BRAIN and NERVE－神経研究の進歩70巻11号

2018年11月発行

総説

多発性硬化症におけるB細胞除去治療

著者： 宮﨑雄生¹² 新野正明²

所属機関： ¹国立病院機構北海道医療センター神経内科 ²国立病院機構北海道医療センター臨床研究部

ページ範囲：P.1289 - P.1294

文献概要

近年，抗CD20抗体によるB細胞除去治療が再発寛解型および一次性進行型多発性硬化症に有効であることが海外における大規模臨床試験で示された。B細胞は抗体産生のみならず，T細胞への抗原提示，サイトカイン産生，リンパ濾胞誘導などの働きにより多発性硬化症の多くの局面に関与することが明らかとなってきた。解決すべき点はあるものの，B細胞除去治療は今後の多発性硬化症治療において重要な選択肢の1つになると思われる。

参考文献

1)Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, et al: Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 376: 221-234, 2017

2)Montalban X, Hauser SL, Kappos L, Arnold D, Bar-Or A, et al: Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 376: 209-220, 2017

3)Brändle SM, Obermeier B, Senel M, Bruder J, Mentele R, et al: Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins. Proc Natl Acad Sci U S A 113: 7864-7869, 2016

4)Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, et al: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47: 707-717, 2000

5)Keegan M, König F, McClelland R, Brück W, Morales Y, et al: Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 366: 579-582, 2005

6)Jarius S, König FB, Metz I, Ruprecht K, Paul F, et al: Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis. J Neuroinflammation 14: 171, 2017

7)Bar-Or A, Calabresi PA, Arnold D, Markowitz C, Shafer S, et al: Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 63: 395-400, 2008

8)Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, et al: B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358: 676-688, 2008

9)Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, et al: Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378: 1779-1787, 2011

10)Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, et al: Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology 82: 573-581, 2014

11)Bar-Or A, Grove RA, Austin DJ, Tolson JM, VanMeter SA, et al: Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: the MIRROR study. Neurology 90: e1805-e1814, 2018［doi: 10.1212/WNL.0000000000005516］

12)Bar-Or A, Fawaz L, Fan B, Darlington PJ, Rieger A, et al: Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Ann Neurol 67: 452-461, 2010

13)Duddy M, Niino M, Adatia F, Hebert S, Freedman M, et al: Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol 178: 6092-6099, 2007

14)Barr TA, Shen P, Brown S, Lampropoulou V, Roch T, et al: B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J Exp Med 209: 1001-1010, 2012

15)Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, et al: Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med 7: 310ra166, 2015［doi: 10.1126/scitranslmed.aab4176］

T-cell proliferation and IFN-γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Eur J Immunol 40: 2942-2956, 2010

17)Hawker K, O'Connor P, Freedman MS, Calabresi PA, Antel J, et al: Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 66: 460-471, 2009

18)Komori M, Lin YC, Cortese I, Blake A, Ohayon J, et al: Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol 3: 166-179, 2016

19)Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F: Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14: 164-174, 2004

20)Hughes S: PML reported in patient receiving ocrelizumab. Medscape: May 25 2017．www.medscape.com/viewarticle/880654（最終閲覧日2018年6月8日）

21)Kappos L, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F, et al: Long-term safety and efficacy of ocrelizumab in patients with relapsing-remitting multiple sclerosis: week 144 results of a phase II, randomised, multicentre trial. Mult Scler 18: 140-141, 2012