Inflammation and the Balance of Cytopathic versus Regulatory T Cells

炎症以及细胞病变与调节性 T 细胞的平衡

基本信息

批准号：
7338986
负责人：
TERRY B. STROM
金额：
$ 39.9万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7338986
关键词：
Adoptive Transfer Allogenic Allografting Anti-Inflammatory Agents Anti-inflammatory Antigens Breeding C57BL/6 Mouse CD4 Positive T Lymphocytes Cells Clinical Commit Condition Cytoprotection Data Engraftment Environment Equilibrium Graft Rejection Green Fluorescent Proteins Immune response Immunity Inbred BALB C Mice Inbred NOD Mice Inflammation Inflammatory Insulin Insulin Resistance Interleukin-10 Interleukin-17 Interleukin-6 Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Knock-in Mouse Mediating Mediator of activation protein Modeling Mus Outcome Pattern Phenotype Protein C Inhibitor Regulation Research Personnel Role Signal Transduction System T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Tea Testing Tissues Transgenic Organisms Translations Transplantation Trypsin Work concept cytokine diabetic islet islet allograft prevent programs promoter research study resilience response restoration tool

Adoptive Transfer Allogenic Allografting Anti-Inflammatory Agents Anti-inflammatory Antigens Breeding C57BL/6 Mouse CD4 Positive T Lymphocytes Cells Clinical Commit Condition Cytoprotection Data Engraftment Environment Equilibrium Graft Rejection Green Fluorescent Proteins Immune response Immunity Inbred BALB C Mice Inbred NOD Mice Inflammation Inflammatory Insulin Insulin Resistance Interleukin-10 Interleukin-17 Interleukin-6 Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Knock-in Mouse Mediating Mediator of activation protein Modeling Mus Outcome Pattern Phenotype Protein C Inhibitor Regulation Research Personnel Role Signal Transduction System T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Tea Testing Tissues Transgenic Organisms Translations Transplantation Trypsin Work concept cytokine diabetic islet islet allograft prevent programs promoter research study resilience response restoration tool

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项目摘要

We have long hypothesized that the balance of donor-reactive cytopathic effector T cells to donor reactive graft protecting cells determines the outcome of the allograft response, namely rejection or tolerance. New data and tools have emerged that prompt us"nowto examine the role of pro- and anti-inflammatory cytokines upon the phenotype and function of antigen activated T cells in the allograft response, and upon graft outcome itself. Our working model is that the commitment of alloreactive cells to a regulatory or graft- destructive phenotype is governed by the balance of these cytokines. Our test systems will employ islet allografts, a tissue known to be particularly vulnerable in the peri-operative period to toxic and noxious insults. We further postulate that blockade of inflammation will provide cytoprotection that will promote successful engraftment and assist in tolerance induction. In particular, we will focus on <xi-anti-trypsin(AAT), an agent which our preliminary data shows to provide potent cytoprotection to islets. To perform this work we have several lines of genetically manipulated mice, including bicistronic knock-in mice that express foxpS and GFP under control of the foxpS promoter. These mice have been bred to the alloreactive TEa TCR transgenic line. We also have founders for knock-in mice in which the 1L-17 promoterdrives expression of lL-17 and RFP. These tools will be used as part of adoptive transfer systems along with detailed phenotypic, expression, and functional analyses for the following: In aim #1, we will test the hypothesis that the Th17 subset of cells are uniquely potent in mediating rejection and opposing regulation; in aim #2, we will determine whether AAT can alter the expression of pro- and anti-inflammatory cytokines within the graft and reduce the islet mass needed to achieve euglycemia; and in aim #3, we will test whether the combination of the cytoprotective and anti-inflammatory effects of AAT can synergize with costimulatory blockade to suppress inflammation, promote regulation, and induce tolerance. As these agents are currently clinically available, we feel that this work, if successful, has the potential for rapid translation into new clinical approaches in islet transplantation.

长期以来，我们已经假设供体反应性细胞病的效应T细胞与供体反应性的平衡保护细胞的移植物决定了同种异体移植反应的结果，即排斥或耐受性。新的已经出现了数据和工具，促使我们“现在检查促疾病和抗炎细胞因子的作用在同种异体移植反应中抗原激活的T细胞的表型和功能以及移植物上结果本身。我们的工作模型是同种反应性细胞对调节或移植的承诺破坏性表型受这些细胞因子平衡的控制。我们的测试系统将采用胰岛同种异体移植物，该组织在围手术期间特别容易受到有毒和有害的组织侮辱。我们进一步假设，炎症的阻塞将提供细胞保护，以促进成功植入并协助耐受性诱导。特别是，我们将专注于<xi-anti-trypsin（aat），我们的初步数据显示的代理为胰岛提供有效的细胞保护作用。执行这项工作我们有几行遗传操纵的小鼠，包括表达Foxps 和GFP在FOXPS启动子的控制下。这些小鼠已经繁殖到同种异体茶TCR上转基因线。我们还拥有敲入小鼠的创始人，其中1L-17启动器表达的表达 LL-17和RFP。这些工具将用作收养转移系统的一部分，以及详细的表型，表达和以下功能分析：在AIM＃1中，我们将测试TH17的假设细胞的子集在介导排斥和相反调节方面具有独特的效力。在AIM＃2中，我们将确定AAT是否可以改变移植物内的促和抗炎细胞因子的表达减少达到尤利克血症所需的胰岛质量；在AIM＃3中，我们将测试是否组合 AAT的细胞保护作用和抗炎作用可以与共同障碍协同作用抑制炎症，促进调节并诱导耐受性。由于这些代理商目前在临床上可用，我们认为这项工作（如果成功）有可能快速转化为新的临床胰岛移植的方法。