IL-12 is a cytokine, critical for type 1 cellular immunity that is strongly implicated in the pathogenesis of inflammatory neurological diseases such as multiple sclerosis (MS). In the previous funding periods we showed that IL-12 can be produced by microglia and to a lesser extent by astrocytes, suggesting that localized IL-12 may regulate cellular immune responses in the CNS. To test this further, transgenic mice were generated with astrocyte-production of bioactive IL-12. These GF-IL12 mice develop neurologic disease in association with active type 1 cellular immune pathology in the brain. These and subsequent findings confirm that local production of IL-12 can initiate and drive spontaneous as well as target peripherally induced type I adaptive and innate cell-mediated immune responses in the CNS. The GF-IL12 mice are a unique and valuable new paradigm in which we now propose to study basic mechanisms of action of IL-12 in the brain as well as investigate specific processes underlying the localization, extravasation and activation of immune cells in the CNS and the subsequent interactions between these cells which contdbute to CNS damage. Consistent with this goal here we propose to: (1) determine the expression, regulation and role of the IL-12 receptor (IL-12R) and the signal transducers and activators of transcription (STAT) and suppressors of cytokine signaling (SOCS) in the development of the clinical, cellular and molecular alterations in the CNS of the GF-IL12 mice, (2) elucidate the role of IL-12-induced IFN-gamma production by mononuclear cells in the development of spontaneous and induced cellular immune responses in the brain of the GF-IL12 mice, (3) clarify whether or not and what role is played by NK cells versus antigen-specific autoimmune T-cell responses in the development of immune-mediated disease pathology in the CNS of the GF-IL12 mice. (4) To investigate whether antigen presentation can occur from within the brain driven by the local production of IL-12. The studies outlined in this continuing proposal will provide valuable new knowledge concerning the role of IL-12 in regulating molecular and cellular processes involved in cellular immune responses in the CNS. They are extremely relevant to our understanding of the pathogenesis of a wide spectrum of neurologic disorders that involve cellular immune responses in the CNS. Finally, the results from these studies could lay the conceptual foundations for the development of novel therapeutic approaches to ameliorate CNS diseases of immunoinflammatory origin in which IL-12 is implicated.
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