A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury.
A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury.
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DOI：
10.4049/jimmunol.181.11.8068
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Tomlinson S
中科院分区：
文献类型：
--
作者：
Huang Y;Qiao F;Atkinson C;Holers VM;Tomlinson S
可溶性Crry是一种所有补体激活途径的小鼠抑制剂，当与补体受体2（CR2）（一种靶向C3激活产物的受体）的片段连接时，其生物利用度和治疗功效显著增强。在这项研究中，我们表征了替代途径特异性抑制剂组成的一个单一的或二聚体的N-末端区域的小鼠因子H（fH;短的共识重复1-5）连接到相同的CR2片段（CR2-fH和CR2-fHfH）。CR2-fH和CR2-fHfH在体外抑制旁路途径方面都是高度有效的，并且表现出比CR2-Crry更高的比活性。CR2-fH在阻断C3靶向沉积方面也比内源性血清fH更有效。CR2-fH/CR2-fHfH的靶结合和补体抑制活性依赖于CR2和C3介导的相互作用。补体旁路途径在肠缺血/再灌注损伤中起重要作用。然而，血清fH不能提供针对肠缺血/再灌注损伤的保护，尽管它可以结合到细胞表面并提供针对补体的保护，并且以高浓度存在于血浆中。在小鼠模型中，CR2-fH和CR2-fHfH提供了对局部（肠）和远端（肺）损伤的完全保护。CR2-fH靶向局部损伤部位并大大降低组织C3沉积水平。因此，靶向机制显著增强fH的N-末端结构域的替代途径特异性补体抑制活性，并具有减少可能与全身补体阻断相关的副作用的潜力。这些数据进一步表明，在临床相关的治疗范例中，肠缺血/再灌注后局部和远端损伤的旁路途径依赖性。
Bioavailability and therapeutic efficacy of soluble Crry, a mouse inhibitor of all complement activation pathways, is significantly enhanced when linked to a fragment of complement receptor 2 (CR2), a receptor that targets C3 activation products. In this study, we characterize alternative pathway-specific inhibitors consisting of a single or dimeric N-terminal region of mouse factor H (fH; short consensus repeats 1–5) linked to the same CR2 fragment (CR2-fH and CR2-fHfH). Both CR2-fH and CR2-fHfH were highly effective at inhibiting the alternative pathway in vitro and demonstrated a higher specific activity than CR2-Crry. CR2-fH was also more effective than endogenous serum fH in blocking target deposition of C3. Target binding and complement inhibitory activity of CR2-fH/CR2-fHfH was dependent on CR2- and C3-mediated interactions. The alternative pathway of complement plays a role in intestine ischemia/reperfusion injury. However, serum fH fails to provide protection against intestine ischemia/reperfusion injury although it can bind to and provide cell surfaces with protection from complement and is present in plasma at a high concentration. In a mouse model, CR2-fH and CR2-fHfH provided complete protection from local (intestine) and remote (lung) injury. CR2-fH targeted to the site of local injury and greatly reduced levels of tissue C3 deposition. Thus, the targeting mechanism significantly enhances alternative pathway-specific complement inhibitory activity of the N-terminal domain of fH and has the potential to reduce side effects that may be associated with systemic complement blockade. The data further indicate alternative pathway dependence for local and remote injury following intestinal ischemia/reperfusion in a clinically relevant therapeutic paradigm.
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