REGULATION OF CHRONIC IMMUNE/INFLAMMATORY DISORDERS

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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.