MOLECULAR MECHANISMS UNDERLYING ACAID INDUCTION

酸诱导的分子机制

• 批准号: 6760466
• 负责人: SHARMILA MASLI
• 金额: $ 39.2万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760466
• 关键词: CD antigens; I kappa B beta; antigen presenting cell; biological signal transduction; cytokine; cytokine receptors; cytotoxic T lymphocyte; delayed hypersensitivity; eye disorder; immunopathology; interferon gamma; interleukin 12; laboratory mouse; molecular pathology; nuclear factor kappa beta; protein biosynthesis; transforming growth factors; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Immune response to ocular antigens is unique in that it is selectively deficient in delayed type hypersensitivity (DTH) mediating Th1 effectors and complement fixing immunoglobulins, while non-complement fixing immunglobulins and cytotoxic T cells remain detectable. Such deviation from a conventional immune response is referred to as Anterior Chamber Associated Immune Deviation (ACAID). This immune response is known to contribute to the immune privilege status of the eye. Resident ocular antigen presenting cells (APCs) are endowed with the ability to induce this response in an antigen specific manner by migrating out to the recipient spleen and presenting antigen to the responders T cells in a manner that generates regulatory cells. These cells in turn are known to prevent DTH responses. The ACAID-inducing ability of ocular APCs is mainly attributed to their exposure to TGFbeta in the eye. Conventional APCs derived from non-ocular sources are also known to acquire such unique ACAID-inducing properties when exposed to TGFbeta. Understanding molecular mechanisms underlying this functional transformation in APCs offers potential to develop therapeutic strategies to prevent ocular inflammation as well as to generate regulatory APCs ex vivo to be used for various clinical applications that require regulation of an undesirable immune response. To this end we have attempted identification of genes that are selectively expressed in TGFbeta-treated APCs. Applying differential analysis of genes (RAP-PCR and Genechip Microarrays) to RNA isolated from untreated APCs and TGFbeta-treated APCs, we isolated several differentially expressed genes that can be relevant in ACAID-inducing properties of APCs. Such an approach has allowed us to select potentially significant genes that have been unsuspected, so far, to be relevant in ACAID-induction. To begin with, we have chosen genes based on their known properties and as they relate to existing information available regarding various aspects of ACAID and APCs involved in its induction as well as the unique ocular microenvironment. We now propose to analyze the participation of these gene products (thrombospondin, TNFR II and IkappaBetaalpha) and their role in ACAID induction by TGFbeta-treated APCs. First, significance of these molecules in development of various aspects of ACAID will be evaluated followed by analysis of individual mechanisms regulated by these gene products. By comparing the effects of these genes and assessing interrelated mechanisms we propose to test a possibility to effectively use TGFbeta-treated APCs to prevent experimental autoimmune uveitis (EAU) and skin allograft rejection.

描述（由申请人提供）：对眼部抗原的免疫反应是独特的，因为它选择性地缺乏介导 Th1 效应子的迟发型超敏反应 (DTH) 和补体固定免疫球蛋白，而非补体固定免疫球蛋白和细胞毒性 T 细胞仍然可检测到。这种与传统免疫反应的偏差被称为前房相关免疫偏差（ACAID）。众所周知，这种免疫反应有助于眼睛的免疫特权状态。常驻眼部抗原呈递细胞 (APC) 具有以抗原特异性方式诱导这种反应的能力，通过迁移到受体脾脏并以产生调节细胞的方式将抗原呈递给应答者 T 细胞。众所周知，这些细胞又可以阻止 DTH 反应。眼 APC 的 ACAID 诱导能力主要归因于它们在眼中暴露于 TGFbeta。已知来自非眼源的传统 APC 在暴露于 TGFbeta 时也会获得这种独特的 ACAID 诱导特性。了解 APC 中这种功能转变背后的分子机制，为开发预防眼部炎症的治疗策略以及离体产生调节性 APC 以用于需要调节不良免疫反应的各种临床应用提供了潜力。为此，我们尝试鉴定在 TGFbeta 处理的 APC 中选择性表达的基因。通过对从未处理的 APC 和经 TGFbeta 处理的 APC 中分离的 RNA 进行基因差异分析（RAP-PCR 和 Genechip 微阵列），我们分离出了几个与 APC 的 ACAID 诱导特性相关的差异表达基因。这种方法使我们能够选择迄今为止未被怀疑与 ACAID 诱导相关的潜在重要基因。首先，我们根据基因的已知特性来选择基因，因为它们与有关 ACAID 和参与其诱导的 APC 的各个方面以及独特的眼部微环境的现有信息相关。我们现在建议分析这些基因产物（血小板反应蛋白、TNFR II 和 IkappaBetaalpha）的参与及其在 TGFbeta 处理的 APC 诱导 ACAID 中的作用。首先，将评估这些分子在 ACAID 各个方面的发展中的重要性，然后分析这些基因产物调节的个体机制。通过比较这些基因的作用并评估相关机制，我们建议测试有效使用 TGFbeta 处理的 APC 来预防实验性自身免疫性葡萄膜炎 (EAU) 和皮肤同种异体移植排斥的可能性。