Adaptive and innate regulation of immuneprivilege

免疫特权的适应性和先天调节

• 批准号: 7195014
• 负责人: Joan Stein-Streilein
• 金额: $ 48.73万
• 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/7195014
• 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

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.

产品说明：对前房衍生抗原的全身免疫是异常的：某些免疫效应物（迟发性超敏反应、补体固定抗体）被删除/抑制，而其他免疫效应物（细胞毒性T细胞、非补体固定抗体）被促进。眼前房相关免疫偏离（ACAID）是眼免疫赦免的重要表现。在过去的几年中，我们的ACAID研究已经（i）鉴定了赋予APC ACAID诱导特性的基因，（ii）记录了能够产生T调节（T细胞）细胞的ACAID-APC;（iii）定义了这些APC的新的淋巴细胞运输模式;（iv）并显示ACAID APC与新的细胞（NKT细胞、边缘区B细胞）以及脾边缘区中的T细胞相互作用。基于这些结果，我们现在提出了一个新的实验计划，为期五年，以测试三个相关的假设，关于T调节细胞，影响外周耐受性的ACAID：（i）我们提出，基因的档案上调ACAID CD 4+和CD 8 + Treg细胞将是不同的基因档案免疫T细胞或天真。(ii)我们提出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，并且在ACAID CD 4 + Treg中上调的独特基因对于它们在ACAID过程中的功能是至关重要的。（iii）ACAID的CD 8+调节性T细胞使用独特的基因产物来实现对免疫原性炎症的诱导和表达的抑制。缺乏某些对T细胞调节至关重要的基因会导致免疫豁免和眼部炎症的出现。为了验证这些假设，我们描述了两个具体的目标：1。分析ACAID中CD 4 + T细胞调节功能的性质和机制; 2.探讨ACAID中CD 8 + T细胞的诱导表达机制。我们的长期目标是将我们对ACAID和眼部免疫豁免的理解推向分子水平，然后设计毒性非常有限（或没有）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物的存活，以及（iii）减轻多因素眼部疾病。