Gan Poh-Yi, Dick Jonathan, O'Sullivan Kim M, Oudin Virginie, Cao Le Anne, Koo Yuk Cheong Daniel, Shim Raymond, Alikhan Maliha, Kitching A Richard, Ooi Joshua D, Holdsworth Stephen R
Center for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.
Department of Immunology, Monash Medical Center, Clayton, Victoria, Australia.
J Am Soc Nephrol. 2021 May 3;32(5):1071-1083. doi: 10.1681/ASN.2020060834. Epub 2021 Mar 31.
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.
MPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN.
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 -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.
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.
髓过氧化物酶抗中性粒细胞胞浆抗体相关性血管炎是终末期肾病的主要病因。在该疾病的小鼠模型中测试了抗CD20单克隆抗体治疗的疗效。
髓过氧化物酶免疫诱导抗髓过氧化物酶自身免疫，亚肾炎剂量的羊抗小鼠肾小球基底膜球蛋白引发肾小球肾炎。
抗CD20单克隆抗体治疗增加了髓过氧化物酶特异性调节性T细胞（Tregs）的数量和免疫调节能力，减弱了T细胞介导的和体液性抗髓过氧化物酶自身免疫及肾小球肾炎。Tregs功能丧失使抗CD20治疗的益处消失。Treg活性增强的机制可归因于抗CD20单克隆抗体诱导B细胞凋亡的作用。将抗CD20单克隆抗体诱导凋亡的脾细胞给予发生抗髓过氧化物酶肾小球肾炎的小鼠，在诱导Tregs以及减弱抗髓过氧化物酶自身免疫和肾小球肾炎方面与抗CD20单克隆抗体治疗效果相同。通过将抗CD20单克隆抗体诱导凋亡的脾细胞给予未处理的小鼠可减弱自身免疫和肾小球肾炎，而删除脾边缘区巨噬细胞可阻止抗CD20单克隆抗体诱导的免疫调节和治疗效果，从而证明了脾巨噬细胞在介导抗CD20单克隆抗体诱导的免疫调节中起非冗余作用。给患有鼠抗髓过氧化物酶肾小球肾炎的小鼠注射抗CD20单克隆抗体6天后，细胞介导的抗髓过氧化物酶反应和肾小球肾炎减弱，Tregs增加，但抗中性粒细胞胞浆抗体水平未变，提示此时体液性自身免疫是多余的。
总体而言，这些数据表明，抗CD20单克隆抗体除了降低体液性自身免疫外，还通过脾脏对抗CD20诱导的凋亡B细胞的处理，更快速地诱导具有保护作用的抗髓过氧化物酶Treg介导的免疫调节。
