Mechanisms of Transplantation Tolerance Induction

移植耐受诱导机制

• 批准号: 8279391
• 负责人: DALE Leslie GREINER
• 金额: $ 37.01万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279391
• 关键词: Address; Affect; Agonist; 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; Ligation; Maintenance; Methods; Modeling; 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; Toll-like receptors; Transgenic Mice; Translating; Transplantation Tolerance; Viral; Virus; Virus Diseases; Work; base; central tolerance; cytokine; cytotoxicity; immune activation; in vivo; innovation; new technology; peripheral tolerance; programs

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.

诱导期感染和移植物存活之间复杂相互关系的机制， 移植耐受性的维持尚不清楚。我们的目标是了解感染 阻断外周和中枢耐受性的诱导。我们开发了几项创新技术 用于鉴定病毒免疫T细胞并确定它们在免疫原性水平上的抗病毒和交叉反应同种异体反应性。 单细胞水平。我们还开发了用于1）使用“同步嵌合体”定量同种异体反应性T细胞的方法。 基于CD 8 + TCR Tg小鼠的模型，2）通过其快速免疫反应性T细胞鉴定幼稚和效应同种异体反应性T细胞， 在同种异体素刺激后产生细胞因子，和3）定量体内CDS T细胞效应子 使用体内细胞毒性测定法测定其功能。我们将利用这些技术和令人兴奋的新技术， 体内递送siRNA以阻断CD 40-CD 154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的诱导是一种基本机制， 该先天免疫活性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血淋巴细胞增殖诱导的机制， 宽容我们将检验TLR激动剂或病毒感染引起的先天免疫激活 通过产生促炎细胞因子消除外周耐受的诱导， IFNI。具体目标2是确定TLR连接或病毒感染调节的机制 造血嵌合体和中枢耐受的建立。我们将测试假设， 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淋巴细胞诱导的机制， 中枢移植耐受该项目将与研究维护 项目3研究同种异体反应性CDS T细胞如何在cosfimulation后通过凋亡死亡 封锁这些发现将在项目4中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。