigozhina
T
Gurevitch
O
Slavin
S
Non-myeloblative conditioning to induce tolerance after allogeneic bone marrow transplantation in mice.
Exp Hematol.
27
1999
1503
1510
338
Weiss
L
Slavin
S
Prevention and treatment of graft vs host disease by down regulation of anti-host reactivity with veto cells of host origin.
Bone Marrow Transplant.
23
1999
1139
1143
339
Yin
JA
Jowitt
SN
Resolution of immune-mediated diseases following allogeneic bone marrow transplantation for leukaemia.
Bone Marrow Transplant.
9
1992
31
33
340
Cooley
HM
Snowden
JA
Grigg
AP
Wicks
IP
Outcome of rheumatoid arthritis and psoriasis following autologous stem cell transplantation for hematologic malignancy.
Arthritis Rheum.
40
1997
1712
1715
341
Olalla
JI
Ortin
M
Hermida
G
et al
Disappearance of lupus anticoagulant after allogeneic bone marrow transplantation.
Bone Marrow Transplant.
23
1999
83
85
342
Adkins
DR
Abidi
MH
Brown
RA
et al
Resolution of psoriasis after allogeneic bone marrow transplantation for chronic myelogenous leukemia: late complications of therapy.
Bone Marrow Transplant.
26
2000
1239
1241
343
Snowden
JA
Kearney
P
Kearney
A
et al
Long-term outcome of autoimmune disease following allogeneic bone marrow transplantation.
Arthritis Rheum.
41
1998
453
459
344
Baldwin
JL
Storb
R
Thomas
ED
Mannik
M
Bone marrow transplantation in patients with gold-induced marrow aplasia.
Arthritis Rheum.
20
1977
1043
1048
345
Jacobs
P
Vincent
MD
Martell
RW
Prolonged remission of severe refractory rheumatoid arthritis following allogeneic bone marrow transplantation for drug-induced aplastic anaemia.
Bone Marrow Transplant.
1
1986
237
239
346
Eedy
DJ
Burrows
D
Bridges
JM
Jones
FGC
Clearance of severe psoriasis after allogeneic bone marrow transplantation.
BMJ.
300
1990
908
347
Liu-Yin
JA
Jowitt
SN
Resolution of immune mediated diseases following allogeneic bone marrow transplantation for leukaemia.
Bone Marrow Transplant.
9
1992
31
33
348
Lowenthal
RM
Cohen
ML
Atkinson
K
Biggs
JC
Apparent cure of rheumatoid arthritis following bone marrow transplantation.
J Rheumatol.
20
1993
137
140
349
McKendry
RJR
Huebsch
L
Leclair
B
Progression of rheumatoid arthritis following bone marrow transplantation: a case report with a 13-year followup.
Arthritis Rheum.
39
1996
1246
1253
350
Vento
S
Cainelli
F
Renzini
C
Ghironzi
G
Concia
E
Resolution of autoimmune hepatitis after bone marrow transplantation.
Lancet.
348
1996
544
545
351
Roychoudhury
DF
Linker
CA
Pure red cell aplasia complicating an ABO-compatible allogeneic bone marrow transplantation, treated successfully with antithymocyte globulin.
Bone Marrow Transplant.
16
1995
471
472
352
Lopez-Cubero
SO
Sullivan
KM
McDonald
GB
Course of Crohn's disease after allogeneic marrow transplantation.
Gastroenterology.
114
1998
433
440
353
Nelson
JL
Torrez
R
Louie
FM
Choe
OS
Storb
R
Sullivan
KM
Pre-existing autoimmune disease in patients with long-term survival after allogeneic bone marrow transplantation.
J Rheumatol.
48(suppl)
1997
23
29
354
De Stefano
P
Zecca
M
Giorgiani
G
Perotti
C
Giraldi
E
Locatelli
F
Resolution of immune haemolytic anaemia with allogeneic bone marrow transplantation after an unsuccessful autograft.
Br J Haematol.
106
1999
1063
1064
355
Muller
BU
Tichelli
A
Passweg
JR
Nissen
C
Wodnar-Filipowicz
A
Gratwohl
A
Successful treatment of refractory acquired pure red cell aplasia (PRCA) by allogeneic bone marrow transplantation.
Bone Marrow Transplant.
23
1999
1205
1207
356
Raetz
E
Beatty
PG
Adams
RH
Treatment of severe Evans syndrome with an allogeneic cord blood transplant.
Bone Marrow Transplant.
20
1997
427
429
357
Oyama
Y
Papadopoulos
EB
Miranda
M
Traynor
A
Burt
RK
Allogeneic stem cell transplantation for Evans syndrome.
Bone Marrow Transplant.
28
2001
903
905
358
Nash
RA
Dansey
R
Storek
J
et al
Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) after high-dose immunosuppressive therapy (HDIT) and autologous CD34-selected stem cell transplantation (SCT) for severe autoimmune diseases [abstract].
Blood.
96(suppl)
2000
406a

Author notes

Richard K. Burt, Division of Immune Therapy and Autoimmune Disease, Northwestern University Medical Center, 320 E Superior, Searle Bldg, Rm 3-489, Chicago, IL 60611; e-mail:rburt@nwu.edu.

Sign in via your Institution