Project 3. The Role of IL-23 in CNS Inflammatory DemyelinaUon. We have shown that antibodies against the p40 subunit of interleukin-12 (IL-12) prevent spontaneous and superantigen-induced relapses of experimental autoimmune encephalomyelitis (EAE). Conversely, IL-12 enhanced the severity of relapses in this model. IL-23 is an IL-12-related cytokine which shares the p40 subunit with IL-12 and has recently been shown to be critical for susceptibility to EAE, whereas IL-12 is dispensable. Although the role of IL-23 in EAE susceptibility has recently been established, no studies have addressed the involvement of IL-23 in the pathogenesis of EAE relapse. We hypothesize that: 1) IL-23 is required for the induction of EAE relapse and for T-cell epitope spreading 2) IL-12Rbeta2 regulates the induction of EAE relapse; and 3) the IL-23 and IL-12-associated Jak/Stat system is the dominant signal transduction pathway in the pathogenesis of EAE relapse. To test these hypotheses, we propose the following Specific Aims: 1) to differentiate the role of IL-23 and IL-12 in the pathogenesis of EAE relapse. 2) to determine the role of the Il-12Rbeta2 chain in the pathogenesis of EAE relapse. 3) to study the role of IL-23 and IL-12-associated signal transduction pathways in the pathogenesis of EAE susceptibility and relapse. These studies should elucidate the role of IL-12/IL-23 in the pathogenesis of CNS demyelination and relapse in EAE and may pave the way for better understanding of the immunopathogenesis of multiple sclerosis.
| Gran, B; Yu, S; Zhang, G X et al. (2010) Accelerated thymocyte maturation in IL-12R?2-deficient mice contributes to increased susceptibility to autoimmune inflammatory demyelination. Exp Mol Pathol 89:126-34 |
| Fitzgerald, Denise C; Rostami, Abdolmohamad (2009) Therapeutic potential of IL-27 in multiple sclerosis? Expert Opin Biol Ther 9:149-60 |
| Fitzgerald, Denise C; Zhang, Guang-Xian; El-Behi, Mohamed et al. (2007) Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol 8:1372-9 |
