The Complement System and the CD14/TLR4/MD2 Complex as Targets for Therapy in Sepsis, 2016

The aim of this project was to develop a new therapeutic regime in conditions where the congenital immune system is over-activated and causes serious disease, as seen by sepsis (blood poisoning). Previous studies showed that inhibition of two important branches of the immune system, the complement system and the TRL system, inhibits the activation triggered by bacteria and other foreign substances in the test tube. In particular, combined inhibition of these systems gives a good effect. In this project it was found that a substance called coversin (OmCI) effectively inhibits complement factor 5 in both pigs and human beings. Further, the study worked with an antibody targeting CD14, a central molecule in the TLR system, and compared this to other inhibitors of the TLR family, such as anti-MD2. It was found that inhibition of CD14 is particularly effective in inhibiting activation and that the combination of inhibiting complement and CD14 is particularly effective in sepsis in pigs. The latest work published in the project, revealed to a large degree why clinical trials conducted to treat blood poisoning with the inhibition of the innate immune system (TLR4 / MD2) have not worked. This worked was published in the 'Journal of Infectious Diseases'.

本项目旨在针对先天性免疫系统（innate immune system）过度活化引发重症疾病的场景开发全新治疗方案，这类病症以败血症（sepsis，血液中毒）为典型表现。既往研究表明，抑制免疫系统的两大关键分支——补体系统（complement system）与Toll样受体（TLR, Toll-like Receptor）系统，可在体外实验中阻断细菌及其他外源物质触发的免疫活化反应。尤为重要的是，联合抑制这两大系统可获得优良的干预效果。本项目研究发现，一种名为coversin（OmCI）的物质可有效抑制猪与人类体内的补体5因子（complement factor 5）。此外，本研究针对TLR系统的核心分子CD14开发了靶向抗体，并将其与抗MD2等TLR家族其他抑制剂进行了对照研究。实验结果显示，抑制CD14在阻断免疫活化过程中效果尤为显著；而联合抑制补体系统与CD14，则对猪败血症模型展现出极佳的治疗效果。本项目最新发表的研究成果，在很大程度上阐明了此前以抑制先天性免疫系统（TLR4/MD2）治疗血液中毒的临床试验未能取得成功的原因。该项研究成果已发表于《Journal of Infectious Diseases》。