Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
PLoS One. 2011;6(6):e21621. doi: 10.1371/journal.pone.0021621. Epub 2011 Jun 24.
Inappropriate activation of complement on the vascular endothelium of specific organs, or systemically, underlies the etiology of a number of diseases. These disorders include atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, atherosclerosis, age-related macular degeneration, diabetic retinopathy, and transplant rejection. Inhibition of the terminal step of complement activation, i.e. formation of the membrane attack complex, using CD59 has the advantage of retaining the upstream processes of the complement cascade necessary for fighting pathogens and retaining complement's crucial role in tissue homeostasis. Previous studies have shown the necessity of membrane targeting of soluble CD59 in order for it to prove an effective inhibitor of complement deposition both in vitro and in vivo. In this study we have generated an in vivo model of human complement activation on murine liver vascular endothelium. This model should prove useful for the development of anti-complement therapies for complement-induced pathologies of vascular endothelium. Using this model, we have demonstrated the viability of a non membrane-targeted soluble CD59 to significantly inhibit complement deposition on the endothelium of murine liver vasculature when expressed in vivo from an adenovirus. This result, unanticipated based on prior studies, suggests that the use of non membrane-targeted sCD59 as an anti-complement therapy be re-visited.
补体在特定器官或全身的血管内皮上的异常激活是许多疾病的病因。这些疾病包括非典型溶血尿毒综合征、膜增生性肾小球肾炎、动脉粥样硬化、年龄相关性黄斑变性、糖尿病性视网膜病变和移植排斥反应。抑制补体激活的终末步骤，即膜攻击复合物的形成，使用 CD59 的优点是保留了对抗病原体所需的补体级联的上游过程，并保留了补体在组织稳态中的关键作用。先前的研究表明，可溶性 CD59 的膜靶向对于其在体外和体内证明是补体沉积的有效抑制剂是必要的。在本研究中，我们在小鼠肝血管内皮上建立了一种人补体激活的体内模型。该模型有望为开发针对补体诱导的血管内皮病变的抗补体疗法提供帮助。使用该模型，我们证明了非膜靶向可溶性 CD59 的可行性，当它从腺病毒在体内表达时，可显著抑制小鼠肝血管内皮上的补体沉积。这个结果与之前的研究不一致，表明需要重新考虑使用非膜靶向 sCD59 作为抗补体疗法。
