Correcting dysregulated peripheral tolerance in NOD mice

纠正 NOD 小鼠失调的外周耐受性

• 批准号: 6806459
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6806459
• 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）： 除了自身免疫性糖尿病的表达外，点头小鼠似乎具有外周耐受性固有的缺陷，这些缺陷使这些动物难以耐受性诱导同种异体移植耐受性。结合在一起，这些问题使得成功的胰岛同种异体移植在该模型中极为困难。重要的是，NOD小鼠的大部分自身免疫性倾向映射到骨髓室。根据供体，骨髓移植可以转移疾病的敏感性或保护。在以前的大多数涉及组织/器官移植的研究中，骨髓已被用作特定供体的耐受性，并已成功地应用于NOD小鼠。但是，尽管从概念上讲非常重要，但涉及的毒性诱导疗法以及随后与MHC不匹配的骨髓植入相关的移植物抗宿主疾病的风险可能会在不久的将来排除这种用于临床应用的方法。在该提案中，与其将骨髓作为供体移植特异性耐受性（MHC匹配（H-2G7）），抗病性骨髓同种异体移植物将被用作“重新编程”点头外周外部免疫系统，以使宿主诱导宿主的诱导剂。因此，该建议将检验一般的工作假设：MHC匹配的，抗病性造血细胞将主要调节易于疾病的细胞并恢复正常的外周耐受性倾向。该假设将通过以下特定目的进行检验：（1）通过在NOD小鼠中引入与MHC匹配的，具有疾病的骨髓的疾病保护程度，（2）确定与抗病骨髓的混合嵌合物与抗病性骨髓的混合嵌合体是否会纠正NOD小鼠中固有的同种异体耐受性，并确定NOD小鼠中的固有量的构造，并确定2）在NOD小鼠中的构造，并确定2）在NOD小鼠中的构造，并确定2）的组合构成的构造量是否会在NOD小鼠中进行保护。2）点头小鼠的倾向。