We have recently shown that antibodies against interleukin (IL-12) prevent spontaneous and superantigen-induced relapses of experimental autoimmune encephalomyelitis. Conversely, IL-12 enhanced the severity of relapses in this model. IL-12 is a pro-inflammatory cytokine-produced by activated antigen-presenting cells, with important immunoregulatory activity, which has been discovered, cloned, and largely characterized in one of our laboratories. We hypothesize that IL-12 participates in the pathogenesis of EAE and MS by various mechanisms, including favoring the generation of encephalitogenic Th1 cells, reactivation of quiescent or tolerized autoreactive T cells, and endowing the activated autoreactive T cells with properties that facilitate their migration to the CNS and their ability to survive and provoke tissue damage and demyelination. Neutralization of endogenous IL-12 with antibodies would prevent both the differentiation and functional activation of encephalitogenic Th1 cells, and possibly favor the generation of T cell types able to suppress the progression of the CNS pathology. Specifically, we will: 1. study the effect of IL-12 and anti-IL-12 on inflammatory cytokine production by lymphocyte populations in the periphery and the CNS in a murine model of EAE. 2. Study the effect of IL-12 and anti-IL-12 on apoptosis and trafficking of transplanted TCR-transgenic MBP-reactive inflammatory T cells into the CNS in EAE. 3. analyze the ability of peripheral blood mononuclear cells from multiple sclerosis patients with progressing or remitting/relapsing disease, treated or not with IFN-beta therapy, to produce IL-12, IL-18, and other type 1 or cytokines, and to express receptors for IL-12, IL-18, and chemokines. 4. characterize T cell clones derived from the same patients for cytokine production, expression of receptors for IL-12, IL-18, and chemokines. 5. analyze peripheral blood mononuclear cells and T cell clones from the patients treated with anti-IL-12 antibodies, before and during treatment for cytokine production and receptor expression.
Showing the most recent 10 out of 16 publications
