Mechanisms of Transplantation Tolerance Induction

移植耐受诱导机制

基本信息

批准号：
8661683
负责人：
DALE Leslie GREINER
金额：
$ 52.35万
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：
资助国家：
美国
起止时间：
至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8661683
关键词：
Address Affect Agonist Alloantigen Animals Apoptosis Biological Assay CD4 Positive T Lymphocytes CD8B1 gene Cells Chimerism Clinic Clinical Complex Exposure to 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 TNFRSF5 gene TNFSF5 gene Techniques Technology Testing Time Toll-like receptors Transgenic Mice Translating Translations Transplantation Transplantation Tolerance Tumor Necrosis Factor-alpha Viral Virus Virus Diseases Work base central tolerance cytokine cytotoxicity immune activation in vivo innovation innovative technologies mouse model new technology novel strategies novel therapeutic intervention peripheral tolerance prevent programs skin allograft

项目摘要

Mechanisms underlying the complex interrelationships of infection 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 innovative technologies for identifying virus-immune T cells and determining their anti-viral and cross-reactive alloreactivity 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 alloantigen stimulation, and 3) quantifying 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 induction of pro-inflammatory cytokines and IFN1 is a fundamental mechanism by which innate immune activation modulates the induction 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 production of pro-inflammatory cytokines and IFN1. Specific Aim 2 is to determine mechanisms by which TLR ligation or virus infection modulates establishment of hematopoietic chimerism and central tolerance. We will test the hypothesis that the induction of peripheral and central tolerance involves multiple different but overlapping 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 CD8 T cells die by apoptosis following costimulation 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.

在诱导和维持移植耐受期间感染和移植物存活的复杂相互关系的基础机制尚不清楚。我们的目标是了解感染如何阻止外围和中心耐受性的诱导。我们已经开发了几种创新技术，用于鉴定病毒 - 免疫T细胞并确定其在单细胞水平上的抗病毒和交叉反应性同种异体反应性。我们还开发了用于1）使用基于CD8+ TCR TG小鼠的“同步性T”模型来量化同种反应性T细胞的方法。我们将使用这些技术和令人兴奋的新技术在体内传递CD40-CD154相互作用。这些新技术将使我们能够检验我们的总体假设，即促炎细胞因子和IFN1是一种基本机制，其先天免疫激活调节了外围和中心耐受性的诱导。具体目的1是确定TLR连接或病毒感染调节外周耐受性的机制。我们将检验以下假设：TLR激动剂或病毒感染的先天免疫激活消除了通过产生促炎性细胞因子和IFN1的产生外周耐受性的诱导。具体目的2是确定TLR连接或病毒感染调节造血嵌合和中心耐受性的机制。我们将检验以下假设：诱导外围和中央耐受性涉及多种不同但重叠的机制。该项目应揭示感染损害周围和中央移植耐受性的诱导的机制。该项目将与研究耐受性维持的项目2紧密相互作用，并研究了在共刺激阻滞后通过细胞凋亡死亡的同种反应性CD8 T细胞如何死亡。这些发现将使用病毒和技术核心和动物核心作为实现我们的研究目标的关键资源，将项目4中的人类免疫系统转化为人类免疫系统。