Gan Poh-Yi, Tan Diana S Y, Ooi Joshua D, Alikhan Maliha A, Kitching A Richard, Holdsworth Stephen R
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; and.
Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; and Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
J Am Soc Nephrol. 2016 Feb;27(2):385-91. doi: 10.1681/ASN.2015010089. Epub 2015 Jun 5.
Less toxic treatment options for patients with myeloperoxidase (MPO)-ANCA-associated GN are needed. Using an established murine model of focal necrotizing GN mediated by autoimmunity to MPO (autoimmune anti-MPO GN), we assessed the capacity for nasal tolerance induced by nasal insufflation of the immunodominant nephritogenic MPO peptide (MPO409-428) to attenuate this disease. Compared with mice that received an irrelevant immunodominant ovalbumin (OVA) peptide, OVA323-339, mice that received MPO409-428 were protected from the development of humoral and cell-mediated autoimmunity to full-length MPO and the development of GN. In mice with established anti-MPO autoimmunity, nasal insufflation of MPO409-428 as a therapeutic attenuated anti-MPO GN. To investigate the nature of this induced tolerance, we isolated CD4(+) T cells from the upper airway draining lymph nodes of both OVA323-339- and MPO409-428-tolerized mice. Adoptive transfer of CD4(+) T cells from MPO409-428- but not OVA323-339-tolerized mice to animals with established anti-MPO autoimmunity attenuated the subsequent development of GN, confirming that the immunosuppression induced by these T cells is antigen specific. Ex vivo studies showed that nasal tolerance to MPO is mediated by both conventional and induced T regulatory cells. The strong homology between the pathogenic human MPO B cell epitope recognized by ANCA in patients with acute vasculitis and the nephritogenic murine T cell MPO epitope emphasizes the clinical relevance of this study.
需要为髓过氧化物酶（MPO）-抗中性粒细胞胞浆抗体（ANCA）相关肾小球肾炎患者提供毒性较小的治疗选择。我们使用一种既定的小鼠局灶性坏死性肾小球肾炎模型，该模型由针对MPO的自身免疫介导（自身免疫性抗MPO肾小球肾炎），评估通过鼻腔注入免疫显性致肾炎MPO肽（MPO409 - 428）诱导的鼻腔耐受减轻这种疾病的能力。与接受无关免疫显性卵清蛋白（OVA）肽OVA323 - 339的小鼠相比，接受MPO409 - 428的小鼠对全长MPO的体液和细胞介导自身免疫的发展以及肾小球肾炎的发展具有保护作用。在已建立抗MPO自身免疫的小鼠中，鼻腔注入MPO409 - 428作为治疗手段可减轻抗MPO肾小球肾炎。为了研究这种诱导耐受的性质，我们从OVA323 - 339和MPO409 - 428耐受小鼠的上呼吸道引流淋巴结中分离出CD4(+) T细胞。将来自MPO409 - 428耐受而非OVA323 - 339耐受小鼠的CD4(+) T细胞过继转移到已建立抗MPO自身免疫的动物中，可减轻随后肾小球肾炎的发展，证实这些T细胞诱导的免疫抑制是抗原特异性的。体外研究表明，对MPO的鼻腔耐受由传统和诱导性T调节细胞介导。急性血管炎患者中ANCA识别的致病性人类MPO B细胞表位与致肾炎小鼠T细胞MPO表位之间的高度同源性强调了本研究的临床相关性。
