MOLECULAR MECHANISMS UNDERLYING ACAID INDUCTION

酸诱导的分子机制

• 批准号: 7112259
• 负责人: SHARMILA MASLI
• 金额: $ 38.28万
• 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/7112259
• 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一无二的，因为它在介导Th1效应子和补体固定免疫球蛋白的延迟类型高敏性（DTH）中有选择性缺陷，而不固定固定Immunglobulobulins and Nimungotoxic T细胞仍然可检测。与常规免疫反应的这种偏差称为前腔相关的免疫偏差（ACAID）。已知这种免疫反应有助于眼睛的免疫特权状况。驻留的眼部抗原呈递细胞（APC）具有通过迁移到受体脾脏并以产生调节细胞的方式向响应者T细胞呈现抗原来诱导这种反应的能力。这些细胞反过来又可以防止DTH响应。眼APC的ACAID诱导能力主要归因于它们在眼中暴露于TGFBETA。众所周知，源自非目录源的常规APC在暴露于TGFBETA时会获得这种独特的Acaid诱导特性。了解APC中这种功能转化的分子机制提供了开发治疗策略的潜力，以防止眼部炎症，并产生调节性APC，以用于各种临床应用，需要调节不可避免的免疫反应。为此，我们尝试鉴定在TGFBETA处理的APC中选择性表达的基因。将基因（RAP-PCR和Genechip微阵列）的差异分析应用于未经处理的APC和TGFBETA处理的APC分离的RNA，我们分离了几个可能与APC的ACAID诱导特性相关的差异表达的基因。这样的方法使我们能够选择到目前为止尚未引起的潜在重要基因与ACAID诱导相关。首先，我们根据其已知属性选择了基因，并与有关其诱导涉及的ACAID和APC的各个方面以及独特的眼微环境的现有信息有关。现在，我们建议分析这些基因产物（血小板传播，TNFR II和Ikappabetaalpha）的参与，及其在TGFBETA处理的APC中的作用。首先，这些分子在ACAID各个方面的发展中的重要性将评估，然后分析由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互关联的机制，我们建议测试有效使用TGFBETA处理的APC的可能性，以防止实验性自身免疫性葡萄膜炎（EAU）和皮肤同种异体移植抑制。