GENES THAT PROMOTE ACAID AND INHIBIT OCULAR INFLAMMATION

眼球免疫的独特性质是前房相关免疫偏离(ACAID)，这是一种不寻常的免疫反应，其特征是对前房引入的抗原诱导的水蒸气抑制。这种免疫反应本质上是全身性的。已知本地眼抗原提呈细胞在脾中诱导一种独特类型的抗原特异性调节细胞群，这被认为是导致ACAID中被抑制的DH反应的原因。虽然已知眼环境中的各种因素会影响抗原提呈细胞改变其功能，从而使这些细胞获得诱导ACAID的能力，但这些APC获得和表达这种独特能力的确切机制还不是很清楚。眼部环境中发现的一种细胞因子，TGFP，已被证明在APC的功能修饰中发挥重要作用，从而赋予它们诱导ACAID的能力。我们建议通过在遗传水平上检测转化生长因子[3]在这些细胞内诱导的变化来研究ACAID诱导的分子机制，这些变化继而导致APC的功能变化。利用分子生物学技术的最新进展，我们成功地比较了传统APC和ACAID诱导APC的转录程序。应用差异显示分析(使用RAP-PCR)，我们已经确定了APC唯一表达的基因，这些基因在功能上类似于眼睛来源的APC。此外，我们最近利用DNA微阵列技术对这些APC的表达谱进行了更全面的分析。现在，我们建议首先根据我们对ACAID免疫反应的现有知识和现有文献，确定哪些差异表达基因是ACAID诱导的合理候选基因。然后，我们采用系统的方法，采用各种策略(如反义抑制、抗体或拮抗剂介导的抑制、使用选择性缺乏某些基因的转基因小鼠、化学或药物诱导)。试剂或基因转染)，以研究所选候选基因与ACAID的功能相关性。这种检测特定基因产物参与赋予眼源性APC独特功能的方法，不仅将增强我们对仔细调控的眼睛免疫反应的理解，还将产生建议的治疗方案，通过这些疗法可以选择性地操纵眼睛微环境。

The unique nature of ocular immunity is characterized by anterior chamber associated immune deviation (ACAID), an unusual immune response that is eye characterized by suppressed DH induced to antigens introduced in the anterior chamber. Such an immune response is systemic in nature. Indigenous ocular antigen presenting cells are known to induce a unique type of antigen-specific regulatory cell population in the spleen which is believed to be responsible for suppressed DH responses in ACAID. While it is known that various factors in the ocular environment influence antigen presenting cells to modify their function such that these cells acquire the ability to induce ACAID, the exact mechanisms by which these APCs acquire and express this unique ability is not dearly understood. A cytokine found in abundance in the ocular environment, TGFP, has been demonstrated to play a significant role in functional modification of APCs thereby conferring upon them the ability to induce ACAID. We propose to study molecular mechanisms underlying ACAID induction by examining changes induced within these cells at genetic levels, by TGF[3, changes which in turn lead to functional alterations of an APC. Taking advantage of the latest advances in molecular biology techniques we have successfully compared the transcriptional program of conventional APCs with that of ACAID-inducing APCs. Applying differential display analysis (using RAP-PCR) we have identified genes uniquely expressed by the APCs that functionally resemble eye- derived APCs. Furthermore, we have recently employed DNA microarray technology to accomplish a more comprehensive analysis of expression profiles of these APCs. We now propose to first determine which of the differentially expresssed genes are reasonable candidates for ACAID induction based on our current knowledge of the immune response in ACAID and the available literature. We then adopt a systematic approach, employing various strategies (such as antisense inhibition, antibody or antagonist mediated inhibition, use of transgenic mice selectively deficient in certain genes, induction by chemical or pharmacological . agents or gene transfection) to study the functional relevance to ACAID of the selected candidate genes. Such an approach to examine involvement of specific gene products in conferring unique functional capabilities on eye-derived APCs will not only enhance our understanding of carefully regulated ocular immune responses but give rise to suggested therapies by which the ocular microenvironment can be selectively manipulated.