T helper (Th) 1 and Th2 cytokines are important regulators of protective humoral and cell-mediated immune responses and play a role in certain inflammatory immunopathological disorders. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system of unknown etiology and pathogenesis. Current postulates suggest that autoreactive T cells secreting Th1 cytokines are activated by a process involving molecular mimicry and/or bystander activation and migrate into the central nervous system (CNS) and initiate the inflammatory and demyelinating cascade. The long term objectives of this proposal are to elucidate the role of cytokines in the pathogenesis of MS and to provide novel tools for therapeutic intervention in this disorder. Interferon-y (IFN-y), a Th1 cytokine, is a pivotal mediator in the demyelinating disease process and has been shown to exacerbate MS symptoms when used to treat patients. Interleukin-12 (IL-12) is a potent inducer of IFN-y production and promoter of Th1-type responses, while the newly-discovered interleukin-18 (IL-18) shares some functional characteristics with IL-12 and has also been implicated in promoting IFN-y secretion. Conflicting reports regarding the role of IL-12 in MS have been published and the role of IL-18 has not yet been studied in this neurological disease. Studies from this laboratory have observed enhanced IFN-y and reduced transforming growth factor-B (TGF-B) production by autoantigen-reactive T cells as well as decreased secretion of IL-12 p40, a natural IL-12 antagonist in MS. We have also observed a novel finding that IL-18 may be produced by autoantigen-reactive T lymphocytes. We hypothesize that defects in the production of IL-12 p40 and abnormal IL-18 secretion by Th1 cells contribute to dysregulated IFN-y production in MS. We propose to investigate these predictions by investigating the roles of IL-12 and IL-18 in regulating IFN-y production in MS. Elucidating the mechanisms that control IFN-y production is essential for unraveling the pathogenesis of MS and may be of therapeutic benefit.
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