权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

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