Adaptive and innate regulation of immune privilege

描述（由申请人提供）：对前房抗原的全身免疫异常；某些免疫效应器（延迟超敏反应、Th2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）被促进。前房相关免疫偏差（ACAID）是眼部免疫特权的重要表现。在之前的资助期内，我们的ACAID研究(i)表明，ACAID CD8+和ACAID CD4+ CD25- Treg的诱导发生在脾脏边缘区，而不是白髓，而ACAID CD4+ CD25+ Treg的产生则不会；（ii）明确了与ACAID相关的CD8+ Treg细胞基因，发现CD103、FoxP3和MMP9是ACAID输出抑制所必需的。基于这些结果，我们提出了未来五年的实验计划，主要有以下三个目标：(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抑制CD4+ T效应细胞的机制，重点关注CD8+ Treg衍生的- MMP9和-视黄酸受体的特定机制；（iii）通过在ACAID人嵌合体小鼠模型中研究ACAID Treg细胞来检验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和眼部免疫特权的理解推进到分子水平，然后设计出非常有限（或没有）毒性的治疗策略，以预防或抑制眼部炎症性疾病（葡萄膜炎），或者（ii）减轻多因素眼病。

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.