Normal and Pathologic Mechanisms of Inflammation, Innate and Acquired Immunity

这个项目的研究重点是基本的 宿主动员和调节细胞的机制 防御外来抗原的炎性反应和 感染剂。在多学科方法中，机制 整合素黏附、趋化、信号、介体合成和 细胞凋亡在体外被探索，并扩展到实验中 活体分析的动物系统。在感染期间和 炎症，白细胞是由趋化因子从 循环到炎症组织，在那里它们被激活 炎症介质和基质刺激T细胞。 细胞特异性趋化因子在空间上的差异表达 暂时在发炎的部位。因为引发剂是 消退炎症，炎性细胞没有 不再需要，必须从组织中移除 通过细胞凋亡来化解炎症。了解相关机制 它们控制正常的免疫细胞募集、激活和/或 具有潜在异常的缺失是发展的基础 调控炎症性疾病的策略。在新的研究中，我们 已证明CTLA-4与T细胞的结合可诱导 转化生长因子-β的产生介导抑制和抑制 IFNGamma。缺乏转化生长因子-β与过量生产有关 干扰素和无法控制的炎症。的下游目标 干扰素包括诱导型一氧化氮合酶和转录因子、核因子-kappaB和 IRF-1。核因子-kappaB和蛋白表达升高的证据 转化生长因子-β1基因缺失小鼠中的IRF-1支持干扰素-γ和 免疫失调中的下游元件显示在 转化生长因子-β1的缺失及其作为关键调控因子的意义 在这条道路上。

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.