Adaptive and innate regulation of immune privilege.

对前房衍生抗原的系统免疫异常：某些免疫效应器(延迟 超敏反应、补体结合抗体)被删除/抑制，而其他(细胞毒性T细胞， 非补体结合抗体)。前房相关性免疫偏离(ACAID) 是眼睛免疫特免权的重要表现。在过去的几年里，我们的ACAID研究有(I) 确定了赋予ACAID诱导APC特性的基因(II)证明ACAID-APC具有 产生T调节(Tregs)细胞；(Iii)为这些APC定义了一种新的淋巴细胞运输模式；(Iv) ACAID APC与新的细胞(NKT细胞、边缘带B细胞)以及T细胞相互作用 位于脾边缘地带的细胞。基于这些结果，我们现在提出一个新的实验计划 五年来测试与影响外周耐受的T调节细胞有关的三个相关假设 在ACAID中：(I)我们认为ACAID的CD4和CD8 Treg细胞中的基因表达上调 将与免疫T细胞或NATve中的基因图谱不同。(Ii)我们建议ACAID的CD4 Treg 不是天然的CD4CD25树突状细胞，也不是依赖它们来分化的，而且独特的基因 在ACAID中上调的CD4 Treg对于它们在ACAID过程中的功能至关重要，(Iii)CD8 ACAID的调节性T细胞利用独特的基因产物抑制ACAID的诱导和表达 免疫性炎症。某些对T细胞调节至关重要的基因缺失导致臀位 免疫赦免与眼部炎症的表现。为了检验这些假设，我们描述了两个具体的 目的：1.分析ACAID患者CD4T调节功能的性质及机制；2.探讨ACAID患者外周血中CD4T细胞的调节功能 ACAID中CD8 Tregs的诱导和表达机制我们的长期目标是推动我们的 从分子水平了解ACAID和眼免疫豁免，进而制定治疗方案 预防或抑制眼部炎症性疾病的毒性非常有限(或无)的策略 (2)促进原位角膜和视网膜移植物的存活，也许(3)减轻 多因素眼病。

Systemic immunity to anterior chamber derived antigens is deviant: certain immune effectors (delayed hypersensitivity, complement fixing antibodies) are deleted/suppressed, whereas others (cytotoxic T cells, non-complement fixing antibodies) are promoted. Anterior Chamber Associated Immune Deviation (ACAID) is an important expression of ocular immune privilege. During the past years our ACAID studies have (i) identified the genes that confer ACAID -inducing properties on APCs (ii) documented ACAID-APCs capable of generating T regulatory (Tregs) cells; (iii)defined a novel lymphocyte traffic pattern for these APCs ;(iv) and showed that the ACAID APC interacted with novel cells (NKT cells, marginal zone B cells) as well as T cells in the marginal zone of the spleen. Based on these results we now propose a new experimental plan for five years to test three related postulates concerning the T regulatory cell that effects peripheral tolerance in ACAID: (i) We propose that the profile of the genes upregulated in the ACAID CD4+ and CD8+ Treg cell will be distinct from the gene profile in immune T cells or naTve. (ii) We propose that the ACAID CD4+ Treg are not natural CD4 CD25 Tregs or dependent on them for their differentiation and that the unique genes that are up regulated in ACAID CD4+ Treg are critical for their function in the ACAID process, (iii) CD8+ regulatory T cells of ACAID use unique gene products to effect suppression of induction and expression of immunogenic inflammation. Absence of certain genes critical for T cell regulation leads to a breech in immune privilege and appearance ocular inflammation. To test these hypotheses we describe two specific aims: 1. To analyze the quality and mechanism of CD4+ T regulatory function in ACAID; 2: To explore the mechanisms of induction and expression of CD8+ Tregs in ACAID. Our long term goal is to push our understanding of ACAID and ocular immune privilege to the molecular level, and then to devise treatment strategies of very limited (or no) toxicity with which to prevent or suppress ocular inflammatory diseases (uveitis), (ii)to promote survival of orthotopic cornea and retinal grafts, and perhaps (iii)to alleviate multifactorial eye diseases.