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

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.

Keywords: ANCA; apoptosis; end stage kidney disease; glomerulonephritis; immunosuppression.