Targeting innate immune pathways in acute infectious and sterile inflammation – The role of complement

Abstract

The complement system is part of the immediate innate immune response to pending danger. However, uncontrolled activation contributes to the pathophysiology of many human diseases. Complement inhibitory therapy is approved for three rare complement-mediated diseases, and this therapeutic approach is emerging for several other diseases where complement activation is implicated. The aim of this thesis was to study the effect of complement inhibition in human in vitro and porcine in vivo models of acute bacterial and sterile inflammation, and evaluate therapeutic complement inhibition in a case of severe antiphospholipid syndrome. Both complement and toll-like receptor (TLR) activation are implicated in the pathophysiology of sepsis. However, the TLR-4 antagonist eritoran failed in a sepsis trial. We found that combining inhibition of complement and TLR co-receptor CD14 attenuated Gram-negative and Gram-positive bacteria-induced inflammation more efficiently than using eritoran. This effect was demonstrated in human whole blood and endothelial cells, indicating that broad inhibition of innate immunity is necessary to effectively attenuate bacterial induced inflammation. Sterile inflammation occurs during ischemia-reperfusion injury, aggravating the initial injury. We showed in a porcine myocardial infarction model that complement inhibition reduced infarct size and improved cardiac function, highlighting the complement system as a potential treatment target in myocardial infarction. Finally, in a pregnant patient with antiphospholipid syndrome, treatment with the complement C5 blocking monoclonal antibody eculizumab did not affect the infant as merely trace amounts passed the placenta. Further, we showed that closely monitoring this therapy with adequate laboratory methods is needed to ensure efficient C5 inhibition. Overall, complement inhibition has reached the clinic and several acute inflammatory diseases might benefit from this new therapeutic approach.