Correcting dysregulated peripheral tolerance in NOD mice

描述(由申请人提供)： 除了自身免疫性糖尿病的表达外，NOD小鼠似乎在外周耐受方面存在先天缺陷，使这些动物难以诱导同种异体移植耐受。综合起来，这些问题使得成功的同种异体胰岛移植在这个模型中变得格外困难。重要的是，NOD小鼠的大部分自身免疫倾向映射到骨髓室。根据捐赠者的不同，骨髓移植可以传递疾病易感性，也可以传递保护。在之前涉及组织/器官移植的大多数研究中，骨髓被用作特定捐赠者的耐受原，并已成功应用于NOD小鼠。然而，尽管概念上非常重要，但MHC不匹配的骨髓移植所涉及的毒性诱导疗法以及随后的移植物抗宿主病风险可能会阻碍该方法在不久的将来应用于临床。在这项建议中，与其使用骨髓作为胰岛移植特异性耐受原，MHC配型(H-2G7)，抗病异基因骨髓移植将被用作一种手段，‘重新编程’NOD外周免疫系统，使宿主服从耐受诱导。因此，这项提议将检验一般的工作假设：MHC匹配的、抗病的造血细胞将主要调节易患疾病的细胞，并恢复正常的外周耐受倾向。这一假说将通过下列特定目标进行验证：(1)确定通过在NOD小鼠中引入MHC相合的抗病骨髓来提供疾病保护的程度，(2)确定与抗病骨髓的混合嵌合是否将纠正NOD小鼠固有的同种异体移植耐受缺陷，以及(2)确定保护骨髓中的哪些成分能够恢复NOD小鼠的外周耐受倾向。

DESCRIPTION (provided by applicant): Beyond the expression of autoimmune diabetes, NOD mice appear to harbor inherent defects in peripheral tolerance that renders these animals refractory to the induction of allograft tolerance. Combined, these issues make successful islet allotransplantation extraordinarily difficult in this model. Importantly, much of the autoimmune propensity in NOD mice maps to the bone marrow compartment. Depending on the donor, bone marrow transplantation can transfer either disease susceptibility or protection. In most previous studies involving tissue/organ transplantation, bone marrow has been used as a tolerogen for a specific donor and has been successfully applied in the NOD mouse. However, while conceptually very important, the toxic induction therapies involved and subsequent risk of graft-versus-host disease associated with MHC-mismatched bone marrow engraftment may preclude this approach for clinical application in the near future. In this proposal, rather than using bone marrow as a donor islet transplant-specific tolerogen, MHC-matched (H-2g7), disease-resistant bone marrow allografts will be used as a means of 're-programming' the NOD peripheral immune system to make the host amenable for tolerance induction. Thus, this proposal will test the general working hypothesis: MHC-matched, disease-resistant hematopoietic cells will dominantly regulate disease-prone cells and restore normal peripheral tolerance propensity. This hypothesis will be tested by the following specific aims: (1) Determine the extent of disease protection afforded by introducing MHC-matched, disease-resistant bone marrow in NOD mice, (2) Determine whether mixed chimerism with disease-resistant marrow will correct the inherent allograft tolerance defect in NOD mice, and (2) Determine the components within protective marrow that confer restoration of peripheral tolerance propensity in NOD mice.