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

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

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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.

在诱导过程中，无效和移植物生存的复杂相互关系的机制和维持移植耐受性尚不清楚。我们的目标是了解感染阻止外围和中央公差的诱导。我们已经开发了几种创新技术用于鉴定病毒 - 免疫T细胞并确定其在该病毒和交叉反应的同种异体上单细胞水平。我们还开发了1）使用“同步剂”来量化同种反应性T细胞的方法基于CD8+ TCR TG小鼠的模型，2）通过其快速识别幼稚和效应的同种异体T细胞在同叶剂量刺激后产生细胞因子，3）体内CD t细胞效应子中的Quanfififififor 使用体内细胞毒性测定法。我们将使用这些技术以及令人兴奋的新技术体内siRNA到CD40-CD154相互作用的块。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性细胞因子和IFNI是一种基本机制天生的免疫抗炎体调节了外围和中央耐受性的诱导。具体目标1是确定TLR连接或病毒感染调节周围诱导的机制宽容。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通过促炎性细胞因子的产生和 ifni。特定目的2是确定TLR Ligafion或病毒无关的机制建立造血嵌合体和中央耐受性。我们将检验以下假设诱导外围和中央耐受性涉及Mulfiple不同但过度使用的机制。这项目应揭示感染损害周围诱导和的机制中央移植耐受性。该项目将与项目2紧密互动，以研究维护耐受性和项目3研究了同种反应性CD T细胞在同产后因凋亡而死亡封锁。这些发现将在项目4中使用病毒转化为项目4的人类免疫系统技术核心和动物核心是实现我们的研究目标的关键资源。