Nephrologisches Zentrum, Medizinische Poliklinik, Campus Innenstadt, Klinikum der Universität München-LMU, 80336 München, Germany.
J Immunol. 2011 Sep 15;187(6):3413-21. doi: 10.4049/jimmunol.1101125. Epub 2011 Aug 17.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease leading to inflammatory tissue damage in multiple organs (e.g., lupus nephritis). Current treatments including steroids, antimalarials, and immunosuppressive drugs have significant side effects. Activated protein C is a natural protein with anticoagulant and immunomodulatory effects, and its recombinant version has been approved by the U.S. Food and Drug Administration to treat severe sepsis. Given the similarities between overshooting immune activation in sepsis and autoimmunity, we hypothesized that recombinant activated protein C would also suppress SLE and lupus nephritis. To test this concept, autoimmune female MRL-Fas(lpr) mice were injected with either vehicle or recombinant human activated protein C from week 14-18 of age. Activated protein C treatment significantly suppressed lupus nephritis as evidenced by decrease in activity index, glomerular IgG and complement C3 deposits, macrophage counts, as well as intrarenal IL-12 expression. Further, activated protein C attenuated cutaneous lupus and lung disease as compared with vehicle-treated MRL-Fas(lpr) mice. In addition, parameters of systemic autoimmunity, such as plasma cytokine levels of IL-12p40, IL-6, and CCL2/MCP-1, and numbers of B cells and plasma cells in spleen were suppressed by activated protein C. The latter was associated with lower total plasma IgM and IgG levels as well as lower titers of anti-dsDNA IgG and rheumatoid factor. Together, recombinant activated protein C suppresses the abnormal systemic immune activation in SLE of MRL-Fas(lpr) mice, which prevents subsequent kidney, lung, and skin disease. These results implicate that recombinant activated protein C might be useful for the treatment of human SLE.
系统性红斑狼疮 (SLE) 是一种慢性自身免疫性疾病，可导致多个器官的炎症性组织损伤（例如狼疮性肾炎）。目前的治疗方法包括类固醇、抗疟药和免疫抑制剂，但这些方法都有显著的副作用。活化蛋白 C 是一种具有抗凝和免疫调节作用的天然蛋白，其重组版本已获得美国食品和药物管理局批准，可用于治疗严重败血症。鉴于败血症中过度免疫激活与自身免疫之间的相似性，我们假设重组活化蛋白 C 也会抑制 SLE 和狼疮性肾炎。为了验证这一概念，我们在 14-18 周龄的自身免疫性雌性 MRL-Fas(lpr)小鼠中注射了载体或重组人活化蛋白 C。结果表明，活化蛋白 C 治疗显著抑制了狼疮肾炎，表现为活动指数、肾小球 IgG 和补体 C3 沉积、巨噬细胞计数以及肾内 IL-12 表达减少。此外，与载体处理的 MRL-Fas(lpr)小鼠相比，活化蛋白 C 减轻了皮肤狼疮和肺部疾病。此外，活化蛋白 C 还抑制了系统性自身免疫的参数，如血浆细胞因子 IL-12p40、IL-6 和 CCL2/MCP-1 的水平，以及脾中 B 细胞和浆细胞的数量。后者与总血浆 IgM 和 IgG 水平降低以及抗 dsDNA IgG 和类风湿因子滴度降低有关。总之，重组活化蛋白 C 抑制了 MRL-Fas(lpr) 小鼠 SLE 中的异常系统性免疫激活，从而预防了随后的肾脏、肺部和皮肤疾病。这些结果表明，重组活化蛋白 C 可能对人类 SLE 的治疗有用。
