Role of MHC & non-MHC genes in the treatment of 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腺的耐受， 胰岛，移植抗糖尿病骨髓细胞可能导致 糖尿病的潜在治疗方法不幸的是， 从尸体捐献者身上获取的胰岛和骨髓 在人类中被利用，因为与 清髓性宿主调节需要实现植入， allo-BMT相关的并发症我们最近成功地 获得持久的混合嵌合体、对供体组织的耐受性和保护 使用相对无毒、非清髓的 预处理方案后移植糖尿病抵抗骨 骨髓。建立骨髓嵌合体的糖尿病NOD小鼠 接受了捐赠者的胰岛，并治愈了糖尿病。这个项目的目标是 评估供体骨髓细胞表达的机制， 保护性MHC和/或非MHC编码的糖尿病抗性基因介导 预防糖尿病。三种致糖尿病TCR菌株的使用 用非清髓性预处理方案预处理的转基因NOD小鼠 作为不同捐赠者骨髓细胞的接受者， 无反应性、缺失和抑制CD 4+和CD 8+致糖尿病T细胞。 此外，我们将评估是否诱导混合嵌合体， 自体骨髓细胞，其已被逆转录病毒转导， 糖尿病保护性MHC II类基因，足以预防糖尿病。 这些研究将有助于更好地了解MHC和非MHC编码的 抗糖尿病的基因介导。详细分析了这些机制 参与这种保护和耐受诱导将允许发展一种 更具体的方法，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 protection from diabetes. The use of three strains of diabetogenic TCR transgenic NOD mice, conditioned with a non-myeloablative conditioning regimen 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 prevent diabetes. 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 approach, and thus bring us closer to clinical application.