The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice.
The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice.
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DOI：
10.1002/art.30222
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发表时间：
2011-04
影响因子：
--
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
--
作者：
Sekine, Hideharu;Kinser, Ting Ting Hsieh;Qiao, Fei;Martinez, Efrain;Paulling, Emily;Ruiz, Phillip;Gilkeson, Gary S.;Tomlinson, Stephen
由于补体在免疫复合物（IC）和凋亡细胞与炎症的清除中的作用之间的平衡，补体在狼疮中具有保护性和致病性功能。经典途径有助于IC和凋亡细胞清除，而替代途径是肾脏炎症的关键介导者。我们研究了一种新的旁路途径靶向抑制剂CR2-fH对MRL/lpr小鼠狼疮样肾病的影响。用盐水、CR2-fH、CR2-Crry（抑制所有补体途径）或sCR 2（C3 d结合靶向载体）处理小鼠。每2周分析血清中的自身抗体、循环IC和C3。还测定了尿白蛋白，并在23周时收集肾脏进行组织学评价。CR2-fH和CR2-Crry治疗改善了存活率并显著减少了蛋白尿、肾小球C3沉积和循环IC。CR2-fH，而不是CR2-Crry，也显着减少肾小球肾炎，血清抗dsDNA抗体a，肾小球IgG和C1 q沉积。有趣的是，sCR 2还显著降低了抗dsDNA抗体、循环IC和IgG、C1 q和C3的肾小球沉积水平，尽管肾小球肾炎、蛋白尿或死亡率没有显著降低。靶向和选择性抑制补体旁路途径是治疗鼠狼疮的有效方法，并且比阻断所有途径更有效。这些数据证明了保持经典/凝集素途径完整的益处，并表明补体的经典和替代途径在疾病进展中的不同作用。sCR 2靶向载体有助于治疗活性，可能通过调节自身免疫。
Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (IC’s) and apoptotic cells versus inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. We investigated the effect of a new targeted inhibitor of the alternative pathway, CR2-fH, on lupus-like renal disease in MRL/lpr mice. Mice were treated with either saline, CR2-fH, CR2-Crry (inhibits all complement pathways) or sCR2 (C3d-binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs and C3. Urinary albumin was also determined, and kidneys collected for histological evaluation at 23 weeks. CR2-fH and CR2-Crry treatment improved survival and significantly reduced proteinuria, glomerular C3 deposition and circulating IC’s. CR2-fH, but not CR2-Crry, also significantly reduced glomerulonephritis, serum anti-dsDNA antibodiesa, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced levels of anti-dsDNA antibodies, circulating IC’s and glomerular deposition of IgG, C1q and C3, although there was no significant reduction in glomerulonephritis, proteinuria or mortality. Targeted and selective inhibition of the alternative complement pathway is an effective treatment for murine lupus, and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact, and indicate distinct roles for the classical and alternative pathways of complement in progression of the disease. The sCR2 targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity.
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DOI：
10.1084/jem.181.1.151
发表时间：
1995-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kim YU;Kinoshita T;Molina H;Hourcade D;Seya T;Wagner LM;Holers VM
通讯作者：
Holers VM
DOI：
10.4049/jimmunol.181.11.8068
发表时间：
2008-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Huang Y;Qiao F;Atkinson C;Holers VM;Tomlinson S
通讯作者：
Tomlinson S
影响因子：
4.4
作者：
Atkinson, Carl;Qiao, Fei;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen
影响因子：
19.6
作者：
Elliott, MK;Jarmi, T;Gilkeson, GS
通讯作者：
Gilkeson, GS
影响因子：
--
作者：
BUYON, JP;TAMERIUS, J;ABRAMSON, SB
通讯作者：
ABRAMSON, SB