Normal And Pathologic Mechanisms Of Inflammation, Innate

该项目的研究重点是宿主动员和调节细胞炎症反应以防御外来抗原和感染因子的基本机制。在多学科方法中，整合素粘附、趋化性、信号传导、介体合成和细胞凋亡的机制在体外进行了探索，并扩展到实验动物模型（细菌诱导的啮齿动物关节炎;敲除和转基因小鼠）中进行体内分析。此外，在细胞、分子和生物化学水平上探索了对外来植入物、传染性病原体或未知病因作出反应的慢性炎性疾病的人类状况。了解控制正常免疫细胞募集、激活和/或缺失的机制以及向发病机制的转变是调节慢性致病性炎性疾病的策略的基础。在关节炎的实验模型中，我们通过表型、功能和形态学参数，以及DNA微阵列和核糖核酸酶保护测定来表征免疫病理学，以确定治疗干预的靶点，包括白细胞粘附、信号转导、细胞因子、蛋白酶和一氧化氮。在关节内局部转移TNF拮抗剂的基因可抑制滑膜炎和组织破坏。通过在其表面表达TGF-β的CD 4 + CD 25+调节性T细胞调节免疫功能的新见解提高了控制免疫耐受的新方法的前景。这种关键的抑制性T细胞群体在预防和抑制自身免疫性疾病、同种异体移植排斥和癌症发病机制中是重要的。另一种内源性免疫调节分子SLPI被发现在宿主防御细胞内寄生虫中起作用。描述了对L.主要在SLPI缺陷小鼠中的研究将有助于确定SLPI在先天性和适应性免疫中的作用及其作为治疗感染性和炎性疾病的治疗剂的潜力。

Research in this program is focused on the basic mechanisms by which the host mobilizes and 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 models (bacterial induced rodent arthritis; knockout and transgenic mice) for in vivo analysis. In addition, human conditions of chronic inflammatory disease in response to foreign implants, infectious pathogens, or of unknown etiology are explored at the cellular, molecular and biochemical levels. Understanding the mechanisms which control normal immune cell recruitment, activation and/or deletion and the switch to pathogenesis underlies the development of strategies for modulating chronic pathogenic inflammatory diseases. In an experimental model of arthritis, we have characterized the immunopathology through phenotypic, functional and morphologic parameters, in addition to DNA microarrays and ribonuclease protection assays, to identify targets for therapeutic intervention including leukocyte adhesion, signal transduction, cytokines, proteases, and nitric oxide. Gene transfer of a TNF antagonist locally within the joint suppressed synovitis and tissue destruction. New insights into the regulation of immune function through CD4+CD25+ regulatory T cells which express TGF-beta on their surface raise the prospect of novel approaches to controlling immunological tolerance. This key population of suppressor T cells is important in prevention and inhibition of autoimmune diseases, allotransplant rejection and in cancer pathogenesis. Another endogenous immunoregulatory molecule, SLPI, was found to be instrumental in host defense to an intracellular parasite. Delineation of the immune response to L. major in SLPI deficent mice will help define the role of SLPI in innate and adaptive immunity and its potential as a therapeutic agent in the treatment of infectious and inflammatory diseases.