REGULATION OF CHRONIC IMMUNE/INFLAMMATORY DISORDERS

该计划的研究继续侧重于基本机制， 宿主动员并调节细胞炎症反应， 对外来抗原和传染因子的防御。定义这些 途径鉴定激动剂、拮抗剂和/或治疗剂的靶点 干预致病条件。在多学科方法中， 整合素粘附机制，趋化性，信号传导，介质 合成和细胞凋亡进行了体外探索，并扩展到 实验动物系统，包括基因靶向模型（基因 基因敲除和转基因）和对以下疾病的遗传易感性模型 关节炎和其他慢性炎症性疾病。 总局 A组链球菌细胞壁肽聚糖-多糖 复合物诱导关节炎、肝纤维化和脾细胞无反应性， 遗传易感啮齿动物，并提供了一个模型，探索所有阶段 免疫反应及其失调的后果。一 本研究的目的是鉴定已知的和新的分子 在炎症的发展过程中表达，我们关注的是 使用体外、体内和离体方法的趋化因子超家族。 培养的滑膜成纤维细胞表达特定的趋化因子基因，包括 CINC和MCP-1，而不是其他，在促关节病条件下， 暗示白细胞群体的选择性募集。此外，由 工程化CINC和其他趋化因子的突变形式， 预测产生受体拮抗作用（RA）的修饰， 可能阻断趋化性并控制白细胞在部位积聚 炎症。白细胞在炎症部位的积聚也是 由凋亡过程调节。凋亡或细胞辅助自杀 由Th 1和Th 2淋巴细胞因子控制，当这种控制 变得不平衡、不足和/或过量，白细胞积聚 可能会出现 控制这些事件的一种机制是通过口服 宽容 此外，调节这些炎症过程和 通过局部和全身靶向基因治疗的组织破坏可以 为发病机制和治疗干预提供了新的见解。

Research in this program continues to focus on the basic mechanisms by which the host mobilizes and modulates cellular inflammatory reactions in defense against foreign antigens and infectious agents. Defining these pathways identifies targets for agonists, antagonists and/or therapeutic intervention in pathogenic conditions. In a multi-disciplinary approach, mechanisms of integrin adhesion, chemotaxis, signalling, mediator synthesis and apoptosis are explored in vitro and extended into experimental animal systems including gene targeting models (gene knockouts and transgenics) and models of genetic susceptibility to arthritis and other chronic inflammatory diseases. Administration of group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes induces arthritis, liver fibrosis, and spleen cell anergy in genetically susceptible rodents and provides a model to explore all phases of an immune response and the consequences of its dysregulation. One objective of this research is to identify known and novel molecules expressed during the development of inflammation and we have focused on the chemokine superfamily using in vitro, in vivo and ex vivo approaches. Cultured synovial fibroblasts express specific chemokine genes, including CINC and MCP-1, but not others, under pro-arthropathic conditions, implicating selective recruitment of leukocyte populations. Moreover, by engineering mutated forms of CINC and other chemokines with sequence modifications predicted to produce receptor antagonism (ra), it may be possible to block chemotaxis and control leukocyte accumulation at sites of inflammation. Accumulation of leukocytes at inflammatory sites is also regulated by the process of apoptosis. Apoptosis or cell-assisted suicide is controlled by Th 1 and Th2 lymphocyte cytokines and when this control becomes unbalanced, insufficient and/or excessive, leukocyte accumulation may occur. One mechanism for controlling these events is through oral tolerance. In addition, regulation of these processes of inflammation and tissue destruction by both local and systemic targeted gene therapy may provide new insight into pathogenesis and therapeutic intervention.