Role of Peripheral Dendritic Cells in Central and Oral Tolerance

外周树突状细胞在中枢和口腔耐受中的作用

• 批准号: 8736029
• 负责人: HUSEIN HADEIBA
• 金额: $ 33.14万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8736029
• 关键词: Affect; Allergic; Allogenic; Antigens; Applications Grants; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Back; Bone Marrow; CCR9 gene; Cell surface; Cells; Clonal Deletion; Dendritic Cells; Development; Diet; Disease; Enteral; Experimental Autoimmune Encephalomyelitis; Goals; Graft Rejection; Homeostasis; Homing; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Leukocytes; Maintenance; Mediating; Oral; Outcome; Parabiosis; Pathology; Pathway interactions; Peripheral; Play; Population; Positioning Attribute; Prevention; Process; Property; Radiation Chimera; Regulatory T-Lymphocyte; Role; Site; Source; Therapeutic; Thymus Gland; Tissues; Transgenic Organisms; Tumor Antigens; adhesion receptor; base; cell motility; central tolerance; chemokine receptor; feeding; killings; mouse model; novel; oral tolerance; peripheral tolerance; prevent; public health relevance; research study; thymocyte; trafficking; tumor

DESCRIPTION (provided by applicant): We have identified a potent tolerogenic plasmacytoid dendritic cell (pDC) population defined by expression of the chemokine receptor CCR9, and have shown that these CCR9+ pDCs not only induce peripheral tolerance by induction of regulatory T cells (Tregs), but also efficiently transport innocuous peripheral antigens (Ags) to the thymus where they mediate central tolerance through clonal deletion. In dendritic cell (DC) immunotherapeutic approaches we also confirmed an immunosuppressive role for CD103-expressing conventional DCs (cDCs) that also have the ability to access the thymus and delete Ag-specific thymocytes. We therefore hypothesize that specialized DC populations play related or complementary roles in central tolerance to peripheral Ags. Moreover, we propose that CD103 is important in this process by either affecting DC microenvironmental localization within the thymus or their interaction with developing thymocytes. We also suggest that thymic-homing peripheral DCs mediate central tolerance to orally acquired (dietary) Ags; and that they are critical to normal immune homeostasis and prevention of autoimmune pathologies. Studies under Aim 1 will therefore define the role of peripheral cDC subsets in thymic transport of peripheral Ags and in the induction of central tolerance. The mechanisms of tolerogenic DC trafficking to and microenvironmental localization and interactions within the thymus will be studied using bone marrow radiation chimeras, competitive homing studies and parabiosis experiments. Studies under Aim 2 will establish the role of peripheral DCs, their tissue source and trafficking properties in mediating central tolerance to fed Ags. These studies will involve inducible transgenic approaches, to temporarily delete DC populations, followed by DC add back experiments during Ag feeding. Finally, studies under Aim 3 will evaluate the importance of thymic homing DCs and the trafficking and adhesion receptors, CCR9 and CD103, in the maintenance of immune homeostasis, including suppression of MOG-driven EAE pathology.

描述（由申请人提供）：我们已经确定了通过趋化因子受体CCR9表达定义的有效的耐受性浆细胞性树突状细胞（PDC）种群，并表明这些CCR9+ PDC不仅通过诱导周围T细胞（Tregs）诱导外周耐受性（TREGS），而且在这些中诱导外周耐受性（TREGS），在这些中诱导，这些耐受性（Tregs），它们在这些中均具有成效的倾斜度（Tregs），它们（tregs and）（tregs）（tregs and）（tregs and）（tregs and）（tregs and）（Tregs）（tregs）（tregs）通过克隆缺失的中心耐受性。在树突状细胞（DC）免疫治疗方法中，我们还证实了表达CD103的常规DC（CDC）的免疫抑制作用，该作用也具有访问胸腺和删除Ag特异性胸腺细胞的能力。因此，我们假设专业的DC种群在中央耐受性AG中起着相关或互补的作用。此外，我们建议通过影响胸腺内的直流微环境定位或与发展胸腺细胞的相互作用，在此过程中CD103很重要。我们还建议，胸腺含的外围DC介导了对口服（饮食）AGS的中心耐受性。并且它们对于正常的免疫稳态和预防自身免疫性病理至关重要。因此，AIM 1的研究将定义周围CDC亚群在外围AG的胸腺运输以及中央耐受性诱导中的作用。将使用骨髓辐射嵌合体，竞争性归宿研究和抛物性实验来研究耐受性直流运输以及胸腺中微环境定位的机制。 AIM 2的研究将确定周围DC，其组织来源和运输特性在介导对AGS的中央耐受性中的作用。这些研究将涉及可诱导的转基因方法，以暂时删除直流种群，然后在AG进食过程中增加DC添加实验。最后，AIM 3下的研究将评估胸腺归巢DC以及运输和粘附受体CCR9和CD103在维持免疫稳态中的重要性，包括抑制MOG驱动的EAE病理学。