Anti-CD20 mAb-Induced B Cell Apoptosis Generates T Cell Regulation of Experimental Myeloperoxidase ANCA-Associated Vasculitis

Poh Yi Gan, Jonathan Dick, Kim M. O'Sullivan, Virginie Oudin, Anne Cao Le, Daniel Koo Yuk Cheong, Raymond Shim, Maliha Alikhan, A. Richard Kitching, Joshua D. Ooi, Stephen R. Holdsworth

Research output: Contribution to journalArticleResearchpeer-review

Abstract

BACKGROUND: Myeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease. METHODS: MPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN. RESULTS: Anti-CD20 mAb treatment increased the numbers and immunomodulatory capacity of MPO-specific T regulatory cells (Tregs) and attenuated T cell-mediated and humoral anti-MPO autoimmunity and GN. Disabling of Tregs negated the therapeutic benefit of anti-CD20 treatment. The mechanism of enhancement of Treg activity could be attributed to anti-CD20 mAb effects on inducing B cell apoptosis. Administering anti-CD20 mAb-induced apoptotic splenocytes to mice developing anti-MPO GN was as effective as anti-CD20 mAb treatment in inducing Tregs and attenuating both anti-MPO autoimmunity and GN. A nonredundant role for splenic macrophages in mediating the anti-CD20 mAb-induced immunomodulation was demonstrated by showing that administration of anti-CD20 mAb ex vivo-induced apoptotic splenocytes to unmanipulated mice attenuated autoimmunity and GN, whereas deletion of splenic marginal zone macrophages prevented anti-CD20 mAb-induced immunomodulation and treatment efficacy. Six days after administering anti-CD20 mAb to mice with murine anti-MPO GN, cell-mediated anti-MPO responses and GN were attenuated, and Tregs were enhanced, but ANCA levels were unchanged, suggesting humoral autoimmunity was redundant at this time point. CONCLUSIONS: Collectively, these data suggest that, as well as reducing humoral autoimmunity, anti-CD20 mAb more rapidly induces protective anti-MPO Treg-mediated immunomodulation by splenic processing of anti-CD20-induced apoptotic B cells.

Original languageEnglish
Pages (from-to)1071-1083
Number of pages13
JournalJournal of the American Society of Nephrology
Volume32
Issue number5
DOIs
Publication statusPublished - 3 May 2021

Keywords

  • ANCA
  • apoptosis
  • end stage kidney disease
  • glomerulonephritis
  • immunosuppression

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