Diabetes is the fifth leading cause of death by disease in the United States. Diabetes also contributes to higher rates of morbidity — people with diabetes are at higher risk for heart disease, blindness, kidney failure, extremity amputations, and other chronic conditions. Direct medical and indirect expenditures attributable to diabetes in 2002 were estimated at $132 billion. Attributable indirect expenditures resulting from lost workdays, restricted activity days, mortality, and permanent disability due to diabetes totaled $39.8 billion. When adjusting for differences in age, sex, and race/ethnicity between the population with and without diabetes, people with diabetes had medical expenditures that were ~2.4 times higher than expenditures that would be incurred by the same group in the absence of diabetes. Clearly, diabetes is a major health problem. There are two broad types of diabetes, type 1 and 2.
Type 1 diabetes mellitus (DM) is an autoimmune disease resulting from an immune mediated cellular attack on the pancreatic beta cells, which produce insulin. The beta cells are destroyed and thus insulin is no longer produced. At the time of clinical diagnosis, approximately 60 percent to 80 percent of the beta-cell mass has been destroyed. Therefore, preservation of the beta cells is an important target in the management of type 1 DM and in the prevention of its related complications.
The authors report in this manuscript the conduct of a study to examine the effect of high-dose immunosuppression followed by autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) to preserve beta-cell function in 15 patients with newly diagnosed type 1 DM. During a seven- to 36-month follow-up, 14 patients became insulin-free (one for 35 months, four for at least 21 months, seven for at least six months, and two with late response were insulin-free for one and five months, respectively). Among those, one patient resumed insulin use one year after AHST. The only severe adverse effects were pneumonia in one patient and endocrine dysfunction in two others. Ninety-three percent of patients achieved different periods of insulin independence, and treatment-related toxicity was low, with no mortality.
What happened here? There are extensive data demonstrating the success of utilizing allogeneic hematopoietic cell transplantation in animal models and data in humans that type 1 diabetes could be transferred to allogeneic recipients, as well as reversed in allogeneic recipients. This study, however, uses the patients’ own cells, and it is important to note that these cells were not selected, that is, no T-cell depletion of the graft (to remove the autoreactive T cells) as is being done for the national studies on scleroderma and lupus. Moreover, the patients were all young, without an excessive body mass index (BMI), and selected to be very early in the onset of their disease. They were all were intensively immune suppressed with anti-thymocyte globulin and a large dose of cyclophosphamide.
In Brief
Will the hematopoietic cell transplant community be performing autologous rescue for diabetes? There are several caveats to the data presented. First and foremost is the known "honeymoon" period that many patients have in which patients have a relative remission after the onset of the disease. This period can be quite variable, and since there was not a control group in this study, this potential spontaneous remission significantly confounds the results. The follow-up of the whole group is short and thus it is not known if there will be a lasting response. The intensive immune suppression might be beneficial for the patients, but one would predict that returning autologous immune cells back to the patient with the stem cell graft would return the autoimmune cells as well, unless the preparatory regimen changed the presentation of autoimmune antigens. Finally, there is the possibility that there are "other cells" found in the marrow that could possibly repair the damaged pancreas. As the authors conclude, we will need a prospective randomized study to determine the utility of this approach.
This study is the first of what will be many different approaches of cellular therapy for diabetes and other autoimmune diseases. In addition to the use of hematopoietic cells, there is strong interest in regulatory T cells, umbilical cord cells, dendritic cells, mesenchymal cells, and embryonic cells, to name a few. Look for more on the field of cellular therapy and regenerative medicine.
Competing Interests
Dr. Chao indicated no relevant conflicts of interest.
