Adaptive and innate regulation of immune privilege

描述(申请人提供)：对前房抗原的系统免疫异常；某些免疫效应物(迟发型超敏反应、Th2反应、补体结合抗体)被缺失/抑制，而其他免疫效应物(细胞毒性T细胞、非补体结合抗体)被促进。前房相关免疫偏离(ACAID)是眼免疫赦免的重要表现。在以前的资助期间，我们的ACAID研究(I)表明ACAID CD8+和ACAID CD4+CD25-Treg的诱导发生在脾的边缘区域而不是白髓，而ACAID CD4+CD25+Treg的产生不是；(Ii)定义了与ACAID CD8+Treg细胞相关的基因，并表明CD103、FoxP3和MMP9是ACAID传出抑制所必需的。基于这些结果，我们提出了一个未来五年的实验计划，有以下三个目标：(I)比较和对比ACAID CD4+调节性T细胞亚群的抑制机制。(Ii)确定ACAID CD8+Treg用于抑制CD4+T效应细胞的机制，重点是CD8+Treg衍生的MMP9和维甲酸受体使用的特定机制；(Iii)通过在ACAID人嵌合体小鼠模型中研究ACAID Treg细胞来测试我们的发现对人类免疫学的意义。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)，或(Ii)减轻多因素眼部疾病。 公共卫生相关性：了解眼睛内免疫的基础，以及评价对眼源性抗原和病原体的免疫反应的性质，对其他组织和眼睛都相当重要。这些研究将为眼睛和外周T细胞调节领域增加新的信息。

DESCRIPTION (provided by applicant): Systemic immunity to anterior chamber antigens is deviant; certain immune effectors (delayed hypersensitivity, Th2 responses, 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 previous funding periods, our ACAID studies (i) showed that induction of ACAID CD8+ and ACAID CD4+ CD25- Tregs occurs in the marginal zone of the spleen rather than the white pulp while the generation of ACAID CD4+ CD25+ Treg does not; (ii) defined the genes associated with ACAID CD8+ Treg cells and showed that CD103, FoxP3 and MMP9 are necessary for ACAID efferent suppression. Based on these results, we propose an experimental plan for the next five years with the following three aims: (i) Compare and contrast ACAID CD4+ regulatory T cell subpopulations in regards to their mechanisms of suppression. (ii) Determine the mechanisms used by ACAID CD8+ Treg to suppress of CD4+ T effector cells, focusing on particular mechanisms used by CD8+ Treg derived - MMP9 and - retinoic acid receptor; (iii) test the significance of our findings for human immunology by studying ACAID Treg cells in a human chimera mouse model for 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 that prevent or suppress ocular inflammatory diseases (uveitis), or (ii) alleviate multifactorial eye diseases. PUBLIC HEALTH RELEVANCE: Understanding the basis for immunity within the eye, as well as appreciating the nature of immune responses to eye-derived antigens and pathogens are of considerable importance to other tissues as well as the eye. The studies will add new information to the field of T cell regulation in the eye and the periphery.