T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis

Abstract

Interferon-β is the major treatment for multiple sclerosis (MS). However, this treatment is not always effective. Here we see congruence in outcome between responses to IFN-β in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting MS (RRMS). IFN-β is effective in reducing EAE induced by TH1 cells, but exacerbated disease induced by TH17. Effective treatment in TH1 EAE correlated with increased IL-10 in the spleen. In TH17 disease, the amount of IL-10 was unaltered by treatment, though unexpectedly IFN-β still reduced IL-17 without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-γ. In the absence of IFN-γ signaling, IFN-β therapy was ineffective in EAE. In RRMS, IFN-β non-responders had higher IL-17F in serum compared to responders. Non-responders had worse disease with more steroid usage and more relapses than responders. Hence, IFN-β is pro-inflammatory in TH17 induced EAE. Moreover, high IL-17F in the serum of RRMS patients is associated with non-responsiveness to therapy with IFN-β.

Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells

“…After treatment with αDEC205/PLP, splenocytes or lymph node cells were markedly anergic to PLP139-151 and had severely reduced IL-17 production but little or no change in IFNγ secretion. This experiment may reinforce the relative importance of IL-17 in the pathogenesis of EAE in this model system (31). A high level of Foxp3 + CD4 + Vβ6 + T cells was seen after treatment with control GL117 mAb, and no further increase was found after treatment with αDEC205/PLP.…”

Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way

“…Moreover, the frequency of IFNγ-producing CD3 + cells in peripheral blood of MS patients is reported to correlate with the severity of disease in women but not men (16). Finally, analysis of MRI data from a large randomized trial of secondary progressive MS has indicated that women may be more responsive than men to IFNβ therapy (35), a treatment that may preferentially mitigate Th1 inflammation (36). If, indeed, these sex differences in Th cytokine production persist during autoimmune inflammation, it raises the prospect that women and men with MS should be treated differently.…”

Interferon Beta and Glatiramer Acetate Therapy

“…The difficulties in this area are illustrated by recent work on IL-17 F, a cytokine highly expressed by Th17 cells. Based on initial work in EAE in rats, which indicated the presence of Th17 cells corresponded to worsened disease scores [66], Axtell et al retrospectively analyzed 26 patients with RRMS on IFNB and found that elevated pretreatment levels of IL-17 F were present in patients who were poor responders to the IFNBs. In an attempt to replicate these results, Bushnell et al [67] used 118 samples from an IFNB-1a IM dose comparison study and reanalyzed the samples from Axtell et al [66], using very similar methods and a comprehensive assessment for quality.…”