The Role of Thymic Homing Dendritic Cells in Oral Tolerance

胸腺归巢树突状细胞在口服耐受中的作用

• 批准号: 9243210
• 负责人: HUSEIN HADEIBA
• 金额: $ 35万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243210
• 关键词: Adhesions; Adoptive Transfer; Affect; Antigens; Applications Grants; Arthritis; Autoimmune Process; Autoimmune Responses; Autoimmunity; Blood; Cells; Clinic; Clonal Deletion; Dendritic Cells; Development; Diabetes Mellitus; Diet; Disease; Enteral; Event; Genetic; Gut associated lymphoid tissue; Homing; Immune; Immune system; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Intestines; Leukocytes; Mediating; Modeling; Monitor; Multiple Sclerosis; Mus; Nature; Oral; Oral Administration; Outcome; Output; Pathogenicity; Pathologic; Pathology; Peptides; Peripheral; Phenotype; Population; Prevention; Proteins; Protocols documentation; Regulatory T-Lymphocyte; Role; Sampling; Self Administration; Site; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Thymocyte Development; Thymus Gland; Tissues; central tolerance; disorder prevention; experimental study; feeding; in vivo; killings; oral tolerance; prevent; programs; public health relevance; thymocyte; trafficking

DESCRIPTION (provided by applicant): The aim of this grant proposal is to understand the role of the thymus and thymic trafficking dendritic cells (DCs) in oral tolerance. We have shown that oral administration of antigen (Ag) can affect central tolerance through mechanisms of clonal deletion of developing Ag-specific thymocytes, or by induction of natural regulatory T cells (nTregs), depending on the model Ag used. We present preliminary evidence that specialized gut-derived DC populations access intestinal Ags and transport them to the thymus, which is critical to central tolerance induction by oral Ags. We therefore propose that oral Ags are sampled by gut- associated DCs and transported via the blood into the thymus, where they can impact central tolerance of developing thymocytes specific to oral Ags. Studies under Aim 1 will characterize gut-associated peripheral DC populations that traffic to the thymus homeostatically, and after Ag feeding, and will determine the effects of defined Ag peptides and of gut-associated DC subsets on the developmental fate of Ag-specific thymocytes in vivo (i.e. clonal deletion vs. nTreg induction). Studies under Aim 2 will establish the role of endogenous DC subsets and their thymic trafficking programs on central tolerance to oral Ags. Studies under Aim 3 will explore the requirements of defined endogenous DC subsets and their thymic trafficking programs on the prevention of autoimmunity in oral tolerance. More importantly they will establish a critical role for dominant thymic selection events (i.e. thymic nTreg induction) after oral Ag delivery, in controlling autoimmunity during oral tolerance, because this outcome of thymic tolerance generates immunosuppressive cells with the ability to regulate peripheral T cell responses. Therefore oral tolerance protocols need to be revisited in the clinic with the aim of possibly targeting younger individuals with a higher thymic T cell output or using Ags that elicit the development of immunosuppressive thymic T cell populations vs. the clonal deletion of Ag-specific thymocytes.

描述(申请人提供)：这项资助提案的目的是了解胸腺和胸腺运输树突状细胞(DC)在口服耐受中的作用。我们已经证明，口服抗原(Ag)可以通过克隆性删除发育中的Ag特异性胸腺细胞或通过诱导自然调节性T细胞来影响中枢耐受。 (NTregs)，取决于使用的型号Ag。我们提出的初步证据表明，专门的肠道来源的DC群体获得肠道AGs并将它们运输到胸腺，这对口服AGS诱导中枢耐受至关重要。因此，我们认为，口服AGS是由肠道相关的DC采集的，并通过血液运输到胸腺，在那里它们可以影响针对口服AGS的胸腺细胞发育的中枢耐受性。在AIM 1下的研究将表征在体内恒定和在Ag喂养后进入胸腺的肠道相关外周DC群体，并将确定已定义的Ag多肽和肠道相关DC亚群对体内Ag特异性胸腺细胞发育命运的影响(即克隆性缺失与nTreg诱导)。目标2下的研究将确定内源性DC亚群及其胸腺运输计划在口服AGS中枢耐受中的作用。目标3下的研究将探索明确的内源性DC亚群及其胸腺运输计划对预防口服耐受中自身免疫的要求。更重要的是，它们将在口服Ag后的主导胸腺选择事件(即胸腺nTreg诱导)中，在口服耐受期间控制自身免疫方面发挥关键作用，因为胸腺耐受的结果产生了具有调节外周T细胞反应能力的免疫抑制细胞。因此，临床上需要重新考虑口服耐受方案，目的是尽可能针对胸腺T细胞产量较高的年轻个体，或者使用AGS来诱导免疫抑制胸腺T细胞群体的发展，而不是克隆删除抗原特异的胸腺细胞。