Regulation of T cell immunity by indol 2,3 dioxygenase

描述（由申请人提供）： 建议的研究涉及的是确定和评估自然过程， 调节对组织同种异体移植物、肿瘤和细胞的免疫应答 被病原体感染的拟议研究的具体目标 是为了评估表达吲哚胺2，3双加氧酶（IDO）的细胞的作用， 其分解代谢色氨酸，在抑制T细胞介导的免疫中， 针对同种异体组织和肿瘤细胞。这些假设 相关的研究是表达IDO的细胞抑制或修饰T细胞， 提供针对T细胞介导的免疫的增加的保护的应答性 在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， 在局部组织微环境中被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 利用两种新的基因操作小鼠品系， 我们的实验室我们将测量小鼠的炎症和T细胞反应， 不表达IDO（IDO缺陷型小鼠）， 响应炎症信号过度表达IDO（MHCII-IDO小鼠）。目标1 我们将测试IDO的靶向缺失导致增强的 T细胞和补体的辅助和抗原呈递细胞功能 活化和靶向IDO过表达抑制T细胞和补体 activation.在目标2中，我们将评估同种异体和 携带有缺陷IDO等位基因的父母之间交配的同基因胎儿。 在目标3中，我们将评估对组织同种异体移植物的免疫反应， IDO缺陷和MHCII-IDO受体和供体小鼠。在目标4中，我们将测试 IDO活性抑制宿主抗肿瘤免疫的假设。 从这些研究中获得的数据将揭示IDO活性 在局部组织微环境中影响T细胞活化并阐明 T细胞驱动的补体沉积在妊娠中发生的机制 以及当IDO活性被阻断时荷瘤小鼠。知识来自 拟议的研究将使我们能够评估调整IDO的潜力 促进组织同种异体移植物接受的免疫抑制机制， 开发新的治疗策略，以帮助根除肿瘤， 免疫活性宿主。

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.