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

Nature Medicine volume 16, pages 406–412 (2010)Cite this article

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Abstract

Interferon-β (IFN-β) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-β in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS). IFN-β was effective in reducing EAE symptoms induced by T helper type 1 (TH1) cells but exacerbated disease induced by TH17 cells. Effective treatment in TH1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes. In TH17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-β treatment still reduced IL-17 production 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 patients, IFN-β nonresponders had higher IL-17F concentrations in serum compared to responders. Nonresponders had worse disease with more steroid usage and more relapses than did responders. Hence, IFN-β is proinflammatory in TH17-induced EAE. Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-β.

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Figure 1: Effect of IFN-β on mouse TH17 differentiation.
Figure 2: Effects of IFN-β on IFN-γ and IL-10 production in CD4+ T cells.
Figure 3: IFN-β treatment blocks TH1-induced EAE but exacerbates TH17-induced EAE.
Figure 4: IFN-β treatment requires IFN-γ signaling to suppress EAE symptoms.
Figure 5: Effect of IFN-β on human TH differentiation.
Figure 6: Pretreatment cytokine profiles in sera from individuals with multiple sclerosis that do or do not respond to IFN-β.

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Acknowledgements

We would like to thank J. Mountz (University of Alabama at Birmingham) for the kind gift of Rebif and Y. Rosenberg-Hasson for running the multiplex cytokine assay. This study was funded by US National Institutes of Health grant R01NS 55997 to L.S., US National Multiple Sclerosis Society grant RG3891-A1, National Institutes of Health grant RO1AI1076562-01 to C.R. and National Multiple Sclerosis Society grant FG 1817-A-1 to R.C.A.

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Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA

    Robert C Axtell, Brigit A de Jong, Roopa Bhat, May Han, Franklin Zhong, Jim G Castellanos, Robert Mair, Athena Christakos, Ilan Kolkowitz, Liat Katz & Lawrence Steinman

  2. Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Brigit A de Jong

  3. Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands

    Brigit A de Jong, Laura F van der Voort, Joep Killestein & Chris H Polman

  4. Department of Immunology and Schering-Plough Biopharma, Palo Alto, California, USA

    Katia Boniface & René de Waal Malefyt

  5. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Patrizia De Sarno

  6. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Rodrigo Naves & Chander Raman

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Contributions

R.C.A., L.S. and C.R. discussed, designed and wrote this report; L.S. and C.R. contributed equally as senior authors, and R.C.A. conducted or supervised all experiments. C.H.P., J.K. and L.F.v.d.V. characterized RRMS clinical data and collected serum. B.A.d.J., M.H. and I.K. assisted in analyzing multiplex data from RRMS. P.D., R.N., J.G.C., I.K. and R.M. assisted in EAE experiments. B.A.d.J. and L.K. performed histology on EAE spinal cords. A.C. and F.Z. performed the STAT1 activation assays. R.B., J.G.C. and A.C. assisted with mouse T cell experiments. R.d.W.M. and K.B. performed the human T cell experiments.

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Correspondence to Lawrence Steinman or Chander Raman.

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The authors declare no competing financial interests.

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Axtell, R., de Jong, B., Boniface, K. et al. T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis. Nat Med 16, 406–412 (2010). https://doi.org/10.1038/nm.2110

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