Cells of the immune system communicate with each other by cell-cell contacts and via the production of soluble protein factors or cytokines. Cytokines are critical in the regulation of immune responses. Heterogeneity of CD4+ helper T cells based on cytokine secretion patterns has been well documented in the murine system. Studies in humans have also observed helper T cell clones exhibiting Th1 or Th2-like profiles accumulating in the tissues or blood of patients with different diseases. Dysregulated expansion of one or the other subsets may be a contributing factor in the development of autoimmune diseases. Multiple sclerosis is a chronic demyelinating disease of the human central nervous system of unknown etiology and pathogenesis. MS is believed to be an autoimmune disorder, triggered by an infectious agent(s) in which autoreactive T cells specifically migrate into the central nervous system and initiate the inflammatory, demyelinating reaction. We now propose to study cytokine production both in vitro and in vivo in this autoimmune disorder of the central nervous system. Our hypothesis is that there is a dysregulation in the production of Th1-like cytokines which play a role in the demyelination process. It is also proposed that the cytokine secretion pattern seen in the blood may be different from that produced in areas of active disease. T cell clones-specific for a putative target autoantigen, myelin basic protein will be generated from multiple sclerosis and other neurological disease patients as well as from healthy controls. Cerebrospinal fluid lymphocytes will also be cloned and examined for oligoclonality of T cell receptor beta chain gene rearrangements. All the clones will be analyzed for production of a large panel of cytokines by competitive polymerase chain reaction methodology. The cell surface phenotype of representative clones will be ascertained by two color immunofluorescence and cytofluorographic analysis. The in vivo study of cytokine production in central nervous system tissue will be performed in patients with acute multiple sclerosis and controls by immunocytochemical staining and in situ hybridization. The effect of the cytokines produced by autoreactive T cells on cultured human oligodendrocytes will be determined and attempts will be made to neutralize the activity of these cytokines with other cytokines. The present study on the cytokine secretion profile of autoreactive T cell clones (found in the blood and cerebrospinal fluid) may provide information regarding the nature and regulation of these potentially pathogenic T cells. Analysis of the effects of cytokines on glial cells and the identification of cytokine production in vivo may elucidate the role of these products in the pathogenesis of the disease and may provide novel immunologic tools for specific therapeutic intervention in MS.
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