1. Innate immune responses to trauma
Markus Huber-Lang, Peter A Ward, John D Lambris Nat Immunol . 2018 Apr;19(4):327-341. doi: 10.1038/s41590-018-0064-8.
Trauma can affect any individual at any location and at any time over a lifespan. The disruption of macrobarriers and microbarriers induces instant activation of innate immunity. The subsequent complex response, designed to limit further damage and induce healing, also represents a major driver of complications and fatal outcome after injury. This Review aims to provide basic concepts about the posttraumatic response and is focused on the interactive events of innate immunity at frequent sites of injury: the endothelium at large, and sites within the lungs, inside and outside the brain and at the gut barrier.
2. Complement C3 inhibition in severe COVID-19 using compstatin AMY-101
Charalampos Papagoras, Loek Willems, Antonio M Risitano, Georgios Kalopitas, Iliana Fotiadou, Dionysios Kogias, Ioannis Mitroulis, Akrivi Chrysanthopoulou, Angelos Liontos, George N Dalekos, Christina Antoniadou, Konstantinos Ritis, Panagiotis Skendros, Barbro Persson, Georgios Germanidis, Bo Nilsson, Maria Ntinopoulou, Anna Samakidou, Vivek Anand Manivel, John D Lambris, Simona Iacobelli, Efstratios Gavriilidis, Haralampos Milionis, Vasileios Papadopoulos, Markus Huber-Lang, E Sander Connolly, Despina Yancopoulou, Simeon Metallidis, Dainora Cepaityte, Nikolaos K Gatselis, Rodrigo T Calado, Nikoleta Zioga, Dimitrios C Mastellos, Ioanna Karanika, Andreas Smyrlis Sci Adv . 2022 Aug 19;8(33):eabo2341. doi: 10.1126/sciadv.abo2341.
Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 (n= 16) or placebo (n= 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101-treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug's inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.
3. Complement-Dependent Mechanisms and Interventions in Periodontal Disease
Tetsuhiro Kajikawa, Despina Yancopoulou, George Hajishengallis, John D Lambris, Hatice Hasturk, Tomoki Maekawa, Dimitrios C Mastellos, Evlambia Hajishengallis, Edimara S Reis Front Immunol . 2019 Mar 12;10:406. doi: 10.3389/fimmu.2019.00406.
Periodontitis is a prevalent inflammatory disease that leads to the destruction of the tooth-supporting tissues. Current therapies are not effective for all patients and this oral disease continues to be a significant public health and economic burden. Central to periodontal disease pathogenesis is a reciprocally reinforced interplay between microbial dysbiosis and destructive inflammation, suggesting the potential relevance of host-modulation therapies. This review summarizes and discusses clinical observations and pre-clinical intervention studies that collectively suggest that complement is hyperactivated in periodontitis and that its inhibition provides a therapeutic benefit. Specifically, interception of the complement cascade at its central component, C3, using a locally administered small peptidic compound (Cp40/AMY-101) protected non-human primates from induced or naturally occurring periodontitis. These studies indicate that C3-targeted intervention merits investigation as an adjunctive treatment of periodontal disease in humans.
