Mechanisms of Transplantation Tolerance Induction

在诱导和移植过程中感染和移植物存活之间复杂相互关系的机制 移植耐受的维持还不是很清楚。我们的目标是了解感染是如何 阻断外周和中枢耐受的诱导。我们开发了几项创新的五项技术 用于识别病毒免疫的T细胞并确定其ANFI病毒和交叉反应的同种异体反应性 单细胞水平。我们还开发了一种方法，用于1)使用同种异体嵌合体来量化同种异体反应性T细胞 CD8+TCRTg小鼠模型的建立2)快速识别初治和效应型同种异体T细胞 异体肾移植后细胞因子的产生，以及3)体内CDS T细胞效应器的量化 用体内细胞毒性试验测定其功能。我们将使用这些技术和一种令人兴奋的新技术 体内传递siRNA以阻断CD40-CD154相互作用。这些新技术将使我们能够测试 我们的总体假设是，诱导促炎细胞因子和IFNI是一个基本的机制，通过 先天免疫激活调节外周和中枢性耐受的诱导。具体目标1是 确定TLR结扎或病毒感染调节外周血诱导的机制 宽容。我们将检验TLR激动剂或病毒感染激活先天免疫的假设 消除通过产生促炎细胞因子而诱导的外周耐受 如果。具体目的2是确定TLR配体或病毒感染的调节机制 建立造血嵌合体和中枢耐受。我们将检验这一假设 外周和中枢耐受的诱导涉及多种不同但重叠的机制。这 项目应揭示感染损害外周和外周血细胞的诱导的机制(S) 中枢移植耐受。本项目将与项目2密切互动，研究维护 耐受性和研究同种异体反应性CDS T细胞如何在共聚焦后通过凋亡而死亡的项目3 封锁。在项目4中，这些发现将被转化为人类免疫系统，使用两种病毒 以及技术核心和动物核心作为实现我们研究目标的关键资源。

Mechanisms underiying the complex interrelationships of infecfion and graft survival during induction and maintenance of transplantation tolerance are not well understood. Our goal is to understand how infection blocks the induction of peripheral and central tolerance. We have developed several innovafive technologies for identifying virus-immune T cells and determining their anfi-viral and cross-reacfive alloreacfivity at the single cell level. We have also developed methods for 1) quantifying alloreactive T cells using a 'synchimera' model based on CD8+ TCR Tg mice, 2) identifying naive and effector alloreactive T cells by their rapid production of cytokines following alloanfigen sfimulation, and 3) quanfifying in vivo CDS T cell effector function using an in vivo cytotoxicity assay. We will use these techniques with an exciting new technology for in vivo delivery of siRNA to block of CD40-CD154 interaction. These new technologies will allow us to test our overall hypothesis that inducfion of pro-inflammatory cytokines and IFNI is a fundamental mechanism by which innate immune acfivafion modulates the inducfion of peripheral and central tolerance. Specific Aim 1 is to determine mechanisms by which TLR ligation or virus infection modulates the induction of peripheral tolerance. We will test the hypothesis that innate immune activation by TLR agonists or virus infection abrogates the induction of peripheral tolerance through the producfion of pro-inflammatory cytokines and IFNI. Specific Aim 2 is to determine mechanisms by which TLR ligafion or virus infecfion modulates establishment of hematopoietic chimerism and central tolerance. We will test the hypothesis that the induction of peripheral and central tolerance involves mulfiple different but overiapping mechanisms. This project should reveal the mechanism(s) by which infection compromises the induction of peripheral and central transplantation tolerance. This Project will interact closely with Project 2 studying the maintenance of tolerance, and Project 3 studying how alloreactive CDS T cells die by apoptosis following cosfimulation blockade. These discoveries will be translated to human immune systems in Project 4 using both the Viral and Technology Core and Animal Core as critical resources for the accomplishment of our research goals.