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Excerpt
Type 1 diabetes is a systematic autoimmune disease in which the insulin- producing islets are destroyed. The preferred approach for glucose homeostasis in patients with Type 1 diabetes is whole pancreatic or islet transplantation. Graft survival is currently dependent upon the daily use of chronic nonspecific immunosuppression. The use of these agents is associated with an increased risk of malignancy, infection, and end organ toxicity. Moreover, chronic rejection remains the primary cause of late graft loss. The induction of tolerance to donor antigens through HSC chimerism may eliminate the requirement for nonspecific immunosuppression. However, the morbidity and mortality associated with fully ablative conditioning could not be justified in attempts to induce tolerance. The development of partial conditioning strategies to make space for the donor HSC to engraft may allow the application of HSC chimerism for the induction of tolerance to whole pancreas and islet allografts. Like humans with autoimmune diseases, NOD mice demonstrate a relative resistance to engraftment compared to disease-resistant strains. While 600 cGy TBI is sufficient conditioning to make space to achieve HSC chimerism in normal mice, ≥ 750 cGy TBI is required to condition NOD recipients. The goal of the present studies was to identify a strategy to overcome the alloresistance in NOD mice by reducing the irradiation dose for conditioning. NOD mice were treated with two different conditioning approaches and transplanted with 60 × 106 B10.BR bone marrow cells: A) 600 cGy TBI alone; B) 600 cGy TBI followed by a single intraperitoneal injection of 50mg/kg of Cyclophosphamide two days after transplantation. There was no engraftment in Group A (n=10), while in group B there was 100% engraftment with a 91.5% level of donor chimerism (figure 1). These data suggest that although NOD mice exhibit a relative alloresistance to HSC chimerism, this barrier can be overcome with space-making agents, such as cyclophosphamide. Studies are in progress to identify which cells in the recipient bone marrow must be removed to make space for the donor HSC to engraft.
