Adaptive and innate regulation of immune privilege.

对前房衍生抗原的系统免疫是异常的：某些免疫效应物（延迟 超敏反应、补体固定抗体）被删除/抑制，而其他细胞（细胞毒性 T 细胞、 非补体固定抗体）得到推广。前房相关免疫偏差 (ACAID) 是眼部免疫豁免的重要表现。在过去的几年里，我们的 ACAID 研究已经 (i) 鉴定了赋予 APC 诱导 ACAID 特性的基因 (ii) 记录了 ACAID-APC 的能力 产生调节性 T (Treg) 细胞； (iii) 为这些 APC 定义了一种新的淋巴细胞运输模式；(iv) 并表明 ACAID APC 与新细胞（NKT 细胞、边缘区 B 细胞）以及 T 细胞相互作用 脾脏边缘区的细胞。根据这些结果，我们现在提出一个新的实验计划 五年来测试关于影响外周耐受性的 T 调节细胞的三个相关假设 在 ACAID 中：(i) 我们提出 ACAID CD4 和 CD8 Treg 细胞中上调的基因谱 将与免疫 T 细胞或 naTve 中的基因谱不同。 (ii) 我们建议 ACAID CD4 Treg 不是天然的 CD4 CD25 Tregs 或依赖于它们的分化，并且独特的基因 在 ACAID CD4 Treg 中上调的细胞对其在 ACAID 过程中的功能至关重要，(iii) CD8 ACAID 的调节性 T 细胞使用独特的基因产物来抑制 ACAID 的诱导和表达 免疫原性炎症。某些对 T 细胞调节至关重要的基因的缺失会导致 免疫特权和出现眼部炎症。为了检验这些假设，我们描述了两个具体的 目的： 1. 分析ACAID中CD4 T调节功能的质量和机制； 2：探索 ACAID 中 CD8 Tregs 的诱导和表达机制。我们的长期目标是推动我们 从分子水平了解 ACAID 和眼部免疫豁免，然后制定治疗方案 用于预防或抑制眼部炎症疾病的毒性非常有限（或无）的策略 （葡萄膜炎），（ii）促进原位角膜和视网膜移植物的存活，也许（iii）缓解 多因素眼部疾病。

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.