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，抗糖尿病的骨髓细胞移植可能会导致 一种治疗糖尿病的潜在方法。不幸的是，移植的 从身体捐赠者身上采集的胰岛和骨髓还没有 在人类身上被利用，因为与 实现植入所需的清髓性宿主调节，并且因为 与异基因骨髓移植相关的并发症。我们最近成功地做到了 实现持久的混合嵌合体、对供体组织的耐受性和保护 在NOD小鼠中使用一种相对无毒、非清髓剂的糖尿病 抗糖尿病骨移植后的调理方案 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。这个项目的目标是 评价供者骨髓细胞表达的机制 保护性MHC和/或非MHC编码的糖尿病抵抗基因介导 预防糖尿病。三株致糖尿病TCR的应用 转基因NOD小鼠，接受非清髓性预适应方案 作为不同捐赠者骨髓细胞的接受者，将帮助我们确定 CD4和CD8糖尿病T细胞的无能、缺失和抑制。 此外，我们将评估混合嵌合体的诱导是否由 经逆转录病毒转导的自体骨髓细胞 保护糖尿病的MHC II类基因，足以预防糖尿病。 这些研究将有助于更好地理解MHC和非MHC编码 糖尿病抵抗力的基因调节。对这些机制的详细分析 参与这种保护和容忍诱导将允许开发一种 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.