REGULATION OF CHRONIC IMMUNE/INFLAMMATORY DISORDERS

该计划的研究继续集中在基本机制上，由 宿主在其中动员和调节细胞炎症反应 对外来抗原和传染病的防御。定义这些 通路识别激动剂、拮抗剂和/或治疗药物的靶点 对致病条件的干预。在一个多学科的方法中， 整合素黏附、趋化、信号、介体机制 在体外探索合成和凋亡，并扩展到 实验动物系统，包括基因打靶模型(基因 基因敲除和转基因)和遗传易感性模型 关节炎等慢性炎症性疾病。管理 A群链球菌细胞壁(SCW)肽多糖 复合体诱导小鼠关节炎、肝纤维化和脾细胞无能 基因易感的啮齿动物，提供了探索所有阶段的模型 免疫反应及其失调的后果。一 这项研究的目的是识别已知的和新的分子 在炎症的发展过程中表达，我们关注的是 趋化因子超家族采用体外、体内和体外三种方法。 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，但不是其他，在有利于关节病变的条件下， 意味着有选择地招募白细胞群体。此外，通过 利用序列工程CINC等趋化因子的突变形式 预测会产生受体拮抗(Ra)的修饰，它可能是 可能阻断趋化性并控制部位的白细胞聚集 发炎的症状。炎症部位的白细胞聚集也是 受细胞凋亡过程的调控。细胞凋亡或细胞辅助自杀 是由Th1和Th2淋巴细胞细胞因子控制的，当这种控制 变得不平衡、不足和/或过度，白细胞聚集 可能会发生。控制这些事件的一种机制是通过口头 宽容。此外，对这些炎症和炎症过程的调节 局部和全身靶向基因治疗的组织破坏可能 为发病机制和治疗干预提供新的视角。

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.