Regulation of T cell immunity by indol 2,3 dioxygenase

说明(由申请人提供)： 拟议的研究涉及识别和评估 调节对异体组织、肿瘤和细胞的免疫反应性 被病原体感染的。提出了研究的具体目标 是为了评估表达吲哚胺2，3双加氧酶(IDO)的细胞的作用， 它在抑制T细胞介导的定向免疫中分解色氨酸 抗同种异体组织和肿瘤细胞。这些人认为的假设 相关研究表明，表达IDO的细胞抑制或修饰T细胞 增强对T细胞介导的免疫的保护作用 对于局部组织微环境中的细胞。我们还将进行实验 评估T细胞和补体激活之间的机制联系 被局部组织微环境中的IDO活性抑制。 为了评估IDO在炎症和免疫抑制中的作用，我们将 利用两个新的基因操纵小鼠品系最近在 我们的实验室。我们将测量小鼠的炎症反应和T细胞反应 不表达IDO(IDO缺陷小鼠)和在转基因小鼠中 在炎症信号反应中过度表达IDO(MHCII-IDO小鼠)。在目标1中 我们将测试有针对性地删除IDO会导致增强的假设 T细胞和补体的辅助和抗原提呈细胞功能 激活和靶向IDO过表达抑制T细胞和补体 激活。在目标2中，我们将评估异基因和同种异体妊娠的结局 携带缺陷IDO等位基因的父母配对中的同基因胎儿。 在目标3中，我们将评估同种异体组织移植的免疫反应。 IDO缺陷和MHCII-IDO受体和供体小鼠。在目标4中，我们将测试 假设IDO活性抑制宿主抗肿瘤免疫。 从这些研究中获得的数据将揭示IDO活动的程度 局部组织微环境对T细胞活化的影响及意义 孕期T细胞驱动补体沉积的机制 以及当IDO活性被阻断时对荷瘤小鼠的影响。从课程中学到的知识 拟议的研究将使我们能够评估适应IDO的潜力 促进同种异体组织移植接受的免疫抑制机制 开发新的治疗策略以帮助根除肿瘤 有免疫能力的宿主。

DESCRIPTION (provided by the applicant): The long-term objectives to which the proposed studies relate are to identify and evaluate natural processes that regulate immune responsiveness towards tissue allografts, tumors and cells infected with pathogenic organisms. The specific goal of the studies proposed is to evaluate the role of cells expressing indoleamine 2,3 dioxygenase (IDO), which catabolizes tryptophan, in suppressing T cell mediated immunity directed against allogeneic tissues and tumor cells. The hypothesis to which these studies relate is that cells expressing IDO suppress or modify T cell responsiveness providing increased protection against T cell mediated immunity for cells in local tissue microenvironments. We will also conduct experiments to evaluate mechanistic links between T cell and complement activation that are suppressed by IDO activity in local tissue microenvironments. To evaluate the role of IDO in inflammation and immunosuppression we will utilize two new strains of genetically-manipulated mice generated recently in our laboratory. We will measure inflammatory and T cell responses in mice that do not express IDO (IDO-deficient mice) and in transgenic mice that over-express IDO in response to inflammatory signals (MHCII-IDO mice). In Aim 1 we will test the hypothesis that targeted deletion of IDO leads to enhanced accessory and antigen-presenting cell functions for T cell and complement activation and targeted IDO over-expression suppresses T cell and complement activation. In Aim 2 we will evaluate pregnancy outcomes for allogeneic and syngeneic fetuses in matings between parents that carry defective IDO alleles. In Aim 3 we will evaluate immune responses to tissue allografts from IDO-deficient and MHCII-IDO recipient and donor mice. In Aim 4 we will test the hypothesis that IDO activity suppresses host anti-tumor immunity. Data obtained from these studies will reveal the extent to which IDO activity in local tissue microenvironments influences T cell activation and elucidate the mechanism by which T cell driven complement deposition occurs in pregnant and tumor-bearing mice when IDO activity is blocked. Knowledge gained from the proposed studies will allow us to evaluate the potential for adapting the IDO immunosuppressive mechanism to facilitate tissue allograft acceptance and develop novel therapeutic strategies to help eradicate tumors in immunocompetent hosts.