Soluble CD59 expressed from an adenovirus in vivo is a potent inhibitor of complement deposition on murine liver vascular endothelium.

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.

补体在特定器官的血管内皮上不适当激活，或全身性激活，是许多疾病病因的基础。这些疾病包括非典型溶血性尿毒症综合征、膜增生性肾小球肾炎、动脉粥样硬化、年龄相关性黄斑变性、糖尿病视网膜病变和移植排斥反应。利用CD59抑制补体激活的终末步骤，即膜攻击复合物的形成，具有保留补体级联反应上游过程的优势，这些过程对于对抗病原体以及保留补体在组织内稳态中的关键作用是必要的。先前的研究表明，可溶性CD59必须靶向膜，才能在体外和体内都被证明是补体沉积的有效抑制剂。在这项研究中，我们建立了一个在小鼠肝脏血管内皮上人类补体激活的体内模型。这个模型应该有助于开发针对补体诱导的血管内皮病变的抗补体疗法。利用这个模型，我们已经证明，当从腺病毒在体内表达时，一种非膜靶向的可溶性CD59能够显著抑制补体在小鼠肝脏血管内皮上的沉积。这一结果基于先前的研究是出乎意料的，这表明应该重新审视使用非膜靶向的可溶性CD59作为一种抗补体疗法。