IL-12 is a proinflammatory cytokine, produced by activated antigen-presenting cells, with important regulatory activities. IL-12 p40 and p70 are produced by CNS-resident cells (mainly astrocytes and parenchymal microglia) as well as peripheral immune cells (including a portion of perivascular microglia/macrophage). However, the contribution of IL-12 produced by CNS resident cells to inflammatory demyelination is not known. Receptors for IL-12, IL-12beta1 and beta2 have different effects on the development of EAE. The mechanisms of their action in relation to IL-12 or related cytokines in EAE is not clear. IL-23, a newly discovered cytokine, has similarities and differences with IL-12 sharing its p40 and beta1 receptor chain. P40 homodimer is produced in excess and can inhibit IL-12. The contribution of IL-23 and (p40)2 in the pathogenesis of EAE is not known. Neither is it clear what role IL-12 produced in the periphery or by CNS resident cells may play in EAE relapse, especially on epitope spreading. The central hypothesis in this proposal is: cytokines with IL-12p40 subunit, IL-12, IL-23 and (p40) 2, regulate the induction, chronicity, and relapses of EAE. Specifically, we hypothesize that: 1)a) the initial immunologic damage to the CNS in EAE is mediated by the peripheral immune cells that become activated and differentiated and migrate to the CNS under the influence of IL-12p40 (in the context of IL-12 and/or IL-23), and b) IL-12p40 produced by CNS resident cells contributes to the chronicity of the disease; 2) IL-12Rbeta1and IL-12Rbeta2 have differential roles on T helper polarization resulting in differential effects in the pathogenesis of EAE; 3) IL-23 is sufficient to produce MOG-reactive Thl response and 11-12 acts as a secondary stimulus to mediate selective survival and expansion of committed MOG-reactive TH1 cells in EAE; and 4) IL-12p40 produced within the CNS contributes to epitope spreading and genesis of EAE relapse. To test these hypotheses, the following specific aims are proposed:
Aim 1 : To determine the contribution of IL-12p40 produced by peripheral immune cells and CNS resident cells in inflammatory demyelination of EAE.
Aim 2 : To characterize the differential contribution of IL-12Rbeta1 and IL-12beta2 to the pathogenesis of EAE.
Aim 3 : To differentiate the role of IL-12, IL-23 and p40 homodimer in the pathogenesis of EAE.
Aim 4 : To study the role of IL-12p40 and IL-12Rbeta2 produced or expressed on peripheral immune cells and CNS-resident cells in the pathogenesis of EAE relapse.
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