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: 9032434
• 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/9032434
• 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; Health; Homing; Immune; Immune system; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Intestines; Leukocytes; Mediating; Modeling; Monitor; Multiple Sclerosis; Mus; Nature; Oral; Oral Administration; Outcome; Output; Pathologic; Pathology; Peptides; Peripheral; Phenotype; Population; Prevention; Proteins; Protocols documentation; Regulatory T-Lymphocyte; Role; Sampling; Site; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Thymocyte Development; Thymus Gland; Tissues; central tolerance; disorder prevention; feeding; in vivo; killings; oral tolerance; prevent; programs; research study; 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（由申请人提供）：本基金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）可以通过克隆缺失发育中的Ag特异性胸腺细胞或诱导天然调节性T细胞的机制影响中枢耐受性 （nT），取决于所使用的模型Ag。我们目前的初步证据表明，专门的肠道来源的DC群体访问肠道抗原和运输到胸腺，这是至关重要的中央耐受性诱导口服抗原。因此，我们提出口服Ag由肠道相关DC采样并经由血液转运到胸腺中，在那里它们可以影响对口服Ag特异性的发育中的胸腺细胞的中枢耐受性。目标1下的研究将表征稳态运输至胸腺的肠道相关外周DC群以及Ag喂养后的肠道相关外周DC群，并将确定定义的Ag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（即克隆缺失vs. nTreg诱导）。目标2下的研究将确定内源性DC亚群及其胸腺运输程序对口服Ag的中枢耐受性的作用。目标3下的研究将探索确定的内源性DC亚群及其胸腺运输程序对预防口服耐受中自身免疫的要求。更重要的是，它们将确立口服Ag递送后显性胸腺选择事件（即胸腺nTreg诱导）在口服耐受期间控制自身免疫中的关键作用，因为胸腺耐受的这种结果产生具有调节外周T细胞应答能力的免疫抑制细胞。因此，口服耐受方案需要在临床上重新审视，目的是可能靶向具有较高胸腺T细胞输出的年轻个体或使用引发免疫抑制性胸腺T细胞群发展的Ag与Ag特异性胸腺细胞的克隆缺失。