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

• 批准号: 7644028
• 负责人: TERRY B. STROM
• 金额: $ 39.79万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644028
• 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

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，我们一直假设供者反应性致细胞病变效应T细胞与供者反应性致细胞病变效应T细胞之间的平衡， 移植物保护细胞决定同种异体移植反应的结果，即排斥或耐受。新 数据和工具的出现促使我们“现在去研究促炎和抗炎细胞因子的作用， 在同种异体移植物反应中抗原活化的T细胞的表型和功能，以及在移植物 结果本身。我们的工作模型是同种异体反应细胞对调节或移植物的承诺- 破坏性表型由这些细胞因子的平衡控制。我们的测试系统将采用胰岛 同种异体移植物，一种已知在围手术期特别容易受到有毒和有害物质影响的组织， 侮辱。我们进一步假设，阻断炎症将提供细胞保护， 成功植入并有助于耐受诱导。特别地，我们将关注<xi-抗胰蛋白酶（AAT）， 我们的初步数据显示，该试剂可为胰岛提供有效的细胞保护。来完成这项工作 我们有几个基因操作的小鼠品系，包括表达foxpS的双顺反子基因敲入小鼠， 和在foxpS启动子控制下的GFP。这些小鼠已经被培育为同种异体反应性TEa TCR 转基因株系我们也有基因敲入小鼠的创始人，其中1 L-17启动子驱动 IL-17和RFP。这些工具将被用作过继转移系统的一部分，沿着详细的表型， 在目标#1中，我们将测试Th 17表达和功能分析的假设。 一个细胞亚群在介导排斥和对抗调节方面具有独特的效力;在目标#2中，我们将 确定AAT是否可以改变移植物内促炎和抗炎细胞因子的表达， 减少达到正常所需的胰岛质量;在目标#3中，我们将测试 AAT的细胞保护和抗炎作用可以与共刺激阻断协同作用， 抑制炎症、促进调节和诱导耐受。由于这些药物目前在临床上 我们认为，这项工作，如果成功，有可能迅速转化为新的临床 胰岛移植的方法