Alloimmunity and Autoimmunity in NOD Mice

近年来，研究NOD小鼠的移植免疫学家发现，它们除了患糖尿病外，还具有不寻常的特征。NOD小鼠对几种不同方法诱导的耐受具有高度抵抗力，即使是皮肤移植和心脏移植也是如此。NOD小鼠也有一种异常强大的能力，可以完全通过间接途径排斥同种异体移植。 本申请中提出的实验将探索这样一个假设，即 NOD小鼠的自身免疫及其不寻常的移植特征有一个共同的病因，涉及其外周T细胞调节机制的异常。 在第一个特定目标中，我们将确定NOD小鼠对 耐受性诱导和其不寻常的间接效应器反应。这些 实验将使用经典的免疫遗传学方法来确定NOD小鼠的两个移植性状是否具有共同的遗传基础，以及是否涉及糖尿病易感基因。 在第二个特定目标中，我们将使用体外实验来探索NOD小鼠对耐受诱导的抗性以及它们异常强烈的间接效应反应的机制。这些实验将确定外周调节机制紊乱是否与移植特征以及NOD小鼠发展自身免疫的趋势有关。 在第三个具体目标中，我们将进行活体实验，以探索这种机制 对结瘤移植性状负责并克服其耐受性 诱导和其间接效应器反应的不同寻常的强度。这些实验的部分目的是确定可能用于那些可能被识别为具有导致NOD移植表型的基因的患者的治疗方法。

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.