Tcell tolerization in the treatment of Type I diabetes

描述（由申请人提供）： 通过逆转自身免疫性疾病和诱导对供体胰岛的耐受，抗糖尿病骨髓细胞的移植可能导致糖尿病的潜在治愈。不幸的是，从尸体供体收获的胰岛和骨髓的移植尚未在人类中开发，因为与实现植入所需的清髓性宿主调节相关的不可接受的毒性以及因为与allo-BMT相关的并发症。我们最近成功地实现了持久的混合嵌合体，对供体组织的耐受性和保护NOD小鼠免受糖尿病的影响，使用相对无毒，非清髓性预处理方案，然后移植抗糖尿病骨髓。建立骨髓嵌合体的糖尿病NOD小鼠接受供体胰岛并治愈糖尿病。本项目的目的是评估表达保护性MHC和/或非MHC编码的糖尿病抗性基因的供体骨髓细胞介导活化的致糖尿病T细胞耐受化的机制。使用两个品系的糖尿病TCR转基因NOD小鼠作为不同供体骨髓细胞的受体将帮助我们确定无反应性、缺失和抑制CD 4+和CD 8+致糖尿病T细胞的作用。此外，我们将评估是否诱导混合嵌合体，诱导自体骨髓细胞已逆转录病毒转导糖尿病保护性MHC II类基因，足以耐受糖尿病致T细胞。这些研究将有助于更好地了解MHC和非MHC编码基因介导的糖尿病抗性。对这种保护和耐受诱导机制的详细分析将有助于开发更特异、更有针对性的方法，从而使我们更接近临床应用。

DESCRIPTION (provided by applicant): By reversing autoimmune disease and inducing tolerance to donor pancreatic islets, the transplantation of diabetes resistant bone marrow cells could lead to a potential cure for diabetes. Unfortunately, the transplantation of pancreatic islets and bone marrow harvested from cadaveric donors has not yet been exploited in man because of the unacceptable toxicity associated with myeloablative host conditioning needed to achieve engraftment and because of the complications associated with allo-BMT. We have recently succeeded in achieving lasting mixed chimerism, tolerance toward donor tissue and protection from diabetes in NOD mice using a relatively non-toxic, non-myeloablative conditioning regimen followed by transplantation of diabetes resistant bone marrow. Diabetic NOD mice in which bone marrow chimerism was established accepted donor islets and were cured of diabetes. The goal of this project is to evaluate the mechanisms by which donor bone marrow cells that express protective MHC and/or non-MHC encoded diabetes-resistant genes mediate tolerization of activated diabetogenic T cells. The use of two strains of diabetic TCR transgenic NOD mice as recipients of different donor bone marrow cells will help us define the role of anergy, deletion and suppression of both CD4+ and CD8+ diabetogenic T cells. Furthermore, we will evaluate if induction of mixed chimerism, induced by autologous bone marrow cells which have been retrovirally-transduced with diabetes protective MHC class II genes, is sufficient to tolerize diabetogenic T cells. These studies will lead to a better understanding of MHC and non-MHC encoded gene mediation of resistance to diabetes. A detailed analysis of the mechanisms involved in this protection and tolerance induction will allow development of a more specific, targeted approach, and thus bring us closer to clinical application.