Low-dose targeted complement inhibition protects against renal disease and other manifestations of autoimmune disease in MRL/lpr mice
Low-dose targeted complement inhibition protects against renal disease and other manifestations of autoimmune disease in MRL/lpr mice
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DOI：
10.4049/jimmunol.180.2.1231
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发表时间：
2008-01-15
影响因子：
4.4
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
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作者：
Atkinson, Carl;Qiao, Fei;Tomlinson, Stephen
补体似乎在系统性红斑狼疮的进展中发挥双重作用，在增强免疫复合物清除方面发挥有益作用，同时在诱导局部炎症方面发挥致病作用。为了研究补体在治疗环境中的这些不同作用，在16至24周龄（出现蛋白尿后）用靶向鼠C3补体抑制剂CR 2-Crry治疗MRL/lpr小鼠。靶向部分CR2与沉积在补体激活位点的C3分解产物结合，并具有局部提供补体抑制而不引起全身抑制的潜力。静脉内施用CR2-Crry，每周一次0.25 mg的剂量与显著的生存获益、肾功能改善以及肾小球肾炎和肾血管炎的显著减少相关。皮肤病变和肺细支气管和血管炎症的存在也通过CR2-Crry治疗显著减少。CR2-Crry治疗还导致自身抗体产生的显著减少，如通过抗dsDNA Ab水平所测量的，并且不引起循环免疫复合物水平的增加。对自身免疫和循环免疫复合物的这些作用代表了在MRL/lpr小鼠中使用Crry-Ig的显著潜在优势，Crry-Ig是CR2-Crry的全身对应物。CR2-Crry在16周MRL/lpr小鼠中优先定位于肾脏，肾脏定位半衰期类似于24小时。因此，C3水平的靶向补体抑制是鼠狼疮的有效治疗，即使在疾病发作后开始。
Complement appears to play a dual role in the progression of systemic lupus erythematosus, serving a beneficial role in enhancing immune complex clearance, while serving a pathogenic role in inducing local inflammation. To investigate these different roles of complement in a therapeutic setting, MRL/lpr mice were treated with the targeted murine C3 complement inhibitor, CR2-Crry, from 16 to 24 wk of age (after the development of proteinuria). The targeting moiety, CR2, binds to C3 breakdown products deposited at sites of complement activation and has the potential to provide complement inhibition locally without causing systemic inhibition. Administration of CR2-Crry i.v., at a dose of 0.25 mg once a week, was associated with a significant survival benefit, improved kidney function, and a significant reduction in glomerulonephritis and renal vasculitis. The presence of skin lesions and lung bronchiolar and vascular inflammation was also dramatically reduced by CR2-Crry treatment. CR2-Crry treatment also resulted in a significant reduction in autoantibody production, as measured by anti-dsDNA Ab levels, and did not cause an increase in circulating immune complex levels. These effects on autoimmunity and circulating immune complexes represent significant potential advantages over the use of Crry-Ig in MRL/lpr mice, a systemic counterpart of CR2-Crry. CR2-Crry localized preferentially to the kidneys in 16-wk MRL/lpr mice with a kidney-localized half-life of similar to 24 h. Thus, targeted complement inhibition at the C3 level is an effective treatment in murine lupus, even beginning after onset of disease.