Adaptive and innate regulation of immune privilege.

免疫特权的适应性和先天调节。

• 批准号: 7568382
• 负责人: Joan Stein-Streilein
• 金额: $ 1.62万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568382
• 关键词: Address; Adult; Antibodies; Antigen-Presenting Cells; Antigens; Appearance; Area; B-Lymphocytes; CD8B1 gene; Cells; Complement; Cornea; Cytotoxic T-Lymphocytes; Delayed Hypersensitivity; Development; Disease; Effector Cell; Exposure to; Eye; Eye diseases; Five-Year Plans; Generations; Genes; Goals; IL2RA gene; Immune; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; KLRD1 gene; Lymphocyte; Mediating; Molecular; Mouse Strains; Mus; Numbers; Pattern; Peripheral; Personal Satisfaction; Physiologic pulse; Process; Property; Proteins; Pulse taking; Recruitment Activity; Regulation; Research Personnel; Retinal; Role; Spleen; Suppressor-Effector T-Lymphocytes; System; T cell regulation; T-Lymphocyte; Testing; Toxic effect; Transgenic Mice; Transgenic Organisms; Uveitis; Work; anterior chamber; base; cellular targeting; deviant; immunogenic; in vivo; novel; prevent; receptor; trafficking

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.

对前房衍生抗原的系统性免疫是异常的：某些免疫效应物（延迟的 超敏反应，补体结合抗体）被删除/抑制，而其它（细胞毒性T细胞， 非补体结合抗体）。前房相关免疫偏离（ACAID） 是眼免疫赦免重要表现。在过去的几年里，我们的ACAID研究（i） 鉴定了赋予APCs ACAID诱导特性的基因（ii）记录了ACAID-APCs能够 产生调节性T细胞;（iii）为这些APC定义了一种新的淋巴细胞运输模式;（iv） 并显示ACAID APC与新细胞（NKT细胞、边缘区B细胞）以及T细胞相互作用。 脾脏边缘区的细胞基于这些结果，我们现在提出一个新的实验方案 用了五年的时间来测试三个与影响外周耐受的调节性T细胞有关的假设 在ACAID中：（i）我们提出ACAID CD 4+和CD 8 + Treg细胞中上调的基因谱 将不同于免疫T细胞或naTve中的基因谱。(ii)我们建议ACAID CD 4 + Treg 不是天然的CD 4 CD 25 T细胞或依赖于它们的分化， 在ACAID中上调的CD 4 + Treg对其在ACAID过程中的功能至关重要，（iii）CD 8 + 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， 免疫原性炎症缺乏某些对T细胞调节至关重要的基因会导致T细胞的臀位。 免疫豁免和出现眼部炎症。为了验证这些假设，我们描述了两个具体的 目标：1.分析ACAID患者CD 4 + T细胞调节功能的性质和机制; 2.探讨ACAID患者CD 4 + T细胞调节功能的特点， ACAID中CD 8 + T细胞的诱导和表达机制。我们的长期目标是推动我们的 了解ACAID和眼部免疫豁免的分子水平，然后设计治疗方案 预防或抑制眼部炎症性疾病的毒性非常有限（或没有）的策略 （葡萄膜炎），（ii）促进原位角膜和视网膜移植物的存活，以及（iii）可能减轻 多因素眼病