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

Abstract

BackgroundMyeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease.MethodsMPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN.ResultsAnti-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.ConclusionsCollectively, 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.

The frequency of Treg subsets distinguishes disease activity in ANCA vasculitis

“…However, studies in a mouse model of MPO‐ANCA‐induced glomerulonephritis sought to elucidate the relationship between anti‐CD20‐induced B‐cell depletion and T cells. This study was able to demonstrate that antigen‐specific Tregs could be induced by splenic macrophages processing apoptotic B cells 29 . The removal and processing of the apoptotic B cells by splenic macrophages likely results in the release of immunomodulatory cytokines that positively influence the Treg pool.…”

“…This study was able to demonstrate that antigenspecific Tregs could be induced by splenic macrophages processing apoptotic B cells. 29 The removal and processing of the apoptotic B cells by splenic macrophages likely results in the release of immunomodulatory cytokines that positively influence the Treg pool. In addition, it has also been reported in some studies that Tregs are decreased in ANCA vasculitis.…”

Animal models of vasculitis

“…Figure 2 illustrates some of the recently published findings from animal models of ANCA-associated vasculitis, discussed as follows [32 ▪ –37 ▪ ,38 ▪▪ ].…”

“…Although it successfully deletes B cells and subsequently causes reduction in ANCA titre, studies have noted that attainment of clinical remission is not correlated with the effect on ANCA [40]. In the ANCA-independent active T cell animal model of AAV, an anti-CD20 mAb-induced expansion of MPO-specific regulatory T cells, both reducing cell-mediated anti-MPO responses and renal injury [37 ▪ ].…”

The emerging role of regulatory cell-based therapy in autoimmune disease

“…B cell-depletion drugs such as rituximab, an anti-CD20 monoclonal antibody, have yielded promising results in the treatment of autoimmune diseases ( 206 , 207 ). For instance, the use of rituximab for treatment of experimental autoimmune vasculitis has demonstrated that it depletes B cells by inducing B cell apoptosis, enhancing Treg cells’ immunomodulatory capacity via IL-10 ( 208 ). However, removing all B cells also eliminates Breg cells that suppress inflammation.…”