Correcting dysregulated peripheral tolerance in NOD mice

纠正 NOD 小鼠失调的外周耐受性

• 批准号: 6730228
• 负责人: Ronald G Gill
• 金额: $ 22.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730228
• 关键词: MHC class II antigen; NOD mouse; T lymphocyte; antigen presentation; bone marrow transplantation; diabetes mellitus therapy; immune tolerance /unresponsiveness; immunotherapy; insulin dependent diabetes mellitus; nonhuman therapy evaluation; pancreatic islet transplantation; tissue mosaicism

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.

描述（由申请人提供）： 除了表达自身免疫性糖尿病外，NOD 小鼠似乎还存在外周耐受性的固有缺陷，这使得这些动物难以诱导同种异体移植耐受。综合起来，这些问题使得该模型中成功的胰岛同种异体移植变得异常困难。重要的是，NOD 小鼠的大部分自身免疫倾向都映射到骨髓室。根据捐赠者的不同，骨髓移植可以转移疾病易感性或保护作用。在以往大多数涉及组织/器官移植的研究中，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，但所涉及的毒性诱导疗法以及随后与 MHC 不匹配的骨髓移植相关的移植物抗宿主病的风险可能会妨碍这种方法在不久的将来的临床应用。在该提案中，不使用骨髓作为供体胰岛移植特异性耐受原，而是使用 MHC 匹配 (H-2g7)、抗病骨髓同种异体移植物作为“重新编程”NOD 外周免疫系统的手段使宿主能够耐受诱导。因此，该提议将检验一般的工作假设：MHC 匹配的抗病造血细胞将主要调节易患病细胞并恢复正常的外周耐受倾向。该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程度，（2）确定与抗病骨髓的混合嵌合是否会纠正NOD 小鼠固有的同种异体移植耐受缺陷，以及 (2) 确定保护性骨髓内赋予 NOD 小鼠外周耐受倾向恢复的成分。