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MODULATION OF T LYMPHOCYTE REGULATION

T 淋巴细胞调节的调节

基本信息

批准号：
7900230
负责人：
CHRISTIAN LEGUERN
金额：
$ 2.67万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-12 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900230
关键词：
Adoptive Transfer Adverse drug effect Adverse effects Affect Allografting Antigen-Presenting Cells Antigens Binding Bone Marrow CD4 Positive T Lymphocytes Cell Proliferation Cell physiology Cells Cleaved cell Clinical Protocols Complex Data Development Docking Drug or chemical Tissue Distribution Effector Cell Experimental Designs Family suidae Gene Transfer Genes Goals Graft Survival Heart Heart Transplantation Helper-Inducer T-Lymphocyte Histocompatibility Antigens Class II Immune Immune response Immune system Immunity Immunocompetent Immunosuppression Immunosuppressive Agents Implant In Vitro Injection of therapeutic agent Kidney Kidney Transplantation Life Lymphocyte MHC Class II Genes MHC antigen Maintenance Mediating Membrane Minor Molecular Mus Outcome Pattern Peptides Pharmaceutical Preparations Phenotype Play Principal Investigator Process Production Protocols documentation Regulation Rest Role Specificity Surface T-Lymphocyte Testing Time Toxic effect Transgenes Transgenic Organisms Transplantation Transplantation Tolerance allotransplant anergy base cell type clinical application cytokine cytotoxic design expression vector gene therapy in vivo prevent programs research study response therapeutic development transgene expression vector

项目摘要

DESCRIPTION (provided by applicant): There is a crucial need for the development of new strategies that would achieve transplantation tolerance without the deleterious side effects of drug-mediated immunosuppression. Assessing potential alternatives, we have established that the transfer of graft-type MHC class II gene(s) in recipients promotes spreading T cell tolerance to subsequent kidney grafts; i.e., the absence of host T cell response to all graft-associated major and minor antigens. Our long-term goal is to elucidate the mechanism of class ll-mediated tolerance as a prerequisite to the development of therapeutic protocols for transplantation tolerance. The specific hypothesis is that class II peptides, derived from the transferred gene and the class ll-matched graft, are the key inducers of tolerance through the activation of host regulatory T cells (T-regs). This hypothesis is based on the observations that: 1) transferred CI2 molecules are converted into peptides in antigen-presenting cells (ARC); 2) CI2 transgene-derived peptides activate T-regs in vitro for suppression of T effector cell proliferation and 3) the injection of T-regs, but not T effector cells, isolated from graft acceptors convey tolerance to identical grafts implanted in immunocompetent hosts. These observations have defined the focus of the project which is on the CI2-induced, T-reg-mediated, regulatory tolerance to CI2-matched grafts. The specific aims are to: 1. Evaluate the tissue-distribution patterns of the CI2 transgene expression and its effects on the immune system of the recipient. We will correlate the pattern of transgene expression in graft hosts with its outcome on graft survival and immune responses to donor antigens. 2. Analyze the impact of donor CI2 surface expression versus peptide expression on host immune status and tolerance to CI2-matched grafts. Using vectors for directed class II expression as surface molecules or peptides on APCs and non-professional APCs, we will ascertain in vivo whether class II peptide expression on APCs is a requirement for spreading tolerance. 3. Study the specificity of T-reg activation and suppression on alloreactive effector T cells. We will: (i) characterize the class ll-derived peptides that induce T-reg activation; (ii) use peptide-activated T-regs in adoptive transfer experiments; and, (iii) assess whether class II antigens from the graft are involved in T-reg activation and spreading tolerance.

描述（由申请人提供）：迫切需要开发新的策略，以实现移植耐受，而没有药物介导的免疫抑制的有害副作用。评估潜在的替代方案，我们已经确定，移植物型MHC II类基因在受体中的转移促进了T细胞耐受性向随后的肾移植物的扩散;即，宿主T细胞对所有移植物相关的主要和次要抗原的应答的缺乏。我们的长期目标是阐明II类介导的耐受机制，作为开发移植耐受治疗方案的先决条件。具体的假设是，II类肽，来自转移的基因和II类匹配的移植物，是通过激活宿主调节性T细胞（T细胞）的耐受性的关键诱导剂。该假设基于以下观察：1）转移的Cl 2分子在抗原呈递细胞（ARC）中转化为肽; 2）Cl 2转基因衍生的肽在体外激活T-T细胞以抑制T效应细胞增殖，和3）注射从移植物受体分离的T-T细胞而不是T效应细胞传递对植入免疫活性宿主中的相同移植物的耐受性。这些观察结果确定了该项目的重点，即CI 2诱导的T-reg介导的对CI 2匹配移植物的调节耐受性。具体目标是：1.评估CI 2转基因表达的组织分布模式及其对受体免疫系统的影响。我们将把移植宿主中转基因表达的模式与其对移植物存活和对供体抗原的免疫应答的结果相关联。2.分析供体CI 2表面表达相对于肽表达对宿主免疫状态和对CI 2匹配移植物的耐受性的影响。使用用于定向II类表达的载体作为APC和非专业APC上的表面分子或肽，我们将在体内确定APC上的II类肽表达是否是扩散耐受性的要求。3.研究T-reg激活和抑制同种异体反应性效应T细胞的特异性。我们将：（i）表征诱导T-reg活化的II类衍生肽;（ii）在过继转移实验中使用肽活化的T-reg;和（iii）评估来自移植物的II类抗原是否参与T-reg活化和扩散耐受。