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General Principles of Immunotherapy in Neurological Diseases

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Neuroimmune Diseases

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

Abstract

Immunotherapy has changed the prognosis and outcome of many neuroimmunological diseases. In neurology, Immunotherapy aims to suppress or modulate the immune system. Due to the heterogeneity of immunological diseases, not all of the therapeutics are equally suited for different disorders. Thus, it is of importance to understand the pathophysiological and immunological background of the underlying disease as well as the mode of action of the various therapeutic agents. The aim of this chapter is to give an overview on the fundamental principles of the immune system. Selected diseases are presented to show the variety of the respective pathophysiological concepts. The last part describes the immunotherapies that are frequently used in neuroimmunological diseases with the mode of action and effects on the immune system. This chapter is addressed to clinicians who treat neuroimmunological disorders and shall facilitate the decision to find the right drug for the right patient.

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References

  1. Definition of Immunotherapy [Internet]. MedicineNet. [cited 2018 Oct 8]. Available from: https://www.medicinenet.com/script/main/art.asp?articlekey=7824

  2. Gold R, Buttgereit F, Toyka KV. Mechanism of action of glucocorticosteroid hormones: possible implications for therapy of neuroimmunological disorders. J Neuroimmunol. 2001;117(1–2):1–8.

    Article  CAS  PubMed  Google Scholar 

  3. Drug Approval Package: Betaseron Interferon BETA-1B Subcutaneous (Generic Name) NDA # 103471 [Internet]. [cited 2018 Nov 12]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/103471s0000TOC.cfm

  4. Rommer PS, Patejdl R, Zettl UK. Monoclonal antibodies in the treatment of neuroimmunological diseases. Curr Pharm Des. 2012;18(29):4498–507.

    Article  CAS  PubMed  Google Scholar 

  5. Rommer PS, Zettl UK. Managing the side effects of multiple sclerosis therapy: pharmacotherapy options for patients. Expert Opin Pharmacother. 2018;19(5):483–98.

    Article  CAS  PubMed  Google Scholar 

  6. Parkin J, Cohen B. An overview of the immune system. Lancet. 2001;357(9270):1777–89.

    Article  CAS  PubMed  Google Scholar 

  7. Marshall JS, Warrington R, Watson W, Kim HL. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Carow CE, Hangoc G, Broxmeyer HE. Human multipotential progenitor cells (CFU-GEMM) have extensive replating capacity for secondary CFU-GEMM: an effect enhanced by cord blood plasma. Blood. 1993;81(4):942–9.

    Article  CAS  PubMed  Google Scholar 

  9. Kawamoto H, Minato N. Myeloid cells. Int J Biochem Cell Biol. 2004;36(8):1374–9.

    Article  CAS  PubMed  Google Scholar 

  10. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S3–23.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mattner J. Natural killer T (NKT) cells in autoimmune hepatitis. Curr Opin Immunol. 2013;25(6):697–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Perl A. Pathogenesis and spectrum of autoimmunity. Methods Mol Biol. 2012;900:1–9.

    Article  CAS  PubMed  Google Scholar 

  13. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood. 2008;112(5):1570–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009;129(6):1339–50.

    Article  PubMed  CAS  Google Scholar 

  16. Golubovskaya V, Wu L. Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy. Cancer. 2016;8(3)

    Google Scholar 

  17. Shibata K. Close link between development and function of gamma-delta T cells. Microbiol Immunol. 2012;56(4):217–27.

    Article  CAS  PubMed  Google Scholar 

  18. Shibata K, Yamada H, Nakamura M, Hatano S, Katsuragi Y, Kominami R, et al. IFN-γ-producing and IL-17-producing γδ T cells differentiate at distinct developmental stages in murine fetal thymus. J Immunol. 2014;192(5):2210–8.

    Article  CAS  PubMed  Google Scholar 

  19. Wiede F, Dudakov JA, Lu K-H, Dodd GT, Butt T, Godfrey DI, et al. PTPN2 regulates T cell lineage commitment and αβ versus γδ specification. J Exp Med. 2017;214(9):2733–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cellular and molecular immunology – 9th edition [Internet]. [cited 2018 Dec 4]. Available from: https://www.elsevier.com/books/cellular-and-molecular-immunology/abbas/978-0-323-47978-3

  21. Reinhardt RL, Liang H-E, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol. 2009;10(4):385–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang S-H, Gao C-Y, Li L, Chang C, Leung PSC, Gershwin ME, et al. The molecular basis of immune regulation in autoimmunity. Clin Sci. 2018;132(1):43–67.

    Article  CAS  Google Scholar 

  23. Khan U, Ghazanfar H. T lymphocytes and autoimmunity. Int Rev Cell Mol Biol. 2018;341:125–68.

    Article  CAS  PubMed  Google Scholar 

  24. von Boehmer H, Melchers F. Checkpoints in lymphocyte development and autoimmune disease. Nat Immunol. 2010;11(1):14–20.

    Article  CAS  Google Scholar 

  25. Passos GA, Speck-Hernandez CA, Assis AF, Mendes-da-Cruz DA. Update on Aire and thymic negative selection. Immunology. 2018;153(1):10–20.

    Article  CAS  PubMed  Google Scholar 

  26. Murphy KM, Travers P, Walport M. Janeway’s immunobiology (immunobiology: the immune system (Janeway)).

    Google Scholar 

  27. Xiang Z, Yang Y, Chang C, Lu Q. The epigenetic mechanism for discordance of autoimmunity in monozygotic twins. J Autoimmun. 2017;83:43–50.

    Article  CAS  PubMed  Google Scholar 

  28. Kinnunen E, Juntunen J, Ketonen L, Koskimies S, Konttinen YT, Salmi T, et al. Genetic susceptibility to multiple sclerosis. A co-twin study of a nationwide series. Arch Neurol. 1988;45(10):1108–11.

    Article  CAS  PubMed  Google Scholar 

  29. Williams A, Eldridge R, McFarland H, Houff S, Krebs H, McFarlin D. Multiple sclerosis in twins. Neurology. 1980;30(11):1139–47.

    Article  CAS  PubMed  Google Scholar 

  30. Multiple sclerosis in 54 twinships: concordance rate is independent of zygosity. French Research Group on Multiple Sclerosis. Ann Neurol. 1992;32(6):724–7.

    Google Scholar 

  31. Westerlind H, Ramanujam R, Uvehag D, Kuja-Halkola R, Boman M, Bottai M, et al. Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden. Brain J Neurol. 2014;137(Pt 3):770–8.

    Article  Google Scholar 

  32. O’Gorman C, Lin R, Stankovich J, Broadley SA. Modelling genetic susceptibility to multiple sclerosis with family data. Neuroepidemiology. 2013;40(1):1–12.

    Article  PubMed  Google Scholar 

  33. Yu P. The potential role of retroviruses in autoimmunity. Immunol Rev. 2016;269(1):85–99.

    Article  CAS  PubMed  Google Scholar 

  34. Correale J, Gaitán MI. Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein-Barr virus infection. Acta Neurol Scand. 2015;132(199):46–55.

    Article  CAS  PubMed  Google Scholar 

  35. Pane JA, Coulson BS. Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes. Diabetologia. 2015;58(6):1149–59.

    Article  CAS  PubMed  Google Scholar 

  36. Floreani A, Leung PSC, Gershwin ME. Environmental basis of autoimmunity. Clin Rev Allergy Immunol. 2016;50(3):287–300.

    Article  CAS  PubMed  Google Scholar 

  37. Wekerle H. Brain autoimmunity and intestinal microbiota: 100 trillion game changers. Trends Immunol. 2017;38(7):483–97.

    Article  CAS  PubMed  Google Scholar 

  38. Ramanathan S, Dale RC, Brilot F. Anti-MOG antibody: the history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination. Autoimmun Rev. 2016;15(4):307–24.

    Article  CAS  PubMed  Google Scholar 

  39. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group. N Engl J Med. 1998;339(5):285–91.

    Article  CAS  PubMed  Google Scholar 

  40. Fischer-Betz R, Specker C. Pregnancy in systemic lupus erythematosus and antiphospholipid syndrome. Best Pract Res Clin Rheumatol. 2017;31(3):397–414.

    Article  PubMed  Google Scholar 

  41. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018;378(2):169–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bar-Or A. The immunology of multiple sclerosis. Semin Neurol. 2008;28(1):29–45.

    Article  PubMed  Google Scholar 

  43. Kinnunen T, Chamberlain N, Morbach H, Cantaert T, Lynch M, Preston-Hurlburt P, et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest. 2013;123(6):2737–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Frohman EM, Racke MK, Raine CS. Multiple sclerosis – the plaque and its pathogenesis. N Engl J Med. 2006;354(9):942–55.

    Article  CAS  PubMed  Google Scholar 

  45. Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol. 2005;6(12):1182–90.

    Article  CAS  PubMed  Google Scholar 

  46. Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012;12(9):623–35.

    Article  CAS  PubMed  Google Scholar 

  47. Kabat EA, Moore DH, Landow H. An electrophoretic study of the protein components in cerebrospinal fluid and their relationship to the serum proteins. J Clin Invest. 1942;21(5):571–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cepok S, Rosche B, Grummel V, Vogel F, Zhou D, Sayn J, et al. Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain J Neurol. 2005;128(Pt 7):1667–76.

    Article  Google Scholar 

  49. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung H-P, Hemmer B, et al. Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221–34.

    Article  CAS  PubMed  Google Scholar 

  50. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209–20.

    Article  CAS  PubMed  Google Scholar 

  51. Reindl M, Khalil M, Berger T. Antibodies as biological markers for pathophysiological processes in MS. J Neuroimmunol. 2006;180(1–2):50–62.

    Article  CAS  PubMed  Google Scholar 

  52. Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain J Neurol. 2007;130(Pt 5):1235–43.

    Article  Google Scholar 

  53. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106–12.

    Article  CAS  PubMed  Google Scholar 

  54. Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, et al. Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain J Neurol. 2008;131(Pt 11):3072–80.

    Article  CAS  Google Scholar 

  55. Saini H, Rifkin R, Gorelik M, Huang H, Ferguson Z, Jones MV, et al. Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis. BMC Neurol. 2013;13:104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Stellmann J-P, Krumbholz M, Friede T, Gahlen A, Borisow N, Fischer K, et al. Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response. J Neurol Neurosurg Psychiatry. 2017;88(8):639–47.

    Article  PubMed  Google Scholar 

  57. Leypoldt F, Wandinger K-P, Bien CG, Dalmau J. Autoimmune encephalitis. Eur Neurol Rev. 2013;8(1):31–7.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Graus F, Saiz A. Limbic encephalitis: a probably under-recognized syndrome. Neurologia. 2005;20(1):24–30.

    CAS  PubMed  Google Scholar 

  59. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391–404.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Gebauer C, Pignolet B, Yshii L, Mauré E, Bauer J, Liblau R. CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model. Oncoimmunology. 2017;6(2):e1260212.

    Article  PubMed  CAS  Google Scholar 

  61. Nguyen TP, Taylor RS. Guillain Barre syndrome. In: StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2018 [cited 2018 Oct 26]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK532254/

  62. Sinha S, Prasad KN, Jain D, Pandey CM, Jha S, Pradhan S. Preceding infections and anti-ganglioside antibodies in patients with Guillain-Barré syndrome: a single Centre prospective case-control study. Clin Microbiol Infect. 2007;13(3):334–7.

    Article  CAS  PubMed  Google Scholar 

  63. Goodfellow JA, Willison HJ. Guillain-Barré syndrome: a century of progress. Nat Rev Neurol. 2016;12(12):723–31.

    Article  PubMed  Google Scholar 

  64. Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570–81.

    Article  CAS  PubMed  Google Scholar 

  65. Cetin H, Vincent A. Pathogenic mechanisms and clinical correlations in autoimmune myasthenic syndromes. Semin Neurol. 2018;38(3):344–54.

    Article  PubMed  Google Scholar 

  66. Rommer PS, Stüve O, Goertsches R, Mix E, Zettl UK. Monoclonal antibodies in the therapy of multiple sclerosis: an overview. J Neurol. 2008;255(Suppl 6):28–35.

    Article  CAS  PubMed  Google Scholar 

  67. Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, Havrdova E, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology. 2014;82(7):573–81.

    Article  CAS  PubMed  Google Scholar 

  68. Home – ClinicalTrials.gov [Internet]. [cited 2018 Nov 2]. Available from: https://clinicaltrials.gov/

  69. Genovese MC, Kaine JL, Lowenstein MB, Del Giudice J, Baldassare A, Schechtman J, et al. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study. Arthritis Rheum. 2008;58(9):2652–61.

    Article  PubMed  Google Scholar 

  70. Greenberg BM, Graves D, Remington G, Hardeman P, Mann M, Karandikar N, et al. Rituximab dosing and monitoring strategies in neuromyelitis optica patients: creating strategies for therapeutic success. Mult Scler. 2012;18(7):1022–6.

    Article  PubMed  Google Scholar 

  71. Lehmann-Horn K, Kinzel S, Weber MS. Deciphering the role of B cells in multiple sclerosis-towards specific targeting of pathogenic function. Int J Mol Sci. 2017;18(10)

    Google Scholar 

  72. Buggins AGS, Mufti GJ, Salisbury J, Codd J, Westwood N, Arno M, et al. Peripheral blood but not tissue dendritic cells express CD52 and are depleted by treatment with alemtuzumab. Blood. 2002;100(5):1715–20.

    Article  CAS  PubMed  Google Scholar 

  73. Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R, Dyer MJ, et al. Levels of expression of CD52 in normal and leukemic B and T cells: correlation with in vivo therapeutic responses to Campath-1H. Leuk Res. 1998;22(2):185–91.

    Article  CAS  PubMed  Google Scholar 

  74. Rao SP, Sancho J, Campos-Rivera J, Boutin PM, Severy PB, Weeden T, et al. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS One. 2012;7(6):e39416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ruck T, Bittner S, Wiendl H, Meuth SG. Alemtuzumab in multiple sclerosis: mechanism of action and beyond. Int J Mol Sci. 2015;16(7):16414–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhang X, Tao Y, Chopra M, Ahn M, Marcus KL, Choudhary N, et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol. 2013;191(12):5867–74.

    Article  CAS  PubMed  Google Scholar 

  77. Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253(1):98–108.

    Article  PubMed  Google Scholar 

  78. Thompson SAJ, Jones JL, Cox AL, Compston DAS, Coles AJ. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J Clin Immunol. 2010;30(1):99–105.

    Article  CAS  PubMed  Google Scholar 

  79. von Kutzleben S, Pryce G, Giovannoni G, Baker D. Depletion of CD52-positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune-tolerance promoting CD8 T-cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis. Immunology. 2017;150(4):444–55.

    Article  CAS  Google Scholar 

  80. Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord. 2017;10(10):343–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576–85.

    Article  PubMed  Google Scholar 

  82. Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology. 2017;88(9):842–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Burt RK, Loh Y, Pearce W, Beohar N, Barr WG, Craig R, et al. Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. JAMA. 2008;299(8):925–36.

    Article  CAS  PubMed  Google Scholar 

  84. Armitage JO. Bone marrow transplantation. N Engl J Med. 1994;330(12):827–38.

    Article  CAS  PubMed  Google Scholar 

  85. Blanco Y, Saiz A, Carreras E, Graus F. Autologous haematopoietic-stem-cell transplantation for multiple sclerosis. Lancet Neurol. 2005;4(1):54–63.

    Article  PubMed  Google Scholar 

  86. Yong VW, Chabot S, Stuve O, Williams G. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology. 1998;51(3):682–9.

    Article  CAS  PubMed  Google Scholar 

  87. Massey JC, Sutton IJ, Ma DDF, Moore JJ. Regenerating immunotolerance in multiple sclerosis with autologous hematopoietic stem cell transplant. Front Immunol. 2018;9:410.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Collins F, Kazmi M, Muraro PA. Progress and prospects for the use and the understanding of the mode of action of autologous hematopoietic stem cell transplantation in the treatment of multiple sclerosis. Expert Rev Clin Immunol. 2017;13(6):611–22.

    Article  CAS  PubMed  Google Scholar 

  89. Invernizzi P, Benedetti MD, Poli S, Monaco S. Azathioprine in multiple sclerosis. Mini Rev Med Chem. 2008;8(9):919–26.

    Article  CAS  PubMed  Google Scholar 

  90. Rajabally YA. Unconventional treatments for chronic inflammatory demyelinating polyneuropathy. Neurodegener Dis Manag. 2017;7(5):331–42.

    Article  PubMed  Google Scholar 

  91. Friedman AB, Sparrow MP, Gibson PR. The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders. Int J Rheum Dis. 2014;17(2):132–41.

    Article  CAS  PubMed  Google Scholar 

  92. Wagner M, Earley AK, Webster AC, Schmid CH, Balk EM, Uhlig K. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev. 2015;(12):CD007746.

    Google Scholar 

  93. Pelin M, De Iudicibus S, Londero M, Spizzo R, Dei Rossi S, Martelossi S, et al. Thiopurine biotransformation and pharmacological effects: contribution of oxidative stress. Curr Drug Metab. 2016;17(6):542–9.

    Article  CAS  PubMed  Google Scholar 

  94. Elion GB. The purine path to chemotherapy. Science. 1989;244(4900):41–7.

    Article  CAS  PubMed  Google Scholar 

  95. Schwartz R, Stack J, Dameshek W. Effect of 6-mercaptopurine on antibody production. Proc Soc Exp Biol Med. 1958;99(1):164–7.

    Article  CAS  PubMed  Google Scholar 

  96. Lord JD, Shows DM. Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease. World J Gastroenterol. 2017;23(18):3240–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Duley JA, Florin THJ. Thiopurine therapies: problems, complexities, and progress with monitoring thioguanine nucleotides. Ther Drug Monit. 2005;27(5):647–54.

    Article  CAS  PubMed  Google Scholar 

  98. Ertz-Archambault N, Kosiorek H, Taylor GE, Kelemen K, Dueck A, Castro J, et al. Association of therapy for autoimmune disease with myelodysplastic syndromes and acute myeloid leukemia. JAMA Oncol. 2017;3(7):936–43.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Kwong Y-L. Azathioprine: association with therapy-related myelodysplastic syndrome and acute myeloid leukemia. J Rheumatol. 2010;37(3):485–90.

    Article  CAS  PubMed  Google Scholar 

  100. Katara P, Kuntal H. TPMT polymorphism: when shield becomes weakness. Interdiscip Sci Comput Life Sci. 2016;8(2):150–5.

    Article  CAS  Google Scholar 

  101. Yang S-K, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46(9):1017–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Leist TP, Weissert R. Cladribine: mode of action and implications for treatment of multiple sclerosis. Clin Neuropharmacol. 2011;34(1):28–35.

    Article  CAS  PubMed  Google Scholar 

  103. Kawasaki H, Carrera CJ, Piro LD, Saven A, Kipps TJ, Carson DA. Relationship of deoxycytidine kinase and cytoplasmic 5′-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine. Blood. 1993;81(3):597–601.

    Article  CAS  PubMed  Google Scholar 

  104. Carson DA, Wasson DB, Taetle R, Yu A. Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood. 1983;62(4):737–43.

    Article  CAS  PubMed  Google Scholar 

  105. Lotfi K, Juliusson G, Albertioni F. Pharmacological basis for cladribine resistance. Leuk Lymphoma. 2003;44(10):1705–12.

    Article  CAS  PubMed  Google Scholar 

  106. Wiendl H. Cladribine – an old newcomer for pulsed immune reconstitution in MS. Nat Rev Neurol. 2017;13(10):573–4.

    Article  CAS  PubMed  Google Scholar 

  107. Ceronie B, Jacobs BM, Baker D, Dubuisson N, Mao Z, Ammoscato F, et al. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J Neurol. 2018;265(5):1199–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Laugel B, Borlat F, Galibert L, Vicari A, Weissert R, Chvatchko Y, et al. Cladribine inhibits cytokine secretion by T cells independently of deoxycytidine kinase activity. J Neuroimmunol. 2011;240–241:52–7.

    Article  PubMed  CAS  Google Scholar 

  109. Liliemark J. The clinical pharmacokinetics of cladribine. Clin Pharmacokinet. 1997;32(2):120–31.

    Article  CAS  PubMed  Google Scholar 

  110. Sistigu A, Viaud S, Chaput N, Bracci L, Proietti E, Zitvogel L. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. Semin Immunopathol. 2011;33(4):369–83.

    Article  CAS  PubMed  Google Scholar 

  111. Awad A, Stüve O. Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms. Ther Adv Neurol Disord. 2009;2(6):50–61.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Stankiewicz JM, Kolb H, Karni A, Weiner HL. Role of immunosuppressive therapy for the treatment of multiple sclerosis. Neurotherapeutics. 2013;10(1):77–88.

    Article  CAS  PubMed  Google Scholar 

  113. Ficken MD, Barnes HJ. Effect of cyclophosphamide on selected hematologic parameters of the Turkey. Avian Dis. 1988;32(4):812–7.

    Article  CAS  PubMed  Google Scholar 

  114. Unger C, Eibl H, von Heyden HW, Krisch B, Nagel GA. Blood-brain barrier and the penetration of cytostatic drugs. Klin Wochenschr. 1985;63(12):565–71.

    Article  CAS  PubMed  Google Scholar 

  115. Zephir H, de Seze J, Duhamel A, Debouverie M, Hautecoeur P, Lebrun C, et al. Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients. J Neurol Sci. 2004;218(1–2):73–7.

    Article  CAS  PubMed  Google Scholar 

  116. Kanter IC, Huttner HB, Staykov D, Biermann T, Struffert T, Kerling F, et al. Cyclophosphamide for anti-GAD antibody-positive refractory status epilepticus. Epilepsia. 2008;49(5):914–20.

    Article  CAS  PubMed  Google Scholar 

  117. Lehmann JCU, Listopad JJ, Rentzsch CU, Igney FH, von Bonin A, Hennekes HH, et al. Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase 1. J Invest Dermatol. 2007;127(4):835–45.

    Article  CAS  PubMed  Google Scholar 

  118. Schmidt TJ, Ak M, Mrowietz U. Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-L-cysteine – preparation of S-substituted thiosuccinic acid esters. Bioorg Med Chem. 2007;15(1):333–42.

    Article  CAS  PubMed  Google Scholar 

  119. Dubey D, Kieseier BC, Hartung HP, Hemmer B, Warnke C, Menge T, et al. Dimethyl fumarate in relapsing-remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety. Expert Rev Neurother. 2015;15(4):339–46.

    Article  CAS  PubMed  Google Scholar 

  120. Mills EA, Ogrodnik MA, Plave A, Mao-Draayer Y. Emerging understanding of the mechanism of action for dimethyl fumarate in the treatment of multiple sclerosis. Front Neurol. 2018;9:5.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Smith MD, Calabresi PA, Bhargava P. Dimethyl fumarate treatment alters NK cell function in multiple sclerosis. Eur J Immunol. 2018;48(2):380–3.

    Article  CAS  PubMed  Google Scholar 

  122. Wu Q, Wang Q, Mao G, Dowling CA, Lundy SK, Mao-Draayer Y. Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients. J Immunol. 2017;198(8):3069–80.

    Article  CAS  PubMed  Google Scholar 

  123. Diebold M, Sievers C, Bantug G, Sanderson N, Kappos L, Kuhle J, et al. Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis. J Autoimmun. 2018;86:39–50.

    Article  CAS  PubMed  Google Scholar 

  124. Holm Hansen R, Højsgaard Chow H, Sellebjerg F, Rode von Essen M. Dimethyl fumarate therapy suppresses B cell responses and follicular helper T cells in relapsing-remitting multiple sclerosis. Mult Scler 2018;1352458518790417.

    Google Scholar 

  125. Smith MD, Martin KA, Calabresi PA, Bhargava P. Dimethyl fumarate alters B-cell memory and cytokine production in MS patients. Ann Clin Transl Neurol. 2017;4(5):351–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Galloway DA, Williams JB, Moore CS. Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation. Ann Clin Transl Neurol. 2017;4(6):381–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Brennan MS, Matos MF, Richter KE, Li B, Scannevin RH. The NRF2 transcriptional target, OSGIN1, contributes to monomethyl fumarate-mediated cytoprotection in human astrocytes. Sci Rep. 2017;7:42054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007;25(11):1256–64.

    Article  CAS  PubMed  Google Scholar 

  129. Jordan A, Freimer M. Recent advances in understanding and managing myasthenia gravis. F1000Res. 2018;7.

    Google Scholar 

  130. Howard JF, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976–86.

    Article  CAS  PubMed  Google Scholar 

  131. Soliris | European Medicines Agency [Internet]. [cited 2018 Dec 6]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/soliris#overview-section

  132. Soliris (eculizumab) FDA Approval History [Internet]. Drugs.com. [cited 2018 Dec 6]. Available from: https://www.drugs.com/history/soliris.html

  133. Pilch KS, Spaeth PJ, Yuki N, Wakerley BR. Therapeutic complement inhibition: a promising approach for treatment of neuroimmunological diseases. Expert Rev Neurother. 2017;17(6):579–91.

    Article  CAS  PubMed  Google Scholar 

  134. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427(6972):355–60.

    Article  CAS  PubMed  Google Scholar 

  135. Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol. 2007;8(12):1295–301.

    Article  CAS  PubMed  Google Scholar 

  136. Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355(11):1124–40.

    Article  CAS  PubMed  Google Scholar 

  137. Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.

    Article  CAS  PubMed  Google Scholar 

  138. Luessi F, Kraus S, Trinschek B, Lerch S, Ploen R, Paterka M, et al. FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis. Mult Scler. 2015;21(14):1811–22.

    Article  CAS  PubMed  Google Scholar 

  139. Claes N, Dhaeze T, Fraussen J, Broux B, Van Wijmeersch B, Stinissen P, et al. Compositional changes of B and T cell subtypes during fingolimod treatment in multiple sclerosis patients: a 12-month follow-up study. PLoS One. 2014;9(10):e111115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Serpero LD, Filaci G, Parodi A, Battaglia F, Kalli F, Brogi D, et al. Fingolimod modulates peripheral effector and regulatory T cells in MS patients. J Neuroimmune Pharmacol. 2013;8(5):1106–13.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Sato DK, Nakashima I, Bar-Or A, Misu T, Suzuki C, Nishiyama S, et al. Changes in Th17 and regulatory T cells after fingolimod initiation to treat multiple sclerosis. J Neuroimmunol. 2014;268(1–2):95–8.

    Article  CAS  PubMed  Google Scholar 

  142. Yamagata K, Tagami M, Torii Y, Takenaga F, Tsumagari S, Itoh S, et al. Sphingosine 1-phosphate induces the production of glial cell line-derived neurotrophic factor and cellular proliferation in astrocytes. Glia. 2003;41(2):199–206.

    Article  PubMed  Google Scholar 

  143. Edsall LC, Pirianov GG, Spiegel S. Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J Neurosci. 1997;17(18):6952–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G, et al. Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol. 2014;76(3):325–37.

    Article  CAS  PubMed  Google Scholar 

  145. Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol. 1971;1(4):242–8.

    Article  CAS  PubMed  Google Scholar 

  146. Aharoni R, Teitelbaum D, Arnon R, Sela M. Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc Natl Acad Sci U S A. 1999;96(2):634–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Ireland SJ, Guzman AA, O’Brien DE, Hughes S, Greenberg B, Flores A, et al. The effect of glatiramer acetate therapy on functional properties of B cells from patients with relapsing-remitting multiple sclerosis. JAMA Neurol. 2014;71(11):1421–8.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Hong J, Li N, Zhang X, Zheng B, Zhang JZ. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc Natl Acad Sci U S A. 2005;102(18):6449–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kuerten S, Jackson LJ, Kaye J, Vollmer TL. Impact of glatiramer acetate on B cell-mediated pathogenesis of multiple sclerosis. CNS Drugs. 2018;32(11):1039–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Farina C, Weber MS, Meinl E, Wekerle H, Hohlfeld R. Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action. Lancet Neurol. 2005;4(9):567–75.

    Article  CAS  PubMed  Google Scholar 

  151. Ruggieri M, Avolio C, Livrea P, Trojano M. Glatiramer acetate in multiple sclerosis: a review. CNS Drug Rev. 2007;13(2):178–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011;335(1):2–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Buttgereit F, Wehling M, Burmester GR. A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revisited. Arthritis Rheum. 1998;41(5):761–7.

    Article  CAS  PubMed  Google Scholar 

  154. Liberman AC, Budziñski ML, Sokn C, Gobbini RP, Steininger A, Arzt E. Regulatory and mechanistic actions of glucocorticoids on T and inflammatory cells. Front Endocrinol. 2018;9:235.

    Article  Google Scholar 

  155. Barnes PJ. Molecular mechanisms and cellular effects of glucocorticosteroids. Immunol Allergy Clin N Am. 2005;25(3):451–68.

    Article  Google Scholar 

  156. Cronstein BN, Kimmel SC, Levin RI, Martiniuk F, Weissmann G. A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1992;89(21):9991–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Leussink VI, Jung S, Merschdorf U, Toyka KV, Gold R. High-dose methylprednisolone therapy in multiple sclerosis induces apoptosis in peripheral blood leukocytes. Arch Neurol. 2001;58(1):91–7.

    Article  CAS  PubMed  Google Scholar 

  158. Zhang J, Hutton G, Zang Y. A comparison of the mechanisms of action of interferon beta and glatiramer acetate in the treatment of multiple sclerosis. Clin Ther. 2002;24(12):1998–2021.

    Article  CAS  PubMed  Google Scholar 

  159. Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs. 2011;25(6):491–502.

    Article  CAS  PubMed  Google Scholar 

  160. Kavrochorianou N, Markogiannaki M, Haralambous S. IFN-β differentially regulates the function of T cell subsets in MS and EAE. Cytokine Growth Factor Rev. 2016;30:47–54.

    Article  CAS  PubMed  Google Scholar 

  161. Wang K-C, Lin K-H, Lee T-C, Lee C-L, Chen S-Y, Chen S-J, et al. Poor responses to interferon-beta treatment in patients with neuromyelitis optica and multiple sclerosis with long spinal cord lesions. PLoS One. 2014;9(6):e98192.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Palace J, Leite MI, Nairne A, Vincent A. Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol. 2010;67(8):1016–7.

    Article  PubMed  Google Scholar 

  163. Cherin P, Marie I, Michallet M, Pelus E, Dantal J, Crave J-C, et al. Management of adverse events in the treatment of patients with immunoglobulin therapy: a review of evidence. Autoimmun Rev. 2016;15(1):71–81.

    Article  CAS  PubMed  Google Scholar 

  164. Bittner B, Richter W, Schmidt J. Subcutaneous administration of biotherapeutics: an overview of current challenges and opportunities. BioDrugs. 2018;32(5):425–40.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the therapeutics and technology assessment Subcommittee of the American Academy of neurology. Neurology. 2012;78(13):1009–15.

    Article  CAS  PubMed  Google Scholar 

  166. Hughes RAC, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2014;(9):CD002063.

    Google Scholar 

  167. Lancaster E. The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol. 2016;12(1):1–13.

    Article  PubMed  Google Scholar 

  168. Winkelmann A, Rommer PS, Hecker M, Zettl UK. Intravenous immunoglobulin treatment in multiple sclerosis: a prospective, rater-blinded analysis of relapse rates during pregnancy and the postnatal period. CNS Neurosci Ther. 2019;25(1):78–85.

    Article  CAS  PubMed  Google Scholar 

  169. Lünemann JD, Nimmerjahn F, Dalakas MC. Intravenous immunoglobulin in neurology--mode of action and clinical efficacy. Nat Rev Neurol. 2015;11(2):80–9.

    Article  PubMed  CAS  Google Scholar 

  170. Janke AD, Yong VW. Impact of IVIg on the interaction between activated T cells and microglia. Neurol Res. 2006;28(3):270–4.

    Article  CAS  PubMed  Google Scholar 

  171. Lünemann JD, Quast I, Dalakas MC. Efficacy of intravenous immunoglobulin in neurological diseases. Neurotherapeutics. 2016;13(1):34–46.

    Article  PubMed  CAS  Google Scholar 

  172. Vollmer T, Stewart T, Baxter N. Mitoxantrone and cytotoxic drugs’ mechanisms of action. Neurology. 2010;74(Suppl 1):S41–6.

    Article  CAS  PubMed  Google Scholar 

  173. Thomas X, Archimbaud E. Mitoxantrone in the treatment of acute myelogenous leukemia: a review. Hematol Cell Ther. 1997;39(4):63–74.

    Article  CAS  PubMed  Google Scholar 

  174. Chan A, Weilbach FX, Toyka KV, Gold R. Mitoxantrone induces cell death in peripheral blood leucocytes of multiple sclerosis patients. Clin Exp Immunol. 2005;139(1):152–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Neuhaus O, Wiendl H, Kieseier BC, Archelos JJ, Hemmer B, Stüve O, et al. Multiple sclerosis: mitoxantrone promotes differential effects on immunocompetent cells in vitro. J Neuroimmunol. 2005;168(1–2):128–37.

    Article  CAS  PubMed  Google Scholar 

  176. Kopadze T, Dehmel T, Hartung H-P, Stüve O, Kieseier BC. Inhibition by mitoxantrone of in vitro migration of immunocompetent cells: a possible mechanism for therapeutic efficacy in the treatment of multiple sclerosis. Arch Neurol. 2006;63(11):1572–8.

    Article  PubMed  Google Scholar 

  177. Putzki N, Kumar M, Kreuzfelder E, Grosse-Wilde H, Diener HC, Limmroth V. Mitoxantrone does not restore the impaired suppressive function of natural regulatory T cells in patients suffering from multiple sclerosis. A longitudinal ex vivo and in vitro study. Eur Neurol. 2009;61(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  178. Kingwell E, Koch M, Leung B, Isserow S, Geddes J, Rieckmann P, et al. Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS. Neurology. 2010;74(22):1822–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Cocco E, Marrosu MG. The current role of mitoxantrone in the treatment of multiple sclerosis. Expert Rev Neurother. 2014;14(6):607–16.

    Article  CAS  PubMed  Google Scholar 

  180. Research C for DE and. Postmarket drug safety information for patients and providers – mitoxantrone hydrochloride (marketed as Novantrone and generics) – Healthcare Professional Sheet text version [Internet]. [cited 2018 Nov 14]. Available from: https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126445.htm

  181. Xiong W, Lahita RG. Pragmatic approaches to therapy for systemic lupus erythematosus. Nat Rev Rheumatol. 2014;10(2):97–107.

    Article  CAS  PubMed  Google Scholar 

  182. Staatz CE, Tett SE. Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. Arch Toxicol. 2014;88(7):1351–89.

    Article  CAS  PubMed  Google Scholar 

  183. Ginzler EM, Aranow C. Mycophenolate mofetil in lupus nephritis. Lupus. 2005;14(1):59–64.

    Article  CAS  PubMed  Google Scholar 

  184. Felten R, Scher F, Sibilia J, Chasset F, Arnaud L. Advances in the treatment of systemic lupus erythematosus: from back to the future, to the future and beyond. Joint Bone Spine. 2018. pii: S1297-319X(18)30304-X.

    Google Scholar 

  185. Villarroel MC, Hidalgo M, Jimeno A. Mycophenolate mofetil: an update. Drugs Today (Barc). 2009;45(7):521–32.

    CAS  Google Scholar 

  186. Gotterer L, Li Y. Maintenance immunosuppression in myasthenia gravis. J Neurol Sci. 2016;369:294–302.

    Article  PubMed  Google Scholar 

  187. Stüve O, Cravens PD, Frohman EM, Phillips JT, Remington GM, von Geldern G, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology. 2009;72(5):396–401.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Stüve O, Marra CM, Bar-Or A, Niino M, Cravens PD, Cepok S, et al. Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol. 2006;63(10):1383–7.

    Article  PubMed  Google Scholar 

  189. Pagnini C, Arseneau KO, Cominelli F. Natalizumab in the treatment of Crohn’s disease patients. Expert Opin Biol Ther. 2017;17(11):1433–8.

    CAS  PubMed  Google Scholar 

  190. Tsokos GC, Balow JE. Immunosuppressive agents and plasmapheresis in immunological disorders. J Immunopharmacol. 1985;7(1):1–15.

    Article  CAS  PubMed  Google Scholar 

  191. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the therapeutics and technology assessment Subcommittee of the American Academy of neurology. Neurology. 2011;76(3):294–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Gwathmey K, Balogun RA, Burns T. Neurologic indications for therapeutic plasma exchange: 2011 update. J Clin Apher. 2012;27(3):138–45.

    Article  PubMed  Google Scholar 

  193. Lazaridis K, Dalianoudis I, Baltatzidi V, Tzartos SJ. Specific removal of autoantibodies by extracorporeal immunoadsorption ameliorates experimental autoimmune myasthenia gravis. J Neuroimmunol. 2017;312:24–30.

    Article  CAS  PubMed  Google Scholar 

  194. Faissner S, Nikolayczik J, Chan A, Hellwig K, Gold R, Yoon M-S, et al. Plasmapheresis and immunoadsorption in patients with steroid refractory multiple sclerosis relapses. J Neurol. 2016;263(6):1092–8.

    Article  CAS  PubMed  Google Scholar 

  195. Miller AE. Oral teriflunomide in the treatment of relapsing forms of multiple sclerosis: clinical evidence and long-term experience. Ther Adv Neurol Disord. 2017;10(12):381–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Wostradowski T, Prajeeth CK, Gudi V, Kronenberg J, Witte S, Brieskorn M, et al. In vitro evaluation of physiologically relevant concentrations of teriflunomide on activation and proliferation of primary rodent microglia. J Neuroinflammation. 2016;13(1):250.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol. 1999;162(4):2095–102.

    CAS  PubMed  Google Scholar 

  198. González-Alvaro I, Ortiz AM, Domínguez-Jiménez C, Aragón-Bodi A, Díaz Sánchez B, Sánchez-Madrid F. Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway. Ann Rheum Dis. 2009;68(10):1644–50.

    Article  PubMed  CAS  Google Scholar 

  199. Groh J, Hörner M, Martini R. Teriflunomide attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations. J Neuroinflammation. 2018;15(1):194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Araki M. Blockade of IL-6 signaling in neuromyelitis optica. Neurochem Int. 2018. pii: S0197-0186(18)30358-9.

    Google Scholar 

  201. Zola H, Flego L. Expression of interleukin-6 receptor on blood lymphocytes without in vitro activation. Immunology. 1992;76(2):338–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Regulation of interleukin 6 receptor expression in human monocytes and monocyte-derived macrophages. Comparison with the expression in human hepatocytes. J Exp Med. 1989;170(5):1537–49.

    Google Scholar 

  203. Wu T-C, Chiang C-Y, Chan J-S, Lee C-Y, Leu H-B, Huang P-H, et al. Tocilizumab, a humanized monoclonal antibody against the interleukin-6 receptor, inhibits high glucose-induced vascular smooth muscle cell migration through mitogen-activated protein kinase signaling pathways. J Interf Cytokine Res. 2018;38(11):510–6.

    Article  CAS  Google Scholar 

  204. Lin J, Xue B, Li X, Xia J. Monoclonal antibody therapy for neuromyelitis optica spectrum disorder: current and future. Int J Neurosci. 2017;127(8):735–44.

    Article  CAS  PubMed  Google Scholar 

  205. Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S, Okamoto T, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci U S A. 2011;108(9):3701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Araki M, Matsuoka T, Miyamoto K, Kusunoki S, Okamoto T, Murata M, et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology. 2014;82(15):1302–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Ringelstein M, Ayzenberg I, Harmel J, Lauenstein A-S, Lensch E, Stögbauer F, et al. Long-term therapy with interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder. JAMA Neurol. 2015;72(7):756–63.

    Article  PubMed  Google Scholar 

  208. Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387(10031):1921–7.

    Article  CAS  PubMed  Google Scholar 

  209. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017;377(4):317–28.

    Article  CAS  PubMed  Google Scholar 

  210. Cogollo E, Cogollo E, Silva MA, Isenberg D. Profile of atacicept and its potential in the treatment of systemic lupus erythematosus. Drug Des Devel Ther. 2015;9:1331–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Harvey PR, Gordon C. B-cell targeted therapies in systemic lupus erythematosus: successes and challenges. BioDrugs. 2013;27(2):85–95.

    Article  CAS  PubMed  Google Scholar 

  212. Kappos L, Hartung H-P, Freedman MS, Boyko A, Radü EW, Mikol DD, et al. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Neurol. 2014;13(4):353–63.

    Article  CAS  PubMed  Google Scholar 

  213. Vigolo M, Chambers MG, Willen L, Chevalley D, Maskos K, Lammens A, et al. A loop region of BAFF controls B cell survival and regulates recognition by different inhibitors. Nat Commun. 2018;9(1):1199.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. Stohl W, Hiepe F, Latinis KM, Thomas M, Scheinberg MA, Clarke A, et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64(7):2328–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Hewett K, Sanders DB, Grove RA, Broderick CL, Rudo TJ, Bassiri A, et al. Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis. Neurology. 2018;90(16):e1425–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Guptill JT, Soni M, Meriggioli MN. Current treatment, emerging translational therapies, and new therapeutic targets for autoimmune myasthenia gravis. Neurotherapeutics. 2016;13(1):118–31.

    Article  CAS  PubMed  Google Scholar 

  217. Schneider-Gold C, Reinacher-Schick A, Ellrichmann G, Gold R. Bortezomib in severe MuSK-antibody positive myasthenia gravis: first clinical experience. Ther Adv Neurol Disord. 2017;10(10):339–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Scheibe F, Prüss H, Mengel AM, Kohler S, Nümann A, Köhnlein M, et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology. 2017;88(4):366–70.

    Article  CAS  PubMed  Google Scholar 

  219. Musette P, Bouaziz JD. B cell modulation strategies in autoimmune diseases: new concepts. Front Immunol [Internet]. 2018 [cited 2018 Nov 5];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908887/

  220. Roopenian DC, Akilesh S. FcRn: the neonatal fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–25.

    Article  CAS  PubMed  Google Scholar 

  221. Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs. 2018;10(2):183–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Medical University of Vienna, Vienna, Austria

    Paulus S. Rommer & Tobias Zrzavy

  2. Department of Neurology, Neuroimmunological Section, University of Rostock, Rostock, Germany

    Michael Hecker, Nina Boxberger & Uwe K. Zettl

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  1. Medical Education Promotion Center, Tokyo Medical University, Tokyo, Japan

    Hiroshi Mitoma

  2. Department of Neurology, CHU-Charleroi, Charleroi, Belgium, Department of Neurosciences, University of Mons, Mons, Belgium

    Mario Manto

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Rommer, P.S., Hecker, M., Zrzavy, T., Boxberger, N., Zettl, U.K. (2019). General Principles of Immunotherapy in Neurological Diseases. In: Mitoma, H., Manto, M. (eds) Neuroimmune Diseases. Contemporary Clinical Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-030-19515-1_12

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