Adaptive and innate regulation of immuneprivilege

描述：对前房衍生抗原的系统免疫是异常的：某些免疫效应器（延迟超敏反应，补体固定抗体）被删除/抑制，而其他免疫效应器（细胞毒性T细胞，非补体固定抗体）被促进。前房相关免疫偏差（ACAID）是眼部免疫特权的重要表现。在过去的几年里，我们的ACAID研究已经(i)确定了赋予apc ACAID诱导特性的基因（ii）记录了能够产生T调节性（Tregs）细胞的ACAID- apc；（iii）为这些apc定义了一种新的淋巴细胞运输模式；（iv）结果表明，ACAID APC与脾脏边缘区的新细胞（NKT细胞、边缘区B细胞）和T细胞相互作用。基于这些结果，我们现在提出一项为期五年的新实验计划，以测试有关T调节细胞影响ACAID外周耐受性的三个相关假设：(i)我们提出ACAID CD4+和CD8+ Treg细胞中上调的基因谱将不同于免疫T细胞或na - ve中的基因谱。（ii）我们提出ACAID CD4+ Treg不是天然的CD4 CD25 Treg或依赖于它们来分化，并且ACAID CD4+ Treg中上调的独特基因对其在ACAID过程中的功能至关重要；（iii） ACAID的CD8+调节性T细胞使用独特的基因产物来抑制免疫原性炎症的诱导和表达。缺乏某些对T细胞调节至关重要的基因会导致免疫特权的缺失和眼部炎症的出现。为了验证这些假设，我们描述了两个具体目标：分析ACAID患者CD4+ T调节功能的性质及机制；2：探讨CD8+ Tregs在ACAID中的诱导表达机制。我们的长期目标是将我们对ACAID和眼免疫特权的理解推进到分子水平，然后设计出非常有限（或无）毒性的治疗策略，以预防或抑制眼部炎症性疾病（葡萄膜炎），（ii）促进原位角膜和视网膜移植的存活，也许（iii）减轻多因素眼病。

DESCRIPTION: 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 na¿ve. (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.