The last 2 years have seen much excitement in the field of genetics with the identification of a formerly unappreciated level of “structural variation” within the normal human genome. Genetic structural variants include deletions, duplications, and inversions in addition to the recently discovered, copy number variants. Single nucleotide polymorphisms are the most extensively evaluated variant within the genome to date. Combining our knowledge from these studies with our rapidly accumulating understanding of structural variants, it is apparent that the extent of genetic dissimilarity between any 2 individuals is considerable and much greater than that which was previously recognized. Clearly, this more diverse view of the genome has significant implications for allogeneic hematopoietic stem cell transplantation, not least in the generation of transplant antigens but also in terms of individual susceptibility to transplant-related toxicities. With advances in DNA sequencing technology we now have the capacity to perform genome-wide analysis in a high throughput fashion, permitting a detailed genetic analysis of patient and donor prior to transplantation. Understanding the significance of this additional genetic information and applying it in a clinically meaningful way will be one of the challenges faced by transplant clinicians in the future.

Structural variation in the human genome

Recently, much focus has been directed at documenting the extent of normal human genomic variation, particularly in the form of single nucleotide polymorphisms (SNPs; Table 1). In October 2005, phase 1 of the International Hapmap Project was published.2  This project catalogued more than one million SNPs, genome-wide, into a publicly accessible database (www.hapmap.org). Approximately 11 500 of the SNPs recorded in phase 1 are nonsynonymous coding SNPs. Other examples of genomic variation include gene deletions, inverted gene sequences, multiple copy gene duplications, segmental duplications and large-scale copy number variants (CNVs). Each of these structural variants is shown schematically in Figure 1.

Figure 1

Genomic variation definitions. (A) A single nucleotide polymorphism (SNP) occurs as a result of a single base substitution at an individual site in the DNA sequence along the chromosome. Nonsynonymous coding SNPs occur in the coding region of a gene where the alternate SNP allele results in the coding of a different amino acid. (B) A deletion is the loss/absence of DNA sequence. (C) An inversion is a rearrangement causing a segment of DNA to be present in reverse orientation. (D) A copy number variant (CNV) is a segment of DNA that is 1 kb or larger and is present at a variable copy number in comparison with a reference genome. CNVs can be either deletion variants where there is loss of copy number relative to the reference sequence or multicopy duplications where there is gain of copy number relative to the reference sample. (E) A segmental duplication is a segment of DNA at least 1 kb in size that occurs in 2 or more copies per haploid genome, with the different copies sharing at least 90% sequence identity. (F) A large-scale copy number variant is a CNV that involves a segment of DNA more than 50 kb in size.

Figure 1

Genomic variation definitions. (A) A single nucleotide polymorphism (SNP) occurs as a result of a single base substitution at an individual site in the DNA sequence along the chromosome. Nonsynonymous coding SNPs occur in the coding region of a gene where the alternate SNP allele results in the coding of a different amino acid. (B) A deletion is the loss/absence of DNA sequence. (C) An inversion is a rearrangement causing a segment of DNA to be present in reverse orientation. (D) A copy number variant (CNV) is a segment of DNA that is 1 kb or larger and is present at a variable copy number in comparison with a reference genome. CNVs can be either deletion variants where there is loss of copy number relative to the reference sequence or multicopy duplications where there is gain of copy number relative to the reference sample. (E) A segmental duplication is a segment of DNA at least 1 kb in size that occurs in 2 or more copies per haploid genome, with the different copies sharing at least 90% sequence identity. (F) A large-scale copy number variant is a CNV that involves a segment of DNA more than 50 kb in size.

Close modal
Table 1

The extent of human genomic variation

VariableValueSource
Whole genome   
    No. BPs in the human genome 3 × 109 Kruglyak and Nickerson1  
    No. SNPs in the human genome 1 × 107 Kruglyak and Nickerson1  
    No. validated HapMap SNPs 4 × 106 HapMap P2 
    No. validated HapMap exonic SNPs 7 × 104 HapMap P2 
    No. validated HapMap NS coding SNPs 3 × 104 HapMap P2 
    Estimated no. BPs affected by CNVs > 3 × 108 Redon et al101  
Individual genome   
    SNP frequency in the genome 1/300 BP Kruglyak and Nickerson1  
    Estimated no. CNVs per individual genome > 100 Feuk et al8  
VariableValueSource
Whole genome   
    No. BPs in the human genome 3 × 109 Kruglyak and Nickerson1  
    No. SNPs in the human genome 1 × 107 Kruglyak and Nickerson1  
    No. validated HapMap SNPs 4 × 106 HapMap P2 
    No. validated HapMap exonic SNPs 7 × 104 HapMap P2 
    No. validated HapMap NS coding SNPs 3 × 104 HapMap P2 
    Estimated no. BPs affected by CNVs > 3 × 108 Redon et al101  
Individual genome   
    SNP frequency in the genome 1/300 BP Kruglyak and Nickerson1  
    Estimated no. CNVs per individual genome > 100 Feuk et al8  

BP indicates base pair; SNP, single nucleotide polymorphism; NS, nonsynonymous; CNV, copy number variant; P2, phase 2.

In the year prior to the Hapmap publication, 2 landmark studies reported that large-scale CNVs are distributed widely throughout the human genome and that a high proportion of these encompass known genes.3,4  These studies were groundbreaking because they challenged the previously held view that the complete DNA sequences of any 2 individuals are 99.9% identical, the 0.1% difference being largely attributed to SNPs. Subsequently, several studies on CNVs followed,5-7  culminating in a large international study of the Hapmap population by Redon et al101  that identified more than 1400 CNVs spanning approximately 12% of the human genome. Even with this comprehensive evaluation, it is likely that this present index of CNVs is far from complete and new variants are continually being discovered.8  In 2006, 3 studies specifically characterized deletion variants in the human genome.9-11  Combined, these investigations described approximately 1000 deletions of varying size, with the majority being less than 10 000 bp. McCarroll et al identified 10 genes that appeared to be consistently deleted in a homozygous fashion, in regions overlapping coding exons of the gene.9  Over half of the CNVs documented by Redon et al101  also overlap known expressed genes.

The CNV studies indicate that genes subject to structural variation appear to be significantly enriched in immune response, chemosensation, and drug detoxification functions.4,7,10,12  Accordingly, it has been suggested that these genes may have roles in the adaptability and fitness of an organism in response to external pressures and that structural variation represents a process of adaptive evolution.8  Indeed, selection on gene copy number has been reported for CCL3L1, an immune response gene, where relatively low copy number is associated with increased susceptibility to HIV/AIDS.13  More recently, low FCGR3B copy number has been associated with increased susceptibility to immunologically mediated glomerulonephritis in patients with lupus.14 

The implications of the studies mentioned for our understanding of human genetic diversity and for disease susceptibility are considerable. In addition, these studies are significant for the field of allogeneic hematopoietic stem cell transplantation (HSCT). Nonsynonymous coding SNPs and deletion polymorphisms hold importance as ways of generating potentially immunogenic transplantation antigens. SNPs in non-HLA genes can influence immune responses. Genes subject to CNV include MHC, KIR, and the genes encoding Fc and immunoglobulin receptors. Genes involved in drug detoxification, which are prone to structural variation and are of potential relevance in HSCT, include those involved in the metabolism of busulfan (GST family), cyclophosphamide (cytochrome P450, GST family), and calcineurin inhibitors (cytochrome P450, UGT2B family). It is highly probable, therefore, that normal structural genetic variation has an impact on individual patient outcomes during HSCT.

Minor histocompatibility antigens

Minor histocompatibility antigens (mHAs) were originally described by Snell in 194815  as non-MHC genetic loci sufficient to initiate allogeneic tissue rejection in congenic mouse strains (ie animals bred to be identical at the MHC locus but disparate at other areas of the genome). In 1978, Korngold et al demonstrated that lethal graft-versus-host disease (GVHD) could occur across minor histocompatibility barriers in mice and that GVHD appeared to be mediated by T cells.16  In a seminal paper in 1990, Wallny et al demonstrated that mHAs were peptides derived from normal cellular proteins presented by self-MHC and that they were recognized by cytotoxic T lymphocytes (CTLs) in a minor histoincompatible mouse strain.17  In humans also, mHAs have been defined by allospecific CTLs obtained from individuals primed in vivo through organ or bone marrow grafting and blood transfusions18  (Table 2 provides a current list of known human mHAs). The molecular structure of a human mHA was first characterized in 1995.19,20  Although mHAs have been identified as peptide epitopes presented by MHC molecules and recognized by donor T cells, recent studies have shown that antibodies are also capable of recognizing human mHA.21  These antibodies are capable of distinguishing between recipient and donor-derived peptide sequences in soluble form21  and the presence of antibodies has been associated with chronic GVHD rather than acute GVHD.22  Because mHAs are intracellular proteins, the role of mHA antibodies as mediators of GVHD is unknown and further studies are needed to define the mechanisms by which mHA antibodies may contribute to tissue injury.

Table 2

Human mHAs

Mechanism underlying immunogenicity and nameGene/chromosomeTissue distribution
Nonsynonymous coding SNP(s)   
    HA-1 KIAA0223/19p13.3 Hematopoietic 
    HA-2 MYO1G/7p12p13 Hematopoietic 
    HA-3 LBC/15q24q25 Ubiquitous 
    HA-8 KIAA0020/9p24.2 Ubiquitous 
    HB-1 5q32 B-lymphoid cells 
    BCL2A1 BCL2A1/15q24.3 Hematopoietic 
Polymorphism with chromosome X   
    SMCY Yq11.1 Ubiquitous 
    DFFRY Yq11 Ubiquitous 
    UTY Yq11.1 Ubiquitous 
    DBY Yq11 Ubiquitous 
    RPS4Y Yp11.3 Ubiquitous 
Homozygous gene deletion   
    UGT2B17 UGT2B17/4q13 Ubiquitous 
Deletion SNP causing a frameshift   
    LRH-1 P2X5/17p13.2 Hematopoietic 
NS cSNP causing a stop codon   
    PANE1 PANE1/22q13 B-lymphoid cells 
NS cSNP in an alternatively translated peptide   
    ECGF-1 ECGF-1/22q13 Hematopoietic 
NS cSNP resulting in alternate splicing   
    SP110 SP11O/2q37 Hematopoietic 
Unconventional ORF   
    TMSB4Y Yq11 Ubiquitous 
Mechanism underlying immunogenicity and nameGene/chromosomeTissue distribution
Nonsynonymous coding SNP(s)   
    HA-1 KIAA0223/19p13.3 Hematopoietic 
    HA-2 MYO1G/7p12p13 Hematopoietic 
    HA-3 LBC/15q24q25 Ubiquitous 
    HA-8 KIAA0020/9p24.2 Ubiquitous 
    HB-1 5q32 B-lymphoid cells 
    BCL2A1 BCL2A1/15q24.3 Hematopoietic 
Polymorphism with chromosome X   
    SMCY Yq11.1 Ubiquitous 
    DFFRY Yq11 Ubiquitous 
    UTY Yq11.1 Ubiquitous 
    DBY Yq11 Ubiquitous 
    RPS4Y Yp11.3 Ubiquitous 
Homozygous gene deletion   
    UGT2B17 UGT2B17/4q13 Ubiquitous 
Deletion SNP causing a frameshift   
    LRH-1 P2X5/17p13.2 Hematopoietic 
NS cSNP causing a stop codon   
    PANE1 PANE1/22q13 B-lymphoid cells 
NS cSNP in an alternatively translated peptide   
    ECGF-1 ECGF-1/22q13 Hematopoietic 
NS cSNP resulting in alternate splicing   
    SP110 SP11O/2q37 Hematopoietic 
Unconventional ORF   
    TMSB4Y Yq11 Ubiquitous 

NS indicates nonsynonymous; cSNP, coding single nucleotide polymorphism; ORF, open reading frame.

All mHAs arise as a consequence of normal genetic variation but the mechanisms by which they occur are varied.23  Most autosomal mHAs identified thus far are generated as a result of nonsynonymous coding SNPs, which lead to differences in the amino acid sequences of homologous proteins between donor and recipient cells. Single amino acid substitutions can result in altered proteosomal cleavage, peptide transport, HLA binding or T-cell receptor (TCR) contact that ultimately triggers donor T cells to recognize these peptides as foreign. The recently identified mHA SP100 occurs as a result of alternate splicing in the proteosome.24  Autosomal mHAs may also arise when the recipient is confronted with a peptide for which there is no allelic homologue in the donor. In the single instance where this has been described in humans, immunogenicity arose as a consequence of a homozygous gene deletion in the donor, which resulted in expression of the protein in recipient cells but not in donor cells.25  Several mHAs are encoded by genes on the Y chromosome, which show significant polymorphism with homologous regions of the X chromosome. This becomes immunologically relevant in the setting of sex-mismatched transplants when male patients receive stem cell grafts from female donors.26  It has recently been demonstrated that human mHAs can also arise from cryptic polypeptides derived from noncoding regions of the genome, such as untranscribed regions (UTRs) or introns.27 

The absolute risk of acute GVHD in HLA-identical sibling transplants is approximately 40%, with the risk of chronic GVHD exceeding 50%.28  This provides strong evidence that mHAs significantly influence HSCT outcome. It has been estimated that several hundred mHAs exist in mice29  and the number in humans is likely to be at least this large. Experiments in mice indicate that a hierarchy of immunogenicity exists among mHAs, with a limited number of “immunodominant” antigens responsible for an oligoclonal T-cell response in any MHC-identical donor-recipient pair.30  Clinical studies of mHA disparity have largely been restricted to evaluations of single mHAs (most commonly HA-1) and have been limited by small patient numbers due to the fact that mHAs are HLA restricted and the frequency of mHA disparity between recipient and donor is often low (10%-15% for HA-1). A study of 148 HLA-identical sibling donor-recipient pairs showed a significant association between mismatch of HA-1 and the development of GVHD after bone marrow transplantation.31  However, this finding has not been consistently seen, with subsequent studies observing both similar32-34  and conflicting results.35-37  HA-1–specific CTLs have been demonstrated in the peripheral blood of HSCT recipients as early as 14 days after transplantation with significantly increased levels during acute GVHD.38  A study of 3 patients treated with donor lymphocyte infusion (DLI) for hematologic malignancy after allogeneic HSCT showed that a high percentage of the leukemia-reactive T cells in the recipients were directed against HA-1 or HA-2.39  Both of these studies suggest that HA-1 functions as an immunodominant mHA in the HLA-matched allogeneic setting. Male patients receiving a hematopoietic stem cell (HSC) transplant from female donors have a higher risk of GVHD and a lower incidence of leukemia relapse, implying immunodominance for at least some mHAs encoded on the Y chromosome.26  The importance of mHAs on the Y chromosome was further underscored recently with the demonstration that transplants from male donors to female recipients for aplastic anemia are associated with decreased survival as a result of increased rejection.40 

Knowledge of the molecular structure of mHAs brings with it the possibility of genotyping for these antigens, in addition to typing for HLA, prior to transplantation. In fact, the development of a liquid bead array for multiplexed genotyping of the mHAs, HA-1, HA-2, HA-3, HA-8, and HB-1, was recently described.41  With the increased frequency of matched unrelated transplantations, mHAs are likely to become increasingly relevant in selecting an optimal HSC donor because a choice among multiple potential donors often occurs in the matched unrelated setting. Clearly, however, before typing for mHAs becomes part of the routine transplantation evaluation, we need to identify additional human mHAs and ultimately establish a core set of “immunodominant” mHAs with maximal clinical relevance. In the meantime, preferentially choosing male donors for male recipients is appropriate.

Homozygous gene deletions are also a potential source of mHAs. UGT2B17, identified as homozygously deleted in 30% of individuals of European ancestry,9  has been recognized as an mHA in the setting of HSCT.25  A Japanese study of 435 HSC recipients and their HLA-matched unrelated donors found that UGT2B17 was homozygously deleted in 85% of the donors and 82% of recipients.42  However, there was no significant association between UGT2B17 mismatch in the GVHD direction and incidence of acute or chronic GVHD, relapse, or survival. The authors suggested that this may be a result of absent processing or presentation of UGT2B17 peptides on the cell surface or homology between UGT2B17 and other UGT2B family members resulting in overlapping substrate specificity. The same group reported similar findings when they investigated 2 additional genes, GSTM1 and GSTT1, in 373 HLA-matched unrelated HSCT pairs.43 GSTM1 and GSTT1 were also identified as homozygous null at appreciable frequency in the Hapmap population.9  GSTT1 has been identified as a potential alloantigen mediating de novo immune hepatitis in liver transplant recipients who are homozygous null for the gene, but receive a GSTT1+ graft.44  Six of the 10 exonic gene deletions described by McCarroll et al were determined to be homozygous null in 30% or greater of the European/North American Hapmap population. Redon et al101  recently documented 33 homozygous deletions genome-wide, 8 of which involved expressed genes.

As the number of known clinically important mHAs expands, their relevance for clinical practice will increase. One promising application of mHAs is in the field of cellular immunotherapy. The mHAs whose tissue distribution is limited to hematopoietic cells provide candidate target antigens for adoptive immunotherapy of leukemia, lymphoma, and myeloma.45  Fontaine et al demonstrated in mice that CTLs primed against a single MHC class I-restricted immunodominant mHA could eradicate leukemia cells without causing GVHD.46  In humans, Dickinson et al determined that CTLs specific for mHAs whose expression was limited to hematopoietic cells induced no or low GVH reactions.47  In the clinical setting, CTLs recognizing the mHAs, HA-1 and HA-2, on the recipient's hematopoietic cells coincide with the development of complete disease remission and restoration of 100% donor chimerism after DLI.48  Recently, an in vivo translational mouse model was used to show that CTLs specific for a single mHA, HA-1, could eradicate leukemia, thus providing direct evidence of the in vivo antileukemic effects of HA-1–specific CTLs.49  The generation of mHA-specific CTLs from the stem cell donor ex vivo as a potential therapy for relapsed leukemia has been explored.50  It may also be possible to generate mHA-specific CTLs ex vivo from umbilical cord blood.51  Another potential therapeutic strategy is to use mHA peptides to vaccinate either patients after HSCT or donors prior to transplantation,52  in an attempt to augment the donor graft-versus-leukemia (GVL) response. The immunotherapeutic potential of tissue-restricted mHAs underlies the importance of identifying additional members of this group. In fact, in the last 6 months, 3 such mHAs, each with immunotherapeutic potential in chronic myelogenous leukemia (CML),53  chronic lymphocytic leukemia (CLL),54  and myeloma,55  respectively, have been discovered.

Although we know from syngeneic transplants that antigen disparity between host and donor is essential for the development of GVHD, the pathophysiology of the disease is complex. It is now generally accepted that the development of acute GVHD can be summarized into a 3-phase process.56  In phase 1 the conditioning regimen causes host tissue damage resulting in activation of inflammatory cytokines. In this inflammatory milieu there is increased expression of MHC and adhesion molecules leading to enhanced recognition of alloantigens by donor T cells, resulting in their activation and proliferation. In the final phase, T cells induce further target tissue damage through cell-mediated cytotoxicity. In this model, inflammatory cytokines play a key role. It is now well established that many of the genes encoding cytokines are polymorphic and polymorphisms in these genes and in genes associated with innate immune response are among those most extensively studied in HSCT. It has been suggested that polymorphisms in these immune effector genes may be as important as the degree of HLA mismatch in determining GVHD severity and that typing for such allelic polymorphisms may, in the future, be an important consideration when selecting an HSCT donor.57 

Cytokine polymorphisms

A wide range of cytokine gene polymorphisms have been studied in the context of HSCT, including polymorphisms in IL10, TNF, IFNG, IL6, IL1, and TGFB1 (reviewed by Dickinson et al58 ). Typically, studies have focused on SNPs in regulatory regions of these genes because these regions may influence the amount of cytokine produced at a steady state or after stimulation. Most of these studies have been performed at single institutions in patients who received stem cells from HLA-matched siblings after myeloablative conditioning. The majority have attempted to correlate SNP genotype with risk of acute GVHD.

The largest study (almost 1000 patient-donor pairs) was performed by Lin et al who found that the presence of an SNP in the promoter region of the recipient's IL10 gene was significantly associated with a decreased risk of severe acute GVHD and death after HSCT.59  A haplotype analysis showed that the IL-10 SNP in question was a specific marker for a particular IL-10 promoter haplotype. The authors hypothesized that the presence of this haplotype in the recipient caused increased IL-10 production and reduced GVHD-induced inflammation, although IL-10 levels were not measured in the study. This group has recently evaluated a nonsynonymous coding SNP in the IL10RB gene in the same cohort of patient-donor pairs.60  On this occasion they found that the presence of this SNP in the donor was associated with a reduced incidence of severe acute GVHD, suggesting that genetic regulation of the IL-10 pathway plays a role in the development of acute GVHD. The functional significance of the IL-10RB SNP is currently unknown.

These 2 studies are among the best conducted in this area in that they evaluated a large sample population, they studied both donors and recipients, they investigated a homogenous population (HLA-identical siblings, T cell–replete transplants, identical GVH prophylaxis regimens), and at least in the first study, an attempt was made to validate results in an independent cohort (low frequency of the SNP of interest ultimately precluded this). Yet, they also serve as a striking illustration of the problems encountered within this area of research.

Perhaps the greatest weakness of these studies is the absence of a clear understanding of the biologic significance of the findings. In their original study Lin et al showed that the presence of the IL-10-592A/A genotype was a specific marker for a particular haplotype, which they proposed was associated with high IL-10 production. However, earlier studies had suggested increased IL-10 production with the alternative IL-10-592C/C genotype in autologous GVHD.61  As mentioned previously IL-10 levels were not measured in the initial Lin study. Had they been checked and found to be high (as predicted), this finding would have been at odds with 2 earlier (albeit much smaller studies) showing an association between high IL-10 levels after HSCT and more severe acute GVHD62  and increased mortality.63 

Recently, high recipient IL-10 mRNA levels in peripheral blood mononuclear cells on day +14 after nonmyeloablative HSCT were found to be associated with a reduced incidence of acute GVHD.64  This finding is in keeping with an earlier study showing that high endogenous IL-10 production prior to myeloablative HSCT is protective against acute GVHD.65  The cytokine-releasing profile of donor cells in response to recipient alloantigen stimulation has been shown to correlate with the development of acute GVHD, with a high frequency of donor cells producing IL-10 associated with the absence of acute GVHD after myeloablative HSCT.66  In contrast to the studies noted previously,62,63  these studies suggest that higher levels of IL-10 in the peritransplantation period confer protection against the subsequent development of GVHD.

At the time of the Lin study it was suggested that IL-10 genotyping be included as part of the standard evaluation of a patient being considered for HSCT from an HLA-identical sibling donor.67  Clearly, given the biologic complexity of IL-10, we need a much better understanding of the functional significance of immune polymorphisms in this gene before this recommendation can be incorporated into clinical practice. As has been suggested by others, we also need a more extensive evaluation of as many genetic polymorphisms as possible, in larger numbers of patients, so that the most informative variants, predictive of outcome are identified.68 

Polymorphisms in innate immunity genes

Although highly conserved across a wide range of species, innate immunity genes demonstrate substantial interindividual variability predominantly in the form of SNPs.69  The nucleotide oligomerization domain 2 gene (NOD2) encodes a protein involved in the immune response to intracellular bacterial lipopolysaccharides (LPS). In 2001, NOD2 was identified as the first “susceptibility” gene for inflammatory bowel disease (IBD).70,71  Clinical evidence indicates that the innate immune system contributes to the development of acute GVHD through its response to the translocation of bacterial toxins across the gastrointestinal mucosa.72  Indeed, LPS antagonism has been shown to reduce GVHD severity in a mouse model.73  In this context, polymorphisms in NOD2 have been evaluated in the setting of HSCT. Holler at al recently demonstrated a significant association between the presence of SNPs in NOD2 and the development of severe acute GVHD, higher transplant-related mortality (TRM), and reduced survival after transplantation.74 

A number of genetic polymorphisms in innate immunity genes have been evaluated for an association with risk of infection after HSCT. For example, mannose-binding lectin (MBL2) is a pathogen recognition molecule that activates complement independently of specific antibody. As a result of MBL2 polymorphism, MBL levels vary up to 1000-fold in an unselected population, with coding mutation homozygotes having negligible functional MBL activity.75  Mullighan et al found that MBL2-coding polymorphisms associated with low MBL levels were linked to a high risk of major infections after HSCT, and that MBL2 promoter polymorphisms associated with high blood levels of MBL were protective.76  Rocha et al observed that donor myeloperoxidase (MPO) genotype influenced the incidence of severe bacterial infection after HSCT.77  MPO is a lysosomal protein responsible for the microbicidal activity of polymorphonuclear leukocytes (PMNs). In addition, they noted that recipients with a coding polymorphism in FcγRIIa (CD32) had an increased incidence of first severe infection of any type. FcγRIIa is a cell surface receptor found on PMNs, dendritic cells, and endothelial cells. Interestingly, FcγRIIa is also expressed on the surface of acute myeloid leukemia (AML) cells, leading to its evaluation as a potential mHA. A retrospective study of 73 AML patients and their donors found a clear association between FcγRIIa mismatch and acute GVHD with no significant effect on relapse or overall survival.78  Finally, polymorphisms in the bactericidal/permeability-increasing (BPI) gene were recently noted to be significantly associated with the risk of developing bronchiolitis obliterans after HSCT.79  BPI belongs to a family of lipid transport proteins that have a critical role in the innate immune response to bacterial infection.

Natural killer (NK) cells are innate immune lymphocytes that recognize self-MHC class I through a unique class of receptors, NK cell receptors (NKRs). The killer cell immunoglobulin-like receptor (KIR) family of NKRs comprises 2 functionally distinct sets: inhibitory and activating. NK cell responses occur as a result of competing signals mediated through these inhibitory and activating receptors. In general, it appears that inhibitory KIRs have a greater affinity for the corresponding HLA class I alleles than do the activating KIRs.80  Variations in gene content, gene copy number, and allelic polymorphism within individual KIR genes result in significant diversity in KIR haplotypes between individuals81  (Figure 2). The KIR gene locus comprises 15 genes in total. Some of these genes are present on all haplotypes, whereas the presence/absence of others varies with the haplotype. Individual genes present on a particular haplotype may differ in copy number and further diversity exists as a result of polymorphisms within distinct KIR genes. The KIR (chromosome 19) and HLA genes (chromosome 6) segregate independently of each other in a conventional mendelian inheritance pattern. KIR genotype is the dominant factor determining the repertoire of KIR expression on NK cells, that is, the influence of HLA genotype on NK cell KIR expression is subordinate to that of KIR.82  The impact of HLA is to change the frequency of KIR-expressing cells in the NK repertoire. In this way, HLA class I genotype imposes selection during normal development such that NK cells expressing inhibitory KIRs specific for autologous HLA class I become relatively increased in number.

Figure 2

KIR variability. (A) The KIR gene locus on chromosome 19 consists of 15 genes and 2 pseudogenes (shown in blue). Three conserved “framework” genes are located one at either end and one in the middle of the locus (red). These are present on all haplotypes and are inhibitory. The regions between the framework genes (between the brackets) contain a variable number of activating (green) and inhibitory (pink) KIR genes. Based on gene content KIR haplotypes have been divided into 2 primary sets: A and B. (B) Most group A haplotypes have the gene organization shown here. They contain the least genes and only a single activating KIR, 2DS4. (C) Group B haplotypes display a much greater variety of subtypes than group A. Two examples of at least 20 currently reported B haplotypes are shown here. An individual's KIR genotype is the sum of 2 haplotypes, one from each parent. (D) Multiple copies of the same KIR gene have been identified in single individuals as shown here for 2DL4. (E) Further diversification of KIR haplotypes occurs as a result of allelic polymorphism within individual genes. This is a prominent feature of group A haplotypes and 3 possible separate haplotypes arising as a result of polymorphisms within the 2DL3, 2DL1, 3DL1, and 3DL2 genes are shown here. More than 20 group A haplotypes emerging as a result of allelic polymorphism have been described. (Figure reproduced by kind permission of Dr Steven Marsh, Anthony Nolan Research Institute, London, from the IPD-KIR database [www.ebi.ac.uk/ipd/kir/introduction.html]).

Figure 2

KIR variability. (A) The KIR gene locus on chromosome 19 consists of 15 genes and 2 pseudogenes (shown in blue). Three conserved “framework” genes are located one at either end and one in the middle of the locus (red). These are present on all haplotypes and are inhibitory. The regions between the framework genes (between the brackets) contain a variable number of activating (green) and inhibitory (pink) KIR genes. Based on gene content KIR haplotypes have been divided into 2 primary sets: A and B. (B) Most group A haplotypes have the gene organization shown here. They contain the least genes and only a single activating KIR, 2DS4. (C) Group B haplotypes display a much greater variety of subtypes than group A. Two examples of at least 20 currently reported B haplotypes are shown here. An individual's KIR genotype is the sum of 2 haplotypes, one from each parent. (D) Multiple copies of the same KIR gene have been identified in single individuals as shown here for 2DL4. (E) Further diversification of KIR haplotypes occurs as a result of allelic polymorphism within individual genes. This is a prominent feature of group A haplotypes and 3 possible separate haplotypes arising as a result of polymorphisms within the 2DL3, 2DL1, 3DL1, and 3DL2 genes are shown here. More than 20 group A haplotypes emerging as a result of allelic polymorphism have been described. (Figure reproduced by kind permission of Dr Steven Marsh, Anthony Nolan Research Institute, London, from the IPD-KIR database [www.ebi.ac.uk/ipd/kir/introduction.html]).

Close modal

In the setting of allogeneic HSCT, the importance of KIR inhibitory receptors was first demonstrated in HLA haplotype-mismatched transplant recipients. In a subset of these patients, donor NK cell clones could not engage their class I inhibitory ligand as it was absent in the recipient, as a result of donor-recipient mismatch at the HLA class I group, resulting in the development of NK cell alloreactivity against host cells.83,84  Because NK cell alloreactivity appears to target primarily lymphohematopoietic cells, a remarkable GVL effect was observed (at least in patients with AML) in these early studies, and it occurred in the absence of GVHD. In a follow-up study by the same group donor-versus-recipient NK cell alloreactivity did not effect the rate of relapse in patients with AML.85  The original Perugia studies defined KIR ligand incompatibility in the GVL direction as absence in recipients of HLA class I epitopes present in the donor, that is, the “ligand-ligand” model. More recently, a pediatric haploidentical transplantation study demonstrated improved accuracy in predicting relapse by evaluating the KIR repertoire of the donor in addition to HLA genotyping the recipient, that is, “receptor-ligand” model.86  In this model, potential NK alloreactivity is present if the recipient does not have HLA class I alleles for any of the donor's inhibitory KIR. The potency of the antileukemic effect increased as the number of receptor-ligand mismatch pairs rose suggesting that a donor with more mismatched pairs may be a better donor. Leung et al also demonstrated that KIR expression on NK cells derived from donor CD34+ cells always adopted a donor-specific pattern within 3 months of HSCT, despite the fact that transplantation had occurred into an HLA-disparate recipient. This suggests that a mismatched donor could be selected on the basis of a single evaluation of donor KIR repertoire prior to transplantation.

Because the genes that encode HLA and KIR segregate independently, the likelihood of KIR disparity approaches 100% in allogeneic HSCT between unrelated individuals and exceeds 75% between family members regardless of HLA identity.82  This suggests that NK alloreactivity can occur in HLA-identical sibling transplants if the recipient lacks an HLA ligand for the donor's inhibitory KIR. For NK alloreactivity to occur in this setting, an NK clone with autoreactive potential present in the donor (lacking self-HLA class I ligand) would have to expand in the recipient after HSCT. NK cells with autoreactive potential have been observed at low frequency in the blood of healthy donors.81  Recently, these NK cells have been demonstrated to be capable of exerting cytotoxic activity against autologous CD34+ HSCs, although it has been speculated that in healthy individuals these cells remain quiescent and thus are not overtly autoreactive.87  Hsu et al demonstrated in a study of 178 T cell-depleted (TCD) HLA-identical sibling transplants that more than 60% of the pairs exhibited missing KIR ligand in the recipient, that this resulted in an increased overall survival in the patients who received transplants for AML or myelodysplastic syndrome (MDS), and that the increased overall survival occurred as a result of a decrease in disease relapse.88  The potential clinical significance of activating KIRs in autoimmune disease is just beginning to receive attention, where it has been shown that the presence of an activating KIR in the absence of the ligand for its inhibitory counterpart is associated with an increased susceptibility to psoriatic arthritis.89  This prompted Verheyden et al to evaluate the role of activating KIRs in 65 HLA-identical sibling transplant pairs (34 TCD).90  They found that the presence of 2 activating KIRs, 2DS1 and 2DS2, in the donor was significantly associated with a decreased leukemic relapse rate, but this did not appear to be mediated through an HLA ligand interaction.

Overall, these studies suggest that genotyping for KIR to predict NK alloreactivity and optimize donor selection may be useful in the mismatched, unrelated, and sibling transplant settings. Further investigation in this area is needed, however, because the results to date have not been uniformly consistent.

Our increasing knowledge of genetic variability has seen a rapid expansion in the field of pharmacogenomics. The folate metabolism pathway, and more specifically, a key regulatory enzyme in this pathway, methylenetetrahydrofolate reductase (MTHFR), have received the most attention in the HSCT arena. Two nonsynonymous SNPs in the MTHFR gene result in reduced enzymatic activity. The C677T polymorphism results in an alanine-to-valine substitution at codon 222, with the variant TT genotype producing an enzyme with approximately 30% of the activity of the wild-type CC genotype, with heterozygotes (CT) possessing about 60% of normal enzymatic activity.91  The A1298C polymorphism causes alanine to be replaced by glutamic acid at codon 429, leading to reduced MTHFR activity, but to a lesser extent than that seen with C677T.92  Methotrexate (MTX) exerts its cytotoxic effect by inhibiting dihydrofolate reductase (DHFR) and other related enzymes of folate metabolism, including MTHFR.

The C677T polymorphism was first evaluated in 220 patients with CML who received a myeloablative HSCT and MTX for GVHD prophylaxis.93  After controlling for other risk factors, recipients with lower MTHFR activity (TT genotype) were found to have experienced higher MTX toxicity, as evidenced by increased oral mucositis and a trend toward delayed platelet recovery. Recently, Robien et al performed expanded genotyping of additional genes in the folate pathway and again found the MTHFR 677TT genotype to be associated with higher rates of mucositis, as was a deletion polymorphism in the thymidylate synthase (TS) gene.94 

Polymorphisms of the glutathione S-transferase (GST) family of genes have also been investigated in the setting of HSCT. The major route of detoxification of busulfan is through conjugation with glutathione (GSH) which is catalyzed by the GST enzymes. A recent study of pediatric patients undergoing myeloablative HSCT for β-thalassemia found a significantly increased incidence of hepatic veno-occlusive disease (VOD) in patients with the GSTM1 null genotype compared with those with the GSTM1+ genotype.95  In this study, patients with the GSTM1 null genotype showed a significantly higher clearance and a lower steady-state concentration of busulfan after the first dose compared with those with a positive genotype. The authors proposed that this faster rate of busulfan metabolism depleted the GSH pool, allowing the busulfan metabolites generated to damage the sinusoidal endothelial cells and hepatocytes of the liver, culminating in the development of hepatic VOD.

As we delve deeper into the human genome, it is clear that the extent of normal variation therein is considerable. Genetic heterogeneity has an impact on HSCT by generating host-donor antigen disparity and by providing functional polymorphisms that may influence individual patient responses. Identifying additional clinically relevant transplant antigens is a priority because of the therapeutic possibilities and the potential for improved donor selection. Genotyping for KIR as a means to predict NK cell alloreactivity is also becoming increasingly relevant.

Investigation of functional genetic polymorphisms is an area of expanding interest within the field. Other genes which have been evaluated in this regard and which were not included in this review include VDR,58 ACE,96 CPSI,96  and HFE.96  The existing studies in this domain have a number of limitations, not least being that the biologic significance of the genetic polymorphisms in these genes remains largely unknown. Almost all of these analyses have assessed a limited number of arbitrarily chosen SNPs in a single or limited number of genes. In this setting, the influence of SNPs in neighboring genes is unclear. Evaluation of candidate gene pathways using a linkage disequilibrium approach targeting SNPs in a particular haplotype is a more rational and recently applied method of investigation in this area.79  Similarly unclear are the importance of SNPs determined to be of significance in individual studies, relative to that of SNPs identified in other studies. In fact, many studies have demonstrated conflicting results. Also, many polymorphic genes known to play an important role in the immune response have never been evaluated in the context of HSCT (eg, CTLA4,97 FOXP398 ). The recent appreciation of the extent of undiscovered structural variation within the genome adds a further layer of complexity to the situation.

We now possess the ability to perform large scale SNP genotyping using high throughput technologies such as microarrays,99  pyrosequencing,100  and liquid bead arrays.41  In the future, evaluation before transplantation is likely to comprise a more detailed genetic analysis of patient and donor with the ultimate goal of individualized patient treatment based on predictive risk scoring. Before this goal can be realized we need a more comprehensive examination of multiple genomic variants, undertaken in a prospective fashion, with validation in independent HSCT populations. Understanding the biologic and clinical implications of the findings will be the challenge we confront in the postgenomic era.

Contribution: A.M. designed the format of the article and wrote the draft; and J.R. critically reviewed and edited the text, tables, and figures.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Jerome Ritz, MD, Dana-Farber Cancer Institute, 44 Binney St, Mayer 530, Boston, MA 02115; e-mail:jerome_ritz@dfci.harvard.edu.

This work was supported by the Ted and Ilene Pasquarello Research Fund.

1
Kruglyak L and Nickerson DA. Variation is the spice of life.
Nat Genet
2001
;
27
:
234
–236.
2
Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P. A haplotype map of the human genome.
Nature
2005
;
437
:
1299
–1320.
3
Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome.
Nat Genet
2004
;
36
:
949
–951.
4
Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome.
Science
2004
;
305
:
525
–528.
5
Fredman D, White SJ, Potter S, Eichler EE, Den Dunnen JT, Brookes AJ. Complex SNP-related sequence variation in segmental genome duplications.
Nat Genet
2004
;
36
:
861
–866.
6
Sharp AJ, Locke DP, McGrath SD, et al. Segmental duplications and copy-number variation in the human genome.
Am J Hum Genet
2005
;
77
:
78
–88.
7
Tuzun E, Sharp AJ, Bailey JA, et al. Fine-scale structural variation of the human genome.
Nat Genet
2005
;
37
:
727
–732.
8
Feuk L, Carson AR, Scherer SW. Structural variation in the human genome.
Nat Rev Genet
2006
;
7
:
85
–97.
9
McCarroll SA, Hadnott TN, Perry GH, et al. Common deletion polymorphisms in the human genome.
Nat Genet
2006
;
38
:
86
–92.
10
Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK. A high-resolution survey of deletion polymorphism in the human genome.
Nat Genet
2006
;
38
:
75
–81.
11
Hinds DA, Kloek AP, Jen M, Chen X, Frazer KA. Common deletions and SNPs are in linkage disequilibrium in the human genome.
Nat Genet
2006
;
38
:
82
–85.
12
Nguyen DQ, Webber C, Ponting CP. Bias of selection on human copy-number variants.
PLoS Genet
2006
;
2
:
e20
.
13
Gonzalez E, Kulkarni H, Bolivar H, et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility.
Science
2005
;
307
:
1434
–1440.
14
Aitman TJ, Dong R, Vyse TJ, et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans.
Nature
2006
;
439
:
851
–855.
15
Snell GD. Methods for the study of histocompatibility genes.
J Genet
1948
;
49
:
87
–103.
16
Korngold B and Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice: prevention by removing mature T cells from marrow.
J Exp Med
1978
;
148
:
1687
–1698.
17
Wallny HJ and Rammensee HG. Identification of classical minor histocompatibility antigen as cell-derived peptide.
Nature
1990
;
343
:
275
–278.
18
Goulmy E. Human minor histocompatibility antigens.
Curr Opin Immunol
1996
;
8
:
75
–81.
19
den Haan JM, Sherman NE, Blokland E, et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen.
Science
1995
;
268
:
1476
–1480.
20
Wang W, Meadows LR, den Haan JM, et al. Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein.
Science
1995
;
269
:
1588
–1590.
21
Zorn E, Miklos DB, Floyd BH, et al. Minor histocompatibility antigen DBY elicits a coordinated B and T cell response after allogeneic stem cell transplantation.
J Exp Med
2004
;
199
:
1133
–1142.
22
Miklos DB, Kim HT, Miller KH, et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission.
Blood
2005
;
105
:
2973
–2978.
23
Roopenian D, Choi EY, Brown A. The immunogenomics of minor histocompatibility antigens.
Immunol Rev
2002
;
190
:
86
–94.
24
Warren EH, Vigneron NJ, Gavin MA, et al. An antigen produced by splicing of noncontiguous peptides in the reverse order.
Science
2006
;
313
:
1444
–1447.
25
Murata M, Warren EH, Riddell SR. A human minor histocompatibility antigen resulting from differential expression due to a gene deletion.
J Exp Med
2003
;
197
:
1279
–1289.
26
Randolph SS, Gooley TA, Warren EH, Appelbaum FR, Riddell SR. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants.
Blood
2004
;
103
:
347
–352.
27
Torikai H, Akatsuka Y, Miyazaki M, et al. A novel HLA-A*3303-restricted minor histocompatibility antigen encoded by an unconventional open reading frame of human TMSB4Y gene.
J Immunol
2004
;
173
:
7046
–7054.
28
Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials.
J Clin Oncol
2005
;
23
:
5074
–5087.
29
Bailey DW. Four approaches to estimating number of histocompatibility loci.
Transplant Proc
1970
;
2
:
32
–38.
30
Yin L, Poirier G, Neth O, Hsuan JJ, Totty NF, Stauss HJ. Few peptides dominate cytotoxic T lymphocyte responses to single and multiple minor histocompatibility antigens.
Int Immunol
1993
;
5
:
1003
–1009.
31
Goulmy E, Schipper R, Pool J, et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation.
N Engl J Med
1996
;
334
:
281
–285.
32
Tseng LH, Lin MT, Hansen JA, et al. Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation.
Blood
1999
;
94
:
2911
–2914.
33
Gallardo D, Arostegui JI, Balas A, et al. Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation.
Br J Haematol
2001
;
114
:
931
–936.
34
Socie G, Loiseau P, Tamouza R, et al. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.
Transplantation
2001
;
72
:
699
–706.
35
Lin MT, Gooley T, Hansen JA, et al. Absence of statistically significant correlation between disparity for the minor histocompatibility antigen-HA-1 and outcome after allogeneic hematopoietic cell transplantation.
Blood
2001
;
98
:
3172
–3173.
36
Murata M, Emi N, Hirabayashi N, et al. No significant association between HA-1 incompatibility and incidence of acute graft-versus-host disease after HLA-identical sibling bone marrow transplantation in Japanese patients.
Int J Hematol
2000
;
72
:
371
–375.
37
Tait BD, Maddison R, McCluskey J, et al. Clinical relevance of the minor histocompatibility antigen HA-1 in allogeneic bone marrow transplantation between HLA identical siblings.
Transplant Proc
2001
;
33
:
1760
–1761.
38
Mutis T, Gillespie G, Schrama E, Falkenburg JH, Moss P, Goulmy E. Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease.
Nat Med
1999
;
5
:
839
–842.
39
Kloosterboer FM, van Luxemburg-Heijs SA, van Soest RA, et al. Direct cloning of leukemia-reactive T cells from patients treated with donor lymphocyte infusion shows a relative dominance of hematopoiesis-restricted minor histocompatibility antigen HA-1 and HA-2 specific T cells.
Leukemia
2004
;
18
:
798
–808.
40
Stern M, Passweg JR, Locasciulli A, et al. Influence of donor/recipient sex matching on outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia.
Transplantation
2006
;
82
:
218
–226.
41
Pietz BC, Warden MB, Duchateau BK, Ellis TM. Multiplex genotyping of human minor histocompatibility antigens.
Hum Immunol
2005
;
66
:
1174
–1182.
42
Terakura S, Murata M, Nishida T, et al. A UGT2B17-positive donor is a risk factor for higher transplant-related mortality and lower survival after bone marrow transplantation.
Br J Haematol
2005
;
129
:
221
–228.
43
Terakura S, Murata M, Nishida T, et al. Increased risk for treatment-related mortality after bone marrow transplantation in GSTM1-positive recipients.
Bone Marrow Transplant
2006
;
37
:
381
–386.
44
Aguilera I, Sousa JM, Gavilan F, Bernardos A, Wichmann I, Nunez-Roldan A. Glutathione S-transferase T1 mismatch constitutes a risk factor for de novo immune hepatitis after liver transplantation.
Liver Transpl
2004
;
10
:
1166
–1172.
45
Wu CJ and Ritz J. Induction of tumor immunity following allogeneic stem cell transplantation.
Adv Immunol
2006
;
90
:
133
–173.
46
Fontaine P, Roy-Proulx G, Knafo L, Baron C, Roy DC, Perreault C. Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease.
Nat Med
2001
;
7
:
789
–794.
47
Dickinson AM, Wang XN, Sviland L, et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens.
Nat Med
2002
;
8
:
410
–414.
48
Marijt WA, Heemskerk MH, Kloosterboer FM, et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia.
Proc Natl Acad Sci U S A
2003
;
100
:
2742
–2747.
49
Hambach L, Nijmeijer BA, Aghai Z, et al. Human cytotoxic T lymphocytes specific for a single minor histocompatibility antigen HA-1 are effective against human lymphoblastic leukaemia in NOD/scid mice.
Leukemia
2006
;
20
:
371
–374.
50
Mutis T, Blokland E, Kester M, Schrama E, Goulmy E. Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation.
Blood
2002
;
100
:
547
–552.
51
Mommaas B, Stegehuis-Kamp JA, van Halteren AG, et al. Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1.
Blood
2005
;
105
:
1823
–1827.
52
Rice J, Dunn S, Piper K, Buchan SL, Moss PA, Stevenson FK. DNA fusion vaccines induce epitope-specific cytotoxic CD8(+) T cells against human leukemia-associated minor histocompatibility antigens.
Cancer Res
2006
;
66
:
5436
–5442.
53
de Rijke B, van Horssen-Zoetbrood A, Beekman JM, et al. A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia.
J Clin Invest
2005
;
115
:
3506
–3516.
54
Brickner AG, Evans AM, Mito JK, et al. The PANE1 gene encodes a novel human minor histocompatibility antigen that is selectively expressed in B-lymphoid cells and B-CLL.
Blood
2006
;
107
:
3779
–3786.
55
Slager EH, Honders MW, van der Meijden ED, et al. Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer.
Blood
2006
;
107
:
4954
–4960.
56
Reddy P and Ferrara JL. Immunobiology of acute graft-versus-host disease.
Blood Rev
2003
;
17
:
187
–194.
57
Allen RD. The new genetics of bone marrow transplantation.
Genes Immun
2000
;
1
:
316
–320.
58
Dickinson AM, Middleton PG, Rocha V, Gluckman E, Holler E. Genetic polymorphisms predicting the outcome of bone marrow transplants.
Br J Haematol
2004
;
127
:
479
–490.
59
Lin MT, Storer B, Martin PJ, et al. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation.
N Engl J Med
2003
;
349
:
2201
–2210.
60
Lin MT, Storer B, Martin PJ, et al. Genetic variation in the IL-10 pathway modulates severity of acute graft-versus-host disease following hematopoietic cell transplantation: synergism between IL-10 genotype of patient and IL-10 receptor beta genotype of donor.
Blood
2005
;
106
:
3995
–4001.
61
Miura Y, Thoburn CJ, Bright EC, Chen W, Nakao S, Hess AD. Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon gamma may be critical mediators for the development of autologous GVHD.
Blood
2002
;
100
:
2650
–2658.
62
Takatsuka H, Takemoto Y, Okamoto T, et al. Predicting the severity of graft-versus-host disease from interleukin-10 levels after bone marrow transplantation.
Bone Marrow Transplant
1999
;
24
:
1005
–1007.
63
Hempel L, Korholz D, Nussbaum P, Bonig H, Burdach S, Zintl F. High interleukin-10 serum levels are associated with fatal outcome in patients after bone marrow transplantation.
Bone Marrow Transplant
1997
;
20
:
365
–368.
64
Petersen SL, Madsen HO, Ryder LP, Svejgaard A, Dickmeiss E, Vindelov LL. Cytokine gene expression in peripheral blood mononuclear cells and alloreactivity in hematopoietic cell transplantation with nonmyeloablative conditioning.
Biol Blood Marrow Transplant
2006
;
12
:
48
–60.
65
Holler E, Roncarolo MG, Hintermeier-Knabe R, et al. Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation.
Bone Marrow Transplant
2000
;
25
:
237
–241.
66
Weston LE, Geczy AF, Briscoe H. Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD.
Bone Marrow Transplant
2006
;
37
:
207
–212.
67
Cooke KR and Ferrara JL. A protective gene for graft-versus-host disease.
N Engl J Med
2003
;
349
:
2183
–2184.
68
Mullighan CG and Bardy P. Advances in the genomics of allogenic haemopoietic stem cell transplantation.
Drug Dev Res
2004
;
62
:
273
–292.
69
Lazarus R, Vercelli D, Palmer LJ, et al. Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease.
Immunol Rev
2002
;
190
:
9
–25.
70
Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.
Nature
2001
;
411
:
599
–603.
71
Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.
Nature
2001
;
411
:
603
–606.
72
Beelen DW, Haralambie E, Brandt H, et al. Evidence that sustained growth suppression of intestinal anaerobic bacteria reduces the risk of acute graft-versus-host disease after sibling marrow transplantation.
Blood
1992
;
80
:
2668
–2676.
73
Cooke KR, Gerbitz A, Crawford JM, et al. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation.
J Clin Invest
2001
;
107
:
1581
–1589.
74
Holler E, Rogler G, Brenmoehl J, et al. Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination.
Blood
2006
;
107
:
4189
–4193.
75
Mullighan CG and Bardy PG. Mannose-binding lectin and infection following allogeneic hemopoietic stem cell transplantation.
Leuk Lymphoma
2004
;
45
:
247
–256.
76
Mullighan CG, Heatley S, Doherty K, et al. Mannose-binding lectin gene polymorphisms are associated with major infection following allogeneic hemopoietic stem cell transplantation.
Blood
2002
;
99
:
3524
–3529.
77
Rocha V, Franco RF, Porcher R, et al. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation.
Blood
2002
;
100
:
3908
–3918.
78
van der Straaten HM, Fijnheer R, Nieuwenhuis HK, van de Winkel JG, Verdonck LF. The FcgammaRIIa-polymorphic site as a potential target for acute graft-versus-host disease in allogeneic stem cell transplantation.
Biol Blood Marrow Transplant
2005
;
11
:
206
–212.
79
Chien JW, Zhao LP, Hansen JA, Fan WH, Parimon T, Clark JG. Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation.
Blood
2006
;
107
:
2200
–2207.
80
Vales-Gomez M, Reyburn HT, Mandelboim M, Strominger JL. Kinetics of interaction of HLA-C ligands with natural killer cell inhibitory receptors.
Immunity
1998
;
9
:
337
–344.
81
Uhrberg M, Valiante NM, Shum BP, et al. Human diversity in killer cell inhibitory receptor genes.
Immunity
1997
;
7
:
753
–763.
82
Shilling HG, Young N, Guethlein LA, et al. Genetic control of human NK cell repertoire.
J Immunol
2002
;
169
:
239
–247.
83
Ruggeri L, Capanni M, Casucci M, et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation.
Blood
1999
;
94
:
333
–339.
84
Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.
Science
2002
;
295
:
2097
–2100.
85
Aversa F, Terenzi A, Tabilio A, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse.
J Clin Oncol
2005
;
23
:
3447
–3454.
86
Leung W, Iyengar R, Turner V, et al. Determinants of antileukemia effects of allogeneic NK cells.
J Immunol
2004
;
172
:
644
–650.
87
Grau R, Lang KS, Wernet D, et al. Cytotoxic activity of natural killer cells lacking killer-inhibitory receptors for self-HLA class I molecules against autologous hematopoietic stem cells in healthy individuals.
Exp Mol Pathol
2004
;
76
:
90
–98.
88
Hsu KC, Keever-Taylor CA, Wilton A, et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes.
Blood
2005
;
105
:
4878
–4884.
89
Martin MP, Nelson G, Lee JH, et al. Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles.
J Immunol
2002
;
169
:
2818
–2822.
90
Verheyden S, Schots R, Duquet W, Demanet C. A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation.
Leukemia
2005
;
19
:
1446
–1451.
91
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.
Nat Genet
1995
;
10
:
111
–113.
92
Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.
Mol Genet Metab
1998
;
64
:
169
–172.
93
Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.
Blood
2001
;
98
:
231
–234.
94
Robien K, Schubert MM, Chay T, et al. Methylenetetrahydrofolate reductase and thymidylate synthase genotypes modify oral mucositis severity following hematopoietic stem cell transplantation.
Bone Marrow Transplant
2006
;
37
:
799
–800.
95
Srivastava A, Poonkuzhali B, Shaji RV, et al. Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation.
Blood
2004
;
104
:
1574
–1577.
96
Kallianpur AR. Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?
Bone Marrow Transplant
2005
;
35
:
1
–16.
97
Ueda H, Howson JM, Esposito L, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.
Nature
2003
;
423
:
506
–511.
98
Bassuny WM, Ihara K, Sasaki Y, et al. A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes.
Immunogenetics
2003
;
55
:
149
–156.
99
Matsuzaki H, Dong S, Loi H, et al. Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays.
Nat Methods
2004
;
1
:
109
–111.
100
Hochberg EP, Miklos DB, Neuberg D, et al. A novel rapid single nucleotide polymorphism (SNP)-based method for assessment of hematopoietic chimerism after allogeneic stem cell transplantation.
Blood
2003
;
101
:
363
–369.
101
Redon R, Ishikawa S, Fitch KR, et al. Global variation in copy number in the human genome.
Nature
2006
;
444
:
444
–454.
Sign in via your Institution