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）：我们已经鉴定了由趋化因子受体CCR9的表达定义的有效致耐受性浆细胞样树突状细胞（pDC）群体，并且已经表明这些CCR9+ pDC不仅通过诱导调节性T细胞（TCR）诱导外周耐受，而且还有效地将无害的外周抗原（Ag）转运至胸腺，在胸腺中它们通过克隆缺失介导中枢耐受。在树突状细胞（DC）免疫治疗方法中，我们还证实了表达CD 103的常规DC（cDC）的免疫抑制作用，这些DC也有能力进入胸腺并删除Ag特异性胸腺细胞。因此，我们推测，专门的DC人口发挥相关或补充作用，在中央耐受外周抗原。此外，我们建议，CD103是重要的，在这一过程中，通过影响DC微环境定位在胸腺内或他们的相互作用与发展中的胸腺细胞。我们还认为，胸腺归巢外周DC介导的中央耐受口服获得性（饮食）抗原，他们是至关重要的正常免疫稳态和预防自身免疫性病变。因此，目标1下的研究将确定外周cDC亚群在外周Ag的胸腺转运和诱导中枢耐受中的作用。将使用骨髓辐射嵌合体、竞争性归巢研究和联体共生实验来研究致耐受性DC运输到胸腺和胸腺内微环境定位和相互作用的机制。目标2下的研究将确定外周DC、其组织来源和运输特性在介导对饲喂的Ag的中枢耐受性中的作用。这些研究将涉及诱导型转基因方法，以暂时删除DC群体，然后在Ag喂养期间进行DC加回实验。最后，目标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。