Regulation of ACAID by lymphocytes with NK markers

描述(申请人提供)：对自身或外来抗原的耐受是一个由多种机制调节的主动过程。中枢耐受是通过大量能够对自身分子产生反应的淋巴细胞的负选择或中心缺失来促进的。然而，一些自身反应性淋巴细胞仍然受到主动耐受的调节，涉及调节细胞、无能或凋亡。这些机制的崩溃会导致自身免疫反应，比如眼睛中的葡萄膜炎。眼睛是一个免疫特权部位，它已经进化为表现出免疫抑制机制，以防止免疫性炎症性疾病，以保护视力。前房相关免疫偏离(ACAID)是一种小鼠模型，允许探索眼睛使用的耐受诱导机制。淋巴细胞与获得性免疫相关的作用在ACAID文献中有很好的描述。这些研究探讨了先天免疫细胞在前房接种抗原诱导的外周免疫耐受形成过程中的调节机制。在我们第一个资助期的研究结果的基础上，我们将探索NKT细胞在致敏小鼠ACAID中的作用，研究抗原提呈细胞(树突状细胞，DC)如何在耐受发展过程中领导NKT细胞，并探讨边缘带(MZ)B细胞在指导NKT细胞功能和ACAID中的作用。我们将使用细胞免疫学、免疫组织化学、分子生物学技术(包括RT-PCR和核探针分析)、流式细胞术、共聚焦显微镜，通过对1)树突状细胞亚群和2)NKT细胞与MZ B细胞的遗传差异进行微基因分析来探索潜在的基因。这些研究的结果将使我们更好地理解眼睛和个体整体的耐受机制。致敏动物的耐受诱导机制可能导致新的治疗方法，可能适用于免疫性炎症性疾病患者。

DESCRIPTION (provided by applicant): Tolerance to self or foreign antigens is an active process that is mediated by multiple mechanisms. Central tolerance is promoted by negative selection or central deletion of a large number of lymphocytes capable of reacting to self molecules. However, some self-reactive lymphocytes remain to be regulated by active tolerance involving regulatory cells, anergy, or apoptosis. A breakdown in these mechanisms leads to autoimmune reactivity such as uveitis in the eye. The eye is an immune privileged site that has evolved to exhibit immune suppressive mechanisms that prevent immune inflammatory diseases in order to preserve vision. Anterior Chamber Associated Immune Deviation (ACAID) is a mouse model allowing for exploration of tolerance inducing mechanisms used by the eye. The role of lymphocytes associated with acquired immunity are well described in ACAID literature. These studies explore the mechanisms of regulation contributed by innate immune cells in the development of peripheral tolerance induced by antigen inoculation in the anterior chamber (ac). Building on results from studies in our first funding period we will explore the role of NKT cells in ACAID in sensitized mice, study how the antigen presenting cell (dendritic cell, DC) leads the NKT cell in the process of tolerance development and investigate the role of marginal zone (MZ) B cells in directing NKT cell function and ACAID. We will use cellular immunology methods, immunohistochemistry, molecular biology techniques (including rtPCR and Riboprobe analyses), flow cytometry, confocal microscopy and explore the potential genes involved by performing microgene analyses on genetic differences in 1) subsets of DCs, and 2) NKT cells exposed to tolerogenic APCs, versus MZ B cells. The results from these studies will generate better understanding of tolerance mechanisms in the eye and the individual as a whole. Mechanisms of tolerance induction in the sensitized animals may lead to novel therapies, potentially adaptable to patients with immune inflammatory diseases.