Shifting therapeutic attention in MS to osteopontin, type 1 and type 2 IFN.
It is widely debated whether MS is mediated solely by Th1, or solely by Th17, whether it might be mediated by both pathways, or perhaps by neither pathway. We must integrate the following four facts: first, MS lesions have a signature of IL-6-, IL-17-, osteopontin- and IFN-driven transcriptional activity. Second, MS is worsened with administration of IFN-gamma, the quintessential type 2 IFN and Th1 cytokine. Third, blockade of TNF-alpha worsened MS in clinical trials. Fourth, inhibiting the main driver of Th17, IL-23, failed to modulate relapsing-remitting MS (RRMS). Against this backdrop, standing outside the framework of the Th1 and Th17 pathways are the type 1 IFN, notably IFN-beta, the most widely used approved therapy for RRMS. A paper in this issue of the European Journal of Immunology demonstrates that IFN-beta suppresses production in CD4(+) T cells of both osteopontin and IL-17. In this commentary, the roles of these two molecules, i.e. osteopontin and IL-17, are discussed in relation to the pathogenesis of MS. Osteopontin may be more important than Th1 or Th17 in the pathogenesis of RRMS. Trials targeting this small integrin-binding protein ought to be pursued in RRMS.
Steinman
Lawrence
L
Department of Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, Stanford, CA 94305, USA. steinman@stanford.edu
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology* / Q000628:therapy*; D053495:Osteopontin / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D053495:Osteopontin; D016899:Interferon-beta; D007371:Interferon-gamma