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性方面具有固有缺陷，这使得这些动物对同种异体移植物耐受性的诱导是难治的。结合起来，这些问题使得在这种模型中成功的胰岛同种异体移植非常困难。重要的是，NOD小鼠中的许多自身免疫倾向映射到骨髓室。根据供体的不同，骨髓移植可以转移疾病易感性或保护性。在大多数涉及组织/器官移植的先前研究中，骨髓已被用作特定供体的耐受原，并已成功应用于NOD小鼠。然而，虽然在概念上非常重要，但涉及的毒性诱导治疗和随后与MHC不匹配骨髓移植相关的移植物抗宿主病风险可能会在不久的将来排除这种方法的临床应用。在该提议中，而不是使用骨髓作为供体胰岛移植特异性耐受原，MHC匹配（H-2g 7），抗病骨髓同种异体移植物将被用作“重新编程”NOD外周免疫系统的手段，以使宿主适合耐受诱导。因此，该提议将测试一般工作假设：MHC匹配的抗病造血细胞将主要调节疾病易感细胞并恢复正常的外周耐受倾向。这一假设将通过以下具体目标进行检验：（1）确定通过在NOD小鼠中引入MHC匹配的抗病骨髓所提供的疾病保护的程度，（2）确定与抗病骨髓的混合嵌合体是否将纠正NOD小鼠中固有的同种异体移植物耐受性缺陷，和（2）确定保护性骨髓中赋予NOD小鼠外周耐受倾向恢复的组分。

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.