NORMAL AND PATHOLOGIC MECHANISMS OF INFLAMMATION, INNATE AND ACQUIRED IMMUNITY

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。在一个多学科的，但综合的方法，整合素粘附，趋化性，信号传导，介体合成和细胞凋亡的机制进行了探讨，在体外和扩展到实验动物模型（细菌诱导的啮齿动物关节炎;基因敲除和转基因小鼠）的体内分析。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。这种慢性破坏性病变的发病机制非常复杂，并且还与激素、性别、免疫遗传学、免疫失调、人口统计学和年龄有关。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，我们已经成功地表征了免疫病理学并记录了几个水平的治疗干预，包括1）通过合成纤连蛋白肽抑制整合素依赖性粘附和信号转导; 2）通过NMMA和血红蛋白抑制自毒NO; 3）通过全身递送、基因治疗、hCG或口服耐受通过TGF-β抑制募集和炎症介质; 4）通过可溶性TNF受体的基因转移螯合TNF α;和5）通过分泌性白细胞蛋白酶抑制剂（SLPI）阻断丝氨酸蛋白酶。作为治疗性免疫调节剂，TGF-β和SLPI由于其抗炎靶标谱而显得特别有前景，并且这些在TGF-β和SLPI无效和转基因小鼠模型中进一步表征。

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, yet integrative 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. The pathogenesis of such chronic destructive lesions is profoundly complex and is also related to hormones, gender, immunogenetics, dysregulated immunity, demographics and age. 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 successfully characterized the immunopathology and documented therapeutic intervention at several levels, including 1) inhibition of integrin-dependent adhesion and signal transduction by synthetic fibronectin peptides; 2) suppression of autotoxic NO by NMMA and hemoglobin; 3) inhibition of recruitment and inflammatory mediators by TGF-beta through systemic delivery, gene therapy, hCG or oral tolerance; 4) sequestration of TNF alpha by gene transfer of soluble TNF receptors; and 5) blockade of serine proteases by secretory leukocyte protease inhibitor (SLPI). As therapeutic immunomodulators, TGF-beta and SLPI appear particularly promising due to their spectrum of anti-inflammatory targets, and these are being further characterized in TGF-beta and SLPI null and transgenic mouse models.