Therapeutic Efficacy of Suppressing the JAK/STAT Pathway in Multiple Models of Experimental Autoimmune Encephalomyelitis

Abstract

Pathogenic 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 utilized by numerous cytokines for signaling, and is critical for development, regulation and termination of immune responses. Dysregulation of the JAK/STAT pathway has pathological implications in autoimmune and neuroinflammatory diseases. Many of the cytokines involved in MS/EAE, including IL-6, IL-12, IL-23, IFN-γ and GM-CSF, use the JAK/STAT pathway to induce biological responses. Thus, targeting JAKs has implications for treating autoimmune inflammation of the brain. We have utilized AZD1480, a JAK1/2 inhibitor, to investigate the therapeutic potential of inhibiting the JAK/STAT pathway in models of EAE. AZD1480 treatment inhibits disease severity in MOG-induced classical and atypical EAE models by preventing entry of immune cells into the brain, suppressing differentiation of Th1 and Th17 cells, deactivating myeloid cells, inhibiting STAT activation in the brain, and reducing expression of pro-inflammatory cytokines and chemokines. Treatment of SJL/J mice with AZD1480 delays disease onset of PLP-induced relapsing-remitting disease, reduces relapses and diminishes clinical severity. AZD1480 treatment was also effective in reducing ongoing paralysis induced by adoptive transfer of either pathogenic Th1 or Th17 cells. In vivo AZD1480 treatment impairs both the priming and expansion of T-cells, and attenuates antigen-presentation functions of myeloid cells. Inhibition of the JAK/STAT pathway has clinical efficacy in multiple pre-clinical models of MS, suggesting the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases.

Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

“…Active EAE was induced as previously described (3,34). Eight-to 12-wkold SOCS3 fl/fl or LysMCre-SOCS3 fl/fl mice were immunized s.c. with 100 mg MOG emulsified in CFA (supplemented with 2 mg/ml Mycobacterium tuberculosis) and injected i.p.…”

JAK-STAT Lodges in Multiple Sclerosis: Pathophysiology and Therapeutic Approach Overview

“…Many of the MS-promoting cytokines such as IL-1β, TNF-α and especially that of IL-6 and IL-12 either signal through or induce JAK/STAT signaling molecules [84]. Studies have implicated the JAK/STAT axis in regulating clinical manifestations of EAE [85]. JAK inhibitors produced promising result in some inflammatory diseases [86] [87].…”

“…JAK inhibitors produced promising result in some inflammatory diseases [86] [87]. JAK inhibitors interrupt cytokine signaling; consequently, break the inflammatory process, a useful process in MS and EAE [85] (Figure 2). Indeed, previous study reported tyrphostin B42, a JAK2 inhibitor; ameliorate EAE [84].…”

JAK Inhibition: A new therapeutic strategy for management of chronic diseases

“…Thus, inhibition or hyper activation of the JAK / STAT pathway may have therapeutic benefit for several immune-mediated chronic diseases [4]. In 50% to 60% of patients with primary myelofibrosis, a gain-offunction acquired somatic mutation is present in the JAK2 gene.…”

“…In experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis, treatment with AZD1480 decreases disease severity by inhibiting JAK / STAT activation in the brain and reducing expression of proinflammatory cytokines and chemokines [4]. In rheumatoid arthritis patients, Tofacitinib, a JAK inhibitor, has been shown to improve joint symptoms and reduce joint damage in phase 3 trials [8].…”