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.

描述：对前房来源抗原的系统免疫异常：某些免疫效应物(迟发型超敏反应、补体固定抗体)被缺失/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。前房相关免疫偏离(ACAID)是眼免疫赦免的重要表现。在过去的几年里，我们的ACAID研究已经(I)确定了赋予APC诱导ACAID特性的基因；(Ii)证明了ACAID-APC能够产生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)并且显示ACAID APC与新的细胞(NKT细胞、边缘带B细胞)以及脾边缘区域的T细胞相互作用。基于这些结果，我们现在提出一个为期五年的新的实验计划，以测试与ACAID中影响外周耐受的T调节细胞相关的三个假设：(I)我们认为ACAID中CD4+和CD8+Treg细胞上调的基因谱将不同于免疫T细胞或NA的基因谱。(Ii)我们认为ACAID的CD4+Treg不是天然的CD4CD25树突状细胞，也不依赖于它们的分化，ACAID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。缺乏对T细胞调节至关重要的某些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CD4+T细胞调节功能的性质和机制；2：探讨ACAID中CD8+Tregs的诱导和表达机制。我们的长期目标是将我们对ACAID和眼睛免疫豁免的理解推向分子水平，然后设计出毒性非常有限(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，并可能(Iii)减轻多因素眼病。