Reassessing the Physiological Role of Gut-Specific Lymphocyte Homing: Implication

重新评估肠道特异性淋巴细胞归巢的生理作用：意义

• 批准号: 7852613
• 负责人: Jorge Rodrigo Mora
• 金额: $ 265.48万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852613
• 关键词: Antigens; Autoimmune Diseases; CC chemokine receptor 7; CCR9 gene; Dendritic Cells; Diabetes Mellitus; Food; Generations; HIV; Homing; Immune Tolerance; Immune response; Immune system; Integrins; Intestinal Mucosa; Intestines; Lymphocyte; Methods; Multiple Sclerosis; Oral; Physiological; Process; Psoriasis; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Role; Rotavirus; Salmonella infections; T-Lymphocyte; Tretinoin; Tropism; Vaccination; Vitamin A; Work; abstracting; microbial; migration; oral tolerance; public health relevance; receptor

DESCRIPTION (Provided by the applicant) Abstract: Oral immunological tolerance is an essential although poorly understood phenomenon by which the immune system becomes "non-responsive" against antigens administered via the intestinal mucosa. Although this process is vital for the co-existence with non-pathogenic intestinal antigens, such as food and normal microbial flora, the mechanisms responsible for oral tolerance remain poorly understood. Lymphocyte migration (homing) is essential for protective and pathological immune responses and we and others have demonstrated that gut-associated antigen-presenting dendritic cells instruct lymphocytes to express gut-specific homing receptors, integrin 4¿7 and chemokine receptor CCR9, by a mechanism dependent on the vitamin A metabolite retinoic acid (RA). Importantly, RA also contributes to the generation of regulatory T lymphocytes (TREG), which have been shown to be important for the establishment of oral tolerance. Given that RA induces gut-homing lymphocytes and also promotes TREG differentiation, I hypothesize that RA is essential for the establishment of oral tolerance i) by inducing gut-tropism and "sequestering" potentially pathogenic T lymphocytes in the intestinal mucosa and ii) by promoting TREG differentiation in the gut. If successful, my work will highlight a new physiological role of gut-homing in the establishment of oral tolerance, providing also a straightforward approach to induce immune tolerance using RA, which could be used in the treatment of autoimmune diseases. Public Health Relevance: My research could provide a straightforward approach to treat autoimmune diseases, such as multiple sclerosis, diabetes, psoriasis and rheumatoid arthritis. It would also offer a simple method for boosting intestinal immune responses for vaccination purposes, such as in infections by Salmonella, rotavirus, and HIV.

描述（由申请人提供） 摘要：口服免疫耐受是一种重要的现象，尽管对其了解甚少，但免疫系统对通过肠粘膜施用的抗原变得“无应答”。虽然这一过程对于与非致病性肠道抗原（如食物和正常微生物植物群）共存至关重要，但对口服耐受性的机制仍知之甚少。淋巴细胞迁移（归巢）对于保护性和病理性免疫应答是必不可少的，我们和其他人已经证明，肠道相关抗原呈递树突状细胞通过依赖于维生素A代谢物视黄酸（RA）的机制指导淋巴细胞表达肠道特异性归巢受体，整合素4 <$7和趋化因子受体CCR 9。重要的是，RA还有助于调节性T淋巴细胞（Treg）的产生，其已被证明对于建立口服耐受性是重要的。鉴于RA诱导肠道归巢淋巴细胞，也促进TREG分化，我假设RA是建立口服耐受性所必需的i）通过诱导肠道嗜性和“隔离”肠粘膜中的潜在致病性T淋巴细胞和ii）通过促进肠道中的TREG分化。如果成功的话，我的工作将突出肠道归巢在建立口服耐受性中的新生理作用，也提供了一种直接的方法来诱导使用RA的免疫耐受性，这可用于治疗自身免疫性疾病。 公共卫生相关性：我的研究可以提供一种直接的方法来治疗自身免疫性疾病，如多发性硬化症，糖尿病，牛皮癣和类风湿性关节炎。它还将提供一种简单的方法来增强肠道免疫反应，用于疫苗接种，例如沙门氏菌，轮状病毒和艾滋病毒感染。