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: 8720619
• 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/8720619
• 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; 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; public health relevance; 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）：本拨款提案的目的是了解胸腺和胸腺运输树突状细胞（dc）在口腔耐受中的作用。我们已经证明，口服抗原（Ag）可以通过克隆性缺失发育中的Ag特异性胸腺细胞或诱导自然调节性T细胞的机制影响中枢耐受