Alloimmunity and Autoimmunity in NOD Mice

NOD 小鼠的同种免疫和自身免疫

基本信息

批准号：
7252041
负责人：
GILLES A BENICHOU
金额：
$ 41.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2009-04-30
项目状态：
已结题

项目摘要

In recent years, transplantation immunologists working with NOD mice have discovered that they have unusual features besides their development of diabetes. NOD mice are highly resistant to tolerance induction by several different approaches, even for skin grafts and heart transplants. NOD mice also have an unusually powerful capacity to reject allografts entirely through the indirect pathway. The experiments proposed in this application will explore the hypothesis that the development of autoimmunity in NOD mice and their unusual transplantation traits have a common etiology involving abnormalities of their peripheral T cell regulatory mechanisms. In the first Specific Aim we will determine the genetic basis for the resistance of NOD mice to tolerance induction and for the unusual strength of their indirect effector response. These experiments will use a classical immunogenetics approach to determine whether the two transplantation traits of NOD mice have a common genetic basis and whether it involves diabetes susceptibility genes. In the second Specific Aim we will use in vitro experiments to explore the mechanisms responsible for the resistance of NOD mice to tolerance induction and for the unusual strength of their indirect effector response. These experiments will determine whether disordered peripheral regulatory mechanisms are responsible for the transplantation traits as well as the tendency of NOD mice to develop autoimmunity. In the third Specific Aim we will perform in vivo experiments designed to explore the mechanisms responsible for the NOD transplantation traits and to overcome their resistance to tolerance induction and the unusual strength of their indirect effector response. Part of the purpose of these experiments is to identify therapies that might be used for patients who might be identified as having the genes responsible for the NOD transplantation phenotype.

近年来，与NOD小鼠一起工作的移植免疫学家发现，除了糖尿病的发展外，它们具有不寻常的特征。通过几种不同的方法，即使对于皮肤移植物和心脏移植，点头小鼠对耐受性诱导具有高度抗性。点头小鼠还具有异常强大的能力，可以通过间接途径完全拒绝同种异体移植。本应用程序中提出的实验将探讨以下假设 NOD小鼠的自身免疫性及其异常的移植特征具有共同的病因，涉及其周围T细胞调节机制的异常。在第一个特定目的中，我们将确定NOD小鼠抗性的遗传基础耐受性诱导和间接效应子响应的异常强度。这些实验将使用经典的免疫遗传学方法来确定点头小鼠的两个移植特征是否具有共同的遗传基础，以及它是否涉及糖尿病易感性基因。在第二个特定目的中，我们将使用体外实验来探索负责NOD小鼠对耐受性诱导和其间接效应子响应的异常强度的机制。这些实验将确定无序的外围调节机制是否负责移植特征以及点头小鼠发展自身免疫性的趋势。在第三个特定目的中，我们将执行旨在探索机制的体内实验负责点头移植特征并克服其对公差的抵抗力诱导和间接效应子响应的异常强度。这些实验的一部分目的是确定可能被鉴定出可能被识别为具有负责点头移植表型的基因的患者。