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Targeting Th17 Cells for Therapy of Multiple Sclerosis

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IL-17, IL-22 and Their Producing Cells: Role in Inflammation and Autoimmunity

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Multiple sclerosis is a demyelinating disease of the central nervous system mediated by autoreactive T lymphocytes. The Th17 lineage of effectors has been implicated in the inflammatory response against CNS autoantigens. Findings in experimental autoimmune encephalomyelitis (EAE, the animal model for multiple sclerosis) suggest that targeting the Th17 response may have a beneficial outcome for patients suffering from MS. Several existing and emerging therapeutic strategies will be discussed based on the manner in which they target Th17-mediated autoimmunity: lymphocyte depletion, prevention of Th17 development, and prevention of Th17 function. T cell-ablating agents are not Th17 specific and are associated with toxicity and opportunistic infections. The prevention of Th17 differentiation can be achieved experimentally by neutralizing cytokines specifically required for Th17 development and by the administration of cytokines or other drugs that interfere with differentiation; however, these strategies may also lead to enhanced rates of certain infectious diseases. Prevention of functional Th17 responses can be accomplished by inhibiting leukocyte trafficking or by neutralizing Th17 cytokines (IL-17 and/or GM-CSF). While several promising therapeutic candidates have been identified employing the EAE model, both the risks of immunomodulation and the efficacy of such candidates in human patients need to be completely characterized and carefully considered.

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References

  1. Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, Naves R, Han M, Zhong F, Castellanos JG et al (2010) T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 16:406–412

    Article  PubMed  CAS  Google Scholar 

  2. Bailey SL, Schreiner B, McMahon EJ, Miller SD (2007) CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4(+) T(H)-17 cells in relapsing EAE. Nat Immunol 8:172–180

    Article  PubMed  CAS  Google Scholar 

  3. Bettelli E, Oukka M, Kuchroo VK (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8:345–350

    Article  PubMed  CAS  Google Scholar 

  4. Brown BA, Kantesaria PP, McDevitt LM (2007) Fingolimod: a novel immunosuppressant for multiple sclerosis. Ann Pharmacother 41:1660–1668

    Article  PubMed  CAS  Google Scholar 

  5. Chen M, Chen G, Nie H, Zhang X, Niu X, Zang YC, Skinner SM, Zhang JZ, Killian JM, Hong J (2009) Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+ T cells in MS. Eur J Immunol 39:2525–2536

    Article  PubMed  CAS  Google Scholar 

  6. Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L et al (2006) Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116:1317–1326

    Article  PubMed  CAS  Google Scholar 

  7. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12:560–567

    Article  PubMed  CAS  Google Scholar 

  8. Cree B (2006) Emerging monoclonal antibody therapies for multiple sclerosis. Neurologist 12:171–178

    Article  PubMed  Google Scholar 

  9. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T et al (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748

    Article  PubMed  CAS  Google Scholar 

  10. Durelli L, Conti L, Clerico M, Boselli D, Contessa G, Ripellino P, Ferrero B, Eid P, Novelli F (2009) T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol 65:499–509

    Article  PubMed  CAS  Google Scholar 

  11. Elliott M, Benson J, Blank M, Brodmerkel C, Baker D, Sharples KR, Szapary P (2009) Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases. Ann N Y Acad Sci 1182:97–110

    Article  PubMed  CAS  Google Scholar 

  12. Fitzgerald DC, Ciric B, Touil T, Harle H, Grammatikopolou J, Das Sarma J, Gran B, Zhang GX, Rostami A (2007) Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J Immunol 179:3268–3275

    PubMed  CAS  Google Scholar 

  13. Furuzawa-Carballeda J, Vargas-Rojas MI, Cabral AR (2007) Autoimmune inflammation from the Th17 perspective. Autoimmun Rev 6:169–175

    Article  PubMed  CAS  Google Scholar 

  14. Gocke AR, Cravens PD, Ben LH, Hussain RZ, Northrop SC, Racke MK, Lovett-Racke AE (2007) T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. J Immunol 178:1341–1348

    PubMed  CAS  Google Scholar 

  15. Gonsette RE (2007) Compared benefit of approved and experimental immunosuppressive therapeutic approaches in multiple sclerosis. Expert Opin Pharmacother 8:1103–1116

    Article  PubMed  CAS  Google Scholar 

  16. Gutcher I, Becher B (2007) APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest 117:1119–1127

    Article  PubMed  CAS  Google Scholar 

  17. Gyulveszi G, Haak S, Becher B (2009) IL-23-driven encephalo-tropism and Th17 polarization during CNS-inflammation in vivo. Eur J Immunol 39:1864–1869

    Article  PubMed  Google Scholar 

  18. Haak S, Croxford AL, Kreymborg K, Heppner FL, Pouly S, Becher B, Waisman A (2009) IL-17A and IL-17 F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest 119:61–69

    PubMed  CAS  Google Scholar 

  19. Hofstetter HH, Ibrahim SM, Koczan D, Kruse N, Weishaupt A, Toyka KV, Gold R (2005) Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol 237:123–130

    Article  PubMed  CAS  Google Scholar 

  20. Holmoy T, Vartdal F (2007) The immunological basis for treatment of multiple sclerosis. Scand J Immunol 66:374–382

    Article  PubMed  CAS  Google Scholar 

  21. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH, Durez P et al (2010) Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2:52ra72

    Article  PubMed  Google Scholar 

  22. Killestein J, Polman CH (2011) Determinants of interferon beta efficacy in patients with multiple sclerosis. Nat Rev Neurol 7:221–228

    Article  PubMed  CAS  Google Scholar 

  23. Kleinschek MA, Owyang AM, Joyce-Shaikh B, Langrish CL, Chen Y, Gorman DM, Blumenschein WM, McClanahan T, Brombacher F, Hurst SD et al (2007) IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med 204:161–170

    Article  PubMed  CAS  Google Scholar 

  24. Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM (2008) IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 205:1535–1541

    Article  PubMed  CAS  Google Scholar 

  25. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    Article  PubMed  CAS  Google Scholar 

  26. Liao JJ, Huang MC, Goetzl EJ (2007) Cutting edge: alternative signaling of Th17 cell development by sphingosine 1-phosphate. J Immunol 178:5425–5428

    PubMed  CAS  Google Scholar 

  27. Martin-Saavedra FM, Flores N, Dorado B, Eguiluz C, Bravo B, Garcia-Merino A, Ballester S (2007) Beta-interferon unbalances the peripheral T cell proinflammatory response in experimental autoimmune encephalomyelitis. Mol Immunol 44:3597–3607

    Article  PubMed  CAS  Google Scholar 

  28. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913–919

    Article  PubMed  CAS  Google Scholar 

  29. McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O’Shea JJ, Cua DJ (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10:314–324

    Article  PubMed  CAS  Google Scholar 

  30. Mehling M, Lindberg R, Raulf F, Kuhle J, Hess C, Kappos L, Brinkmann V (2010) Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 75:403–410

    Article  PubMed  CAS  Google Scholar 

  31. Rohn TA, Jennings GT, Hernandez M, Grest P, Beck M, Zou Y, Kopf M, Bachmann MF (2006) Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis. Eur J Immunol 36:2857–2867

    Article  PubMed  CAS  Google Scholar 

  32. Ruggieri M, Avolio C, Livrea P, Trojano M (2007) Glatiramer acetate in multiple sclerosis: a review. CNS Drug Rev 13:178–191

    Article  PubMed  CAS  Google Scholar 

  33. Segal BM (2010) Th17 cells in autoimmune demyelinating disease. Semin Immunopathol 32:71–77

    Article  PubMed  CAS  Google Scholar 

  34. Steinman L, Zamvil SS (2005) Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends Immunol 26:565–571

    Article  PubMed  CAS  Google Scholar 

  35. Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19:281–286

    Article  PubMed  CAS  Google Scholar 

  36. Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM (2008) Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med 14:337–342

    Article  PubMed  CAS  Google Scholar 

  37. Uyttenhove C, Van Snick J (2006) Development of an anti-IL-17A auto-vaccine that prevents experimental auto-immune encephalomyelitis. Eur J Immunol 36:2868–2874

    Article  PubMed  CAS  Google Scholar 

  38. Vaknin-Dembinsky A, Balashov K, Weiner HL (2006) IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol 176:7768–7774

    PubMed  CAS  Google Scholar 

  39. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688

    Article  PubMed  CAS  Google Scholar 

  40. Zhu J, Paul WE (2010) Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 238:247–262

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., 6-713 Tarry Building, Chicago, IL, 60611, USA

    Aaron J. Martin & Stephen D. Miller Ph.D. (Judy Gugenheim Professor of Microbiology-Immunology)

Authors
  1. Aaron J. Martin
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  2. Stephen D. Miller Ph.D.
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Corresponding author

Correspondence to Stephen D. Miller Ph.D. .

Editor information

Editors and Affiliations

  1. Institut de Transgénose, Labo. d'Immunologie et, CNRS, rue de la Férollerie 3B, Orleans CX 2, 45071, France

    Valérie Quesniaux

  2. Institut de Transgénose, Labo. d'Immunologie et, CNRS, rue de la Férollerie 3B, Orleans CX 2, 45071, France

    Bernhard Ryffel

  3. Novartis Institute for Biomedical, Research (NIBR), Novartis Pharma AG, Basel, 4002, Switzerland

    Franco Padova

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© 2013 Springer Basel

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Martin, A.J., Miller, S.D. (2013). Targeting Th17 Cells for Therapy of Multiple Sclerosis. In: Quesniaux, V., Ryffel, B., Padova, F. (eds) IL-17, IL-22 and Their Producing Cells: Role in Inflammation and Autoimmunity. Progress in Inflammation Research. Springer, Basel. https://doi.org/10.1007/978-3-0348-0522-3_18

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  • DOI: https://doi.org/10.1007/978-3-0348-0522-3_18

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  • Publisher Name: Springer, Basel

  • Print ISBN: 978-3-0348-0521-6

  • Online ISBN: 978-3-0348-0522-3

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