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B-Zell-gerichtete Multiple-Sklerose-Therapie

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Targeting B cells in multiple sclerosis

Current concepts and strategies

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Zusammenfassung

Die Multiple Sklerose (MS) ist eine entzündlich-demyelinisierende Autoimmunerkrankung des Zentralnervensystems und eine Hauptursache bleibender Behinderung im jüngeren Erwachsenenalter. In den letzten Jahren konnte unser Verständnis der Immunpathogenese dieser Erkrankung wesentlich vertieft werden. Zunehmend anerkannt ist, dass B-Zellen eine wesentliche Rolle hierbei spielen. Sie sind dabei nicht nur Vorstufen antikörperproduzierender Plasmazellen, sondern können als effiziente antigenpräsentierende Zellen oder durch Sezernierung zahlreicher proinflammatorischer Zytokine eine autoreaktive Entzündung unterhalten. Mit diesem Wissen sind mehrere klinische Studien zur Wirksamkeit von Rituximab bei MS durchgeführt worden. Rituximab ist ein chimärischer B-Zell-depletierender monoklonaler Antikörper, der an das auf frühen, naiven und Gedächtnis-B-Zellen, nicht aber Stammzellen oder Plasmazellen exprimierte CD20-Oberflächenantigen bindet. Neben zahlreichen kleineren Studien ist bislang eine doppelblinde, placebokontrollierte klinische Phase-II-Studie durchgeführt worden, die eine beeindruckende klinische Wirksamkeit und eine Wirksamkeit auf den Surrogatmarker MRT nachweisen konnte.

In diesem Übersichtsartikel werden die Rolle autoreaktiver B-Zellen, die Ergebnisse der B-Zell-depletierenden Studien sowie zukünftige B-Zell-gerichtete Therapiestrategien vorgestellt und im Kontext der MS zusammengefasst.

Summary

Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease of the CNS and a leading cause of lasting neurological disability in younger adults. In the last decade our knowledge of its immunopathogenesis expanded vastly. It is now widely appreciated that B cells are key players in the autoreactive immune network. They exert far more functions than merely being the precursors of antibody-producing plasma cells. B cells act as efficient antigen-presenting cells and may stimulate an autoreactive immune response through secretion of proinflammatory cytokines. It is thus only logical to test therapeutic strategies targeting B cells in MS. Rituximab is a depleting chimeric monoclonal antibody directed against CD20 and expressed on developing, naïve, and memory B cells but not stem or plasma cells. Several smaller studies have been conducted that led to a placebo controlled, double blind phase II study on efficacy which was reported recently. The results are very promising, meeting not only the primary endpoint of reduction of the surrogate MRI marker of contrast-enhancing lesions but also showing a reduction in clinical relapse rate of patients treated with rituximab. This review discusses the role of autoreactive B cells in the context of MS, analyzes the B-cell-depleting treatment studies reported, and provides information on planned and future B-cell-directed therapeutic strategies in MS.

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Interessenkonflikte

Der korrespondierende Autor weist auf folgende Beziehungen hin: T.M. erhielt Honorare und Reisekostenzuschüsse von Bayer Healthcare, Biogne Idec, Merck Serono. H.-C.v.B. erhielt Vortragshonorare von Merck Serono, Schweiz. B.C.K und H.-P.H. erhielten in der Vergangenheit nach Genehmigung durch den Ärztlichen Direktor des Universitätsklinikums Düsseldorf und den Rektor der Heinrich-Heine-Universität Vortrags- bzw. Beratungshonorare der Hersteller der im Artikel erwähnten Präparate: Biogen Idec, Merck Serono sowie Genentech (H.-P.H.).

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Menge, T., Büdingen, HC., Dalakas, M. et al. B-Zell-gerichtete Multiple-Sklerose-Therapie. Nervenarzt 80, 190–198 (2009). https://doi.org/10.1007/s00115-008-2664-2

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