Therapeutic efficacy of suppressing the JAK/STAT pathway in models of neuroinflammation (P5199)

Abstract

Abstract T helper cells and myeloid cells are involved in the pathogenesis of Multiple Sclerosis (MS) and Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. The JAK/STAT pathway is used by cytokines for signaling, and is critical for development and regulation of immune responses. Many cytokines involved in MS and EAE, including IL-6, IL-12, IL-23, IFN-γ and GM-CSF, use the JAK/STAT pathway to induce biological responses. As such, targeting JAKs has implications for treating autoimmune inflammation of the brain. We used a JAK1/2 inhibitor, AZD1480, to test the potential of inhibiting the JAK/STAT pathway in EAE. AZD1480 treatment effectively inhibits disease severity in classical, atypical and relapsing-remitting EAE models by preventing entry of immune cells into the brain, suppressing differentiation of Th1 and Th17 cells, deactivating macrophages and dendritic cells, inhibiting STAT activation in the brain, and reducing expression of pro-inflammatory cytokines/chemokines. Suppression of the JAK/STAT pathway was also effective in reducing paralysis induced by transfer of pathogenic Th1 or Th17 cells. In vivo AZD1480 treatment impairs both the priming and expansion of T-cells and attenuates antigen-presentation function of myeloid cells. These results suggest the feasibility of the JAK/STAT pathway as a target for immunomodulatory therapy in MS.