Cytokine production profiles in chronic relapsing–remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse

Abstract

Multiple sclerosis (MS) is a chronic demyelinating disease often displaying a relapsing-remitting course of neurological manifestations that is mimicked by experimental autoimmune encephalomyelitis (EAE) in animal models of MS. In particular, NOD mice immunized with myelin oligodendrocyte glycoprotein peptide 35-55 develop chronic relapsing-remitting EAE (CREAE). To elucidate the mechanisms that cause MS relapse, we investigated the histopathology and cytokine production of spleen cells and mRNA expression levels in the central nervous system (CNS) of CREAE mice. During the first attack, inflammatory cell infiltration around small vessels and in the subarachnoid space was observed in the spinal cord. Spleen cell production and mRNA expression in the CNS of several cytokines, including IFN-γ, TNF-α, IL-6, IL-17, and CC chemokine ligand 2 (CCL2), were higher in CREAE mice than in controls. Afterwards, parenchymal infiltration and demyelination were observed histologically in the spinal cord and corresponded with the more severe clinical symptoms of the first and second relapses. IL-17 and CCL2, but not IFN-γ, TNF-α, or IL-6, were also produced by spleen cells during recurrences. Our results suggested that the immune mechanisms in relapses were different from those in the first attack for CREAE. Further investigation of CREAE mechanisms may provide important insights into successful therapies for human relapsing-remitting MS.

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

“…Our results thus propose that the inhibition of S100B has a significant impact on the extent of neuroinflammatory features, and this appears in line with the typical clinical and neuropathological heterogeneity of the model [41,42]. Remarkably, the expression levels of IFNγ and TNFα are strongly decreased by the PTM treatment, in line with the notion that these two cytokines play a relevant role in the CNS, in both physiological and pathological conditions [43]. Conversely, IL-1β expression levels are not modulated by PTM.…”

Human interferon regulatory factor 5 homologous epitopes ofEpstein-Barrvirus andMycobacterium aviumsubsp.paratuberculosisinduce a specific humoral and cellular immune response in multiple sclerosis patients

“…Indeed it was reported that an increase of IFN-γ production precedes relapse phases in MS patients. 33,34 Moreover, IFN-γ along with other type 1 cytokines, was proven to be augmented in CD4 + , CD8 + and CD14 + cells in MS patients undergoing disease reactivation, while they were normalized in stable patients or individuals undergoing IFN treatment. 35 In addition, it was also demonstrated that IFN-γ levels are upregulated during RR exacerbation phases, while IL-17 levels increase only in clinically isolated syndrome (CIS) patients.…”

New therapeutic approach by G2013 in experimental model of multiple sclerosis

“…Remitting-Relapsing EAE (RR-EAE) induced by active immunization with the immunodominant epitope of MOG 35-55 is characterized by an initial acute phase, followed by a series of remissions and relapses phases [14]. The cytokine and chemokine profiles and the nature of cellular infiltrate are markedly different during the clinical course of RR-EAE, so that the maximal expressions of the pro-inflammatory cytokines IFN-c, IL-17 and TNF-a are important mediators for disease induction [15]. The specific Th2 cells for encephalitogenic peptides in CNS can inhibit Th1 autoimmune clones, presumably by secreting anti-inflammatory cytokine IL-4, IL-10, and TGF-b [16].…”