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者胰岛的耐受，抗糖尿病骨髓细胞移植可能会带来治疗糖尿病的潜在方法。不幸的是，从身体供者身上获取的胰岛和骨髓移植尚未在人类身上应用，因为实现植入所需的清髓性宿主调节相关的不可接受的毒性，以及与allo-BMT相关的并发症。最近，我们成功地在NOD小鼠身上实现了持久的混合嵌合体、对供体组织的耐受性和对糖尿病的保护，方法是使用相对无毒、非清髓性的预适应方案，然后移植抗糖尿病的骨髓。建立了骨髓嵌合体的糖尿病NOD小鼠接受了供体胰岛，并治愈了糖尿病。该项目的目标是评估表达保护性MHC和/或非MHC编码的糖尿病抵抗基因的供体骨髓细胞介导活化的糖尿病原性T细胞耐受的机制。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，将有助于我们明确无能、缺失和抑制CD4和CD8糖尿病原性T细胞的作用。此外，我们将评估由逆转录病毒转导糖尿病保护性MHC II类基因的自体骨髓细胞诱导的混合嵌合体是否足以耐受致糖尿病的T细胞。这些研究将有助于更好地理解MHC和非MHC编码的基因对糖尿病抵抗的调节作用。对这种保护和耐受诱导机制的详细分析将使我们能够开发出更具体、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.