Adaptive and innate regulation of immuneprivilege

免疫特权的适应性和先天调节

• 批准号: 7388130
• 负责人: Joan Stein-Streilein
• 金额: $ 56.12万
• 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/7388130
• 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：对前房衍生抗原的系统免疫发生异常：某些免疫效应器（迟发性超敏反应、补体固定抗体）被删除/抑制，而其他免疫效应器（细胞毒性 T 细胞、非补体固定抗体）则被促进。 ACAID）是眼部免疫特权的重要表达，在过去的几年中，我们的 ACAID 研究已 (i) 确定了赋予 ACAID 诱导特性的基因。 APC (ii) 记录了能够生成 T 调节 (Treg) 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) 并表明 ACAID APC 与新细胞（NKT 细胞、边缘区）相互作用。 B 细胞）以及脾边缘区的 T 细胞 基于这些结果，我们现在提出一项为期五年的新实验计划，以测试有关影响外周耐受性的 T 调节细胞的三个相关假设。 ACAID：（i）我们建议 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¿ (ii) 我们认为 ACAID CD4+ Treg 不是天然的 CD4 CD25 Treg 或依赖于它们的分化，并且 ACAID CD4+ Treg 中上调的独特基因对于它们在 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。某些对 T 细胞调节至关重要的基因的缺失会导致特权免疫和外观的破坏。为了检验这些假设，我们描述了两个具体目标：1.分析ACAID中CD4+T调节功能的质量和机制；2.探索ACAID中CD8+Treg的诱导和表达机制。将我们对 ACAID 和眼部免疫特权的理解提升到分子水平，然后设计毒性非常有限（或无）的治疗策略，用于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，也许（iii）缓解多因素眼部疾病。