Mechanisms of Transplantation Tolerance Induction

移植耐受诱导机制

基本信息

批准号：
7994916
负责人：
DALE Leslie GREINER
金额：
$ 37.34万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994916
关键词：
Address Affect Agonist Alloantigen Animals Apoptosis Arts Biological Assay CD4 Positive T Lymphocytes CD8B1 gene Cells Chimerism Clinic Clinical Complex Exposure to Face Goals Graft Survival Hematopoietic Human Immune Immune Tolerance Immune system Infection Inflammatory Interferons Lead Ligation Maintenance Mediating Methods Modeling Molecular Mus Organ Transplantation Peripheral Pharmaceutical Preparations Process Production Protocols documentation Research Resources Safety Small Interfering RNA Specificity T-Lymphocyte Techniques Technology Testing Toll-like receptors Transgenic Mice Translating Transplantation Tolerance Viral Virus Virus Diseases Work base central tolerance cytokine cytotoxicity immune activation in vivo innovation mouse model new technology novel strategies peripheral tolerance prevent programs skin allograft

项目摘要

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.

诱导和移植过程中感染与移植物存活之间复杂相互关系的机制移植耐受的维持尚不清楚。我们的目标是了解感染是如何发生的阻断外周和中枢耐受的诱导。我们开发了多项创新技术用于识别病毒免疫 T 细胞并确定其抗病毒和交叉反应同种异体反应性单细胞水平。我们还开发了以下方法：1) 使用“同步嵌合体”量化同种异体反应性 T 细胞基于 CD8+ TCR Tg 小鼠的模型，2) 通过快速识别初始 T 细胞和效应同种反应性 T 细胞同种抗原刺激后细胞因子的产生，以及 3) 体内 CDS T 细胞效应物的定量使用体内细胞毒性测定的功能。我们将使用这些技术和令人兴奋的新技术体内递送 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促炎细胞因子和 IFNI 的诱导是一个基本机制先天免疫激活调节外周和中枢耐受的诱导。具体目标 1 是确定 TLR 连接或病毒感染调节外周细胞诱导的机制宽容。我们将检验 TLR 激动剂或病毒感染激活先天免疫的假设通过促炎细胞因子的产生消除外周耐受的诱导干扰素。具体目标 2 是确定 TLR 连接或病毒感染的调节机制造血嵌合和中枢耐受的建立。我们将检验以下假设：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中枢移植耐受。该项目将与研究维护的项目 2 密切互动耐受性，以及研究同种反应性 CDS T 细胞如何在共刺激后通过凋亡死亡的项目 3 封锁。这些发现将在项目 4 中使用病毒和免疫系统转化为人类免疫系统。技术核心和动物核心是实现我们研究目标的关键资源。