Dataset Information

Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis.

ABSTRACT: Pathogenic Th 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 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-?, 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 used 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 myelin oligodendrocyte glycoprotein-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 proinflammatory 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 Ag presentation functions of myeloid cells. Inhibition of the JAK/STAT pathway has clinical efficacy in multiple preclinical models of MS, suggesting the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3934829 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis.

Liu Yudong Y Holdbrooks Andrew T AT De Sarno Patrizia P Rowse Amber L AL Yanagisawa Lora L LL McFarland Braden C BC Harrington Laurie E LE Raman Chander C Sabbaj Steffanie S Benveniste Etty N EN Qin Hongwei H

Journal of immunology (Baltimore, Md. : 1950) 20131209 1

Pathogenic Th 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 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, ...[more]

PMID: 24323580

Similar Datasets

Project description:Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I-IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.

Dataset Information

Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis.

Publications

Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets