title: IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-β in multiple sclerosis.
abstract: The interleukin-7 receptor α chain (IL-7Rα) gene was identified as a top non-major histocompatibility complex-linked risk locus for multiple sclerosis (MS). Recently, we showed that a T helper 1 (T(H)1)-driven, but not a T(H)17-driven, form of MS exhibited a good clinical response to interferon-β (IFN-β) therapy. We now demonstrate that high serum levels of IL-7, particularly when paired with low levels of IL-17F, predict responsiveness to IFN-β and hence a T(H)1-driven subtype of MS. We also show that although IL-7 signaling is neither necessary nor sufficient for the induction or expansion of T(H)17 cells, IL-7 can greatly enhance both human and mouse T(H)1 cell differentiation. IL-7 alone is sufficient to induce human T(H)1 differentiation in the absence of IL-12 or other cytokines. Furthermore, targeting IL-7/IL-7Rα is beneficial in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Mice treated with IL-7Rα-blocking antibodies before or after onset of paralysis exhibited reduced clinical signs of EAE, with reduction in peripheral naïve and activated T cells, whereas central memory T, regulatory T, B, and natural killer cell populations were largely spared. IL-7Rα antibody treatment markedly reduced lymphocyte infiltration into the central nervous system in mice with EAE. Thus, a serum profile of high IL-7 may signify a T(H)1-driven form of MS and may predict outcome in MS patients undergoing IFN-β therapy. Blockade of IL-7 and the IL-7Rα pathway may have therapeutic potential in MS and other autoimmune diseases.
authors.affiliation: Rinat, Pfizer Inc., South San Francisco, USA.
authors.forename: Li-Fen
authors.initials: LF
authors.lastname: Lee
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Axtell
authors.affiliation: Rinat, Pfizer Inc., South San Francisco, USA.
authors.forename: Guang Huan
authors.initials: GH
authors.lastname: Tu
authors.affiliation: Rinat, Pfizer Inc., South San Francisco, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Logronio
authors.affiliation: Rinat, Pfizer Inc., South San Francisco, USA.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Dilley
authors.affiliation: Rinat, Pfizer Inc., South San Francisco, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Yu
authors.affiliation: Rinat, Pfizer Inc., South San Francisco, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Rickert
authors.affiliation: Drug Safety R&D, Pfizer Inc., La Jolla, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Han
authors.affiliation: Drug Safety R&D, Pfizer Inc., La Jolla, USA.
authors.forename: Winston
authors.initials: W
authors.lastname: Evering
authors.affiliation: Walker Bioscience, Carlsbad, CA 92009, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Walker
authors.affiliation: Walker Bioscience, Carlsbad, CA 92009, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Brigit A
authors.initials: BA
authors.lastname: de Jong
authors.affiliation: VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: Killestein
authors.affiliation: VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Rinat, Pfizer Inc., South San Francisco, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Lin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000918:Antibody Specificity / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D016899:Interferon-beta / Q000276:immunology / Q000627:therapeutic use*; D015851:Interleukin-7 / Q000097:blood* / Q000276:immunology*; D051379:Mice; D009103:Multiple Sclerosis / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D015851:Interleukin-7; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D016899:Interferon-beta