Therapeutic potential of staphylococcal superantigen-like protein 7 for complement-mediated hemolysis.
Therapeutic potential of staphylococcal superantigen-like protein 7 for complement-mediated hemolysis.
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DOI：
10.1007/s00109-018-1678-x
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Lin F
中科院分区：
文献类型：
--
作者：
Li Y;Clow F;Fraser JD;Lin F
先前的研究已经证明，由金黄色葡萄球菌产生的葡萄球菌超抗原样蛋白7（SSL 7）通过与补体成分5（C5）结合而有效地抑制补体膜攻击复合物的形成。然而，由于预测的SSL 7作为外源蛋白在人体中的免疫原性，其作为治疗补体介导疾病的新补体抑制剂的潜力尚不确定。在这项研究中，我们发现，在补体介导的血管内溶血小鼠模型中，SSL 7的给药可显著预防补体介导的溶血并减少血红蛋白尿。有趣的是，尽管重复施用SSL 7引起抗SSL 7抗体产生，但在抗体存在下，以2 μg/小鼠的剂量施用SSL 7仍然能够显著减弱体内补体介导的血管内溶血。此外，即使在正常人供体中可检测到抗SSL 7抗体，这些抗体在体外测定中也不会显著降低SSL 7的补体抑制活性。最后，在眼前房中接种SSL 7抑制了重复SSL 7给药后SSL 7反应性抗体的产生。这些结果表明，SSL 7可以开发为现有C5靶向药物依库珠单抗的经济替代品，特别是用于控制灾难性疾病（如药物诱导的免疫性溶血性贫血和ABO不相容红细胞输注）中的急性补体激活。这些数据还表明，可以采用诸如前房相关免疫偏离的方法来建立长期SSL 7给药的抗原特异性免疫耐受。
Previous studies have demonstrated that staphylococcal superantigen-like protein 7 (SSL7), a protein produced by Staphylococcus aureus, potently inhibits the formation of the complement membrane attack complex by binding to complement component 5 (C5). However, because of the predicted immunogenicity of SSL7 as a foreign protein in humans, its potential as a new complement inhibitor for treating complement-mediated diseases is uncertain. In this study, we found that administration of SSL7 significantly prevented complement-mediated hemolysis and reduced hemoglobinuria in a mouse model of complement-mediated intravascular hemolysis. Interestingly, although repetitive administrations of SSL7 elicited anti-SSL7 antibody production, administration of SSL7 at a dose of 2 μg/mouse was still able to significantly attenuate complement-mediated intravascular hemolysis in vivo in the presence of the antibodies. In addition, even though anti-SSL7 antibodies were detectable in normal human donors, these antibodies did not significantly reduce the complement inhibitory activity of SSL7 in in vitro assays. Finally, inoculation of SSL7 in the anterior chamber of the eye suppressed the production of SSL7-reactive antibodies after repetitive SSL7 administration. These results suggest that SSL7 could be developed as an economical alternative to the existing C5-targeted drug, eculizumab, especially for controlling acute complement activation in catastrophic conditions such as drug-induced immune hemolytic anemia and ABO-incompatible erythrocytes transfusions. These data also suggest that approaches such as anterior chamber-associated immune deviation could be employed to establish an antigen-specific immune tolerance for long-term SSL7 administration.
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DOI：
10.1038/nrdp.2017.28
发表时间：
2017-05-18
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Hill A;DeZern AE;Kinoshita T;Brodsky RA
通讯作者：
Brodsky RA
影响因子：
2
作者：
MIZUNO, K;CLARK, AF;STREILEIN, JW
通讯作者：
STREILEIN, JW
影响因子：
14
作者：
Li Y;Qiu W;Zhang L;Fung J;Lin F
通讯作者：
Lin F
影响因子：
3.4
作者：
Bestebroer J;Aerts PC;Rooijakkers SH;Pandey MK;Köhl J;van Strijp JA;de Haas CJ
通讯作者：
de Haas CJ
DOI：
10.1159/000099251
发表时间：
2007-01-01
期刊：
Chemical immunology and allergy
影响因子：
--
作者：
Niederkorn, Jerry Y
通讯作者：
Niederkorn, Jerry Y