Normal and Pathologic Mechanisms of Inflammation, Innate and Acquired Immunity

炎症、先天性和获得性免疫的正常和病理机制

• 批准号: 6104527
• 负责人: Sharon M Wahl
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6104527
• 关键词: Schistosoma mansoni; Sjogren's syndrome; autoimmune disorder; cellular pathology; fibrosis; gene expression; gene targeting; immunoregulation; inflammation; laboratory mouse; molecular pathology; transforming growth factors; wound healing

Research in this program is focused on the basic mechanisms by which the host mobilizesand modulates cellular inflammatory reactions in defense against foreign antigens and infectious agents. In a multi-disciplinary approach, mechanisms of integrin adhesion, chemotaxis, signaling, mediator synthesis and apoptosis are explored in vitro and extended into experimental animal systems for in vivo analysis. During infection and inflammation, leukocytes are recruited by chemokines from the circulation to inflamed tissues where they are activated by inflammatory mediators and matrix to stimulate T cells. Cell-specific chemokines are differentially expressed both spatially and temporally in inflamed sites. As the initiating agents are eliminated and inflammation wanes, the inflammatory cells are no longer necessary and must be removed from the tissues by apoptosis to resolve inflammation. Understanding the mechanisms which control normal immune cell recruitment, activation and/or deletion with potential aberrancies underlies the development of strategies for modulating inflammatory diseases. In new studies, we have demonstrated that engagement of CTLA-4 on T cells induces TGF-beta production to mediate suppression and inhibit IFNgamma. Lack of TGF-beta is associated with overproduction of IFNgamma and uncontrolled inflammation. Downstream targets of IFNgamma include iNOS and transcription factors, NF-kappaB and IRF-1. Demonstration of elevated expression of NF-kappaB and IRF-1 in TGF-beta1 null mice supports the role of IFNgamma and downstream elements in the immune dysregulation displayed in the absence of TGF-beta1 and implicate TGF-beta1 as a key regulator of this pathway.

该计划的研究重点是基本 主机动员和调节细胞的机制 防御外国抗原的炎症反应和 感染者。在多学科的方法中 整合素粘附，趋化性，信号传导，介体合成和 凋亡在体外探索并扩展到实验中 用于体内分析的动物系统。在感染期间 炎症，白细胞是由趋化因子募集的 循环到发炎的组织中被激活的组织 炎症介质和基质以刺激T细胞。 细胞特异性趋化因子在两个空间上都差异表达 并在发炎的站点暂时。作为启动代理人 消除和炎症减弱，炎症细胞不 需要更长的时间，必须通过 凋亡解决炎症。了解机制 哪些控制正常的免疫细胞募集，激活和/或 删除潜在的劣质是发展的基础 调节炎症性疾病的策略。在新研究中，我们 已经证明CTLA-4在T细胞上的参与会诱导 TGF-β产生以介导抑制和抑制 ifngamma。缺乏TGF-β与生产过多有关 Ifngamma和不受控制的炎症。下游目标 Ifngamma包括iNOS和转录因子，NF-kappab和 IRF-1。 NF-kappab表达升高和 TGF-BETA1 NULL小鼠中的IRF-1支持Ifngamma和 免疫失调中显示的下游元素显示在 缺少TGF-BETA1并将TGF-BETA1视为关键调节器 这条路。