Polytrauma as life-threatening injury of various body regions and organ systems and subsequent complications are major causes of death and disability in Germany and worldwide, especially in young people. After trauma, a multitude of physiological reactions can cause a dysbalanced cellular and immune response, resulting in inflammation, infection and (multiple) organ damage. However, many underlying mechanisms remain unclear and, until today, there is no immune-modulatory intervention to prevent an unfavorable outcome. In this study, in close collaboration with the Dept. of Orthopedic Trauma and the Dept. of Anesthesiology and the Collaborative Research Center 1149, we aim to clarify the involved temporal and spatial pathophysiological changes after trauma. The ultimate goal is to find new beneficial therapeutic approaches for the multiply injured patient.
Collaboration Partners:
Prof. Dr. med. F. Gebhard, Department of Orthopedic Trauma, Hand, and Reconstructive Surgery, University Hospital Ulm
Prof. Dr. med. B. Jungwirth, Department of Anesthesiology and Intensive Care Medicine, University Hospital Ulm
Prof. Dr. rer. nat. Borna Relja, Translational and Experimental Trauma Research, University Hospital Ulm
Dr. med. C. Bergmann, Department of Orthopedic Trauma, Hand, and Reconstructive Surgery, University Hospital Ulm
Sepsis is a highly complex disease characterized by life-threatening organ dysfunction caused by a dysregulated immune response to an infection. Therefore, a rapid and accurate diagnosis is crucial. However, traditional blood biomarkers usually reflect static snap-shot analyse with a significant time delay, and are susceptible to clinical interventions, which limits their sensitivity and specificity. Hence, our objective is to develop a rapid, valid, and reliable monitoring system for the functionality of the immune system, serving as an "early warning system." In this study, we screen small blood samples from patients with sepsis in the intensive care unit using a flow-based method to define early changes in innate immune functions.
Collaboration Partners:
Prof. Dr. med. B. Jungwirth, Department of Anesthesiology and Intensive Care Medicine, University Hospital Ulm
Innate Immune Response after Major Cardiac Surgery: Cardiac surgical interventions represent an iatrogenic trauma, particularly when extracorporeal circulation is required. The surgical trauma, contact of blood with artificial surfaces, and ischemia-reperfusion injury (IRI) result in excessive activation of the innate immune system. This activation leads to a systemic inflammatory response syndrome (SIRS), which can cause dysfunction in remote organs, including acute kidney injury (AKI). In this study, in collaboration with Prof. Dr. med. Andreas Liebold (Department of Cardiothoracic and Vascular Surgery), we screen patients undergoing major cardiac surgery with extracorporeal circulation before, during, and after the surgery. We evaluate their multidimensional immune response, focusing on neutrophil granulocytes and the complement system, and correlate these findings with the development of organ failure.
Subarachnoid bleeding (SAB) is a critical medical condition characterized by bleeding in the subarachnoid space surrounding the brain. The resulting ischemia and immune response seem to drive and aggravate the neuronal damage. However, the exact mechanisms remain elusive. Therefore, in collaboration with Prof. Dr. T. Kapapa from the Dept. of Neurosurgery, headed by Prof. Dr. R. Wirtz, we are investigating the innate and adaptive immune response in cerebrospinal fluid and blood using a flowcytometry-based approach. We aim to identify novel therapeutic targets that can prevent further brain damage and improve patient outcomes.
PINA Study (PTSD in Adolescents): Psychological trauma activates the hypothalamic-pituitary-adrenal axis (HPA) stress axis. In particular chronic stress such as child maltreatment leads to a long-term dysregulation of the HPA axis and subsequent inflammatory activation. In collaboration with Prof. Clemens/Prof. Fegert (Child and Adolescent Psychiatry/Psychotherapy), the ITI aims to better understand the role of inflammatory activation in adolescents after psychological trauma with posttraumatic stress disorder (PTSD).
Cystic fibrosis (CF) is a genetic disorder caused by a dysfunction in the "Cystic Fibrosis Transmembrane Conductance Regulator" (CFTR) protein. This dysfunction causes increased viscosity of secretory organs. In the lungs, this primarily results in the retention of secretions, leading to chronic recurrent pulmonary infections and inflammation. The inflammatory process is characterized by the persistent recruitment of neutrophil granulocytes into the airways. Our focus is primarily on the innate cellular and fluid phase immune response. Therefore, we conduct screenings on CF patients before and six months after undergoing the triple combination therapy with Elexacaftor-Tezacaftor-Ivacaftor (ETI), which was approved in 2020 and has shown positive effects on disease activity by improving the residual function of the CFTR channel.
Multimodal analysis of granulocytes, monocytes, and platelets in patients with cystic fibrosis before and after Elexacaftor-Tezacaftor-Ivacaftor treatment
Schmidt H, Höpfer LM, Wohlgemuth L, Knapp CL, Mohamed AOK, Stukan L, Münnich F, Hüsken D, Koller AS, Stratmann AEP, Müller P, Braun CK, Fabricius D, Bode SFN, Huber-Lang M, Messerer DAC. Front Immunol. 2023 Jun 29;14:1180282. doi: 10.3389/fimmu.2023.1180282. PMID: 37457734; PMCID: PMC10347380.
Together with an international team of clinical experts and researchers led by Prof. John D. Lambris, University of Pennsylvania, USA and coordinated by Amyndas Pharmaceuticals, we designed a prospective, randomized, placebo-controlled, phase 2 clinical study to assess the safety, tolerability and efficacy of the potent complement C3 inhibitor, AMY-101, for the management of patients with ARDS caused by SARS-CoV-2 infection. The study design was approved by the BfArM 04/2020 (Eudra-CT2020-001550-22) and served as the base for the collaboratively conducted Covid-19 Phase 2 study in Greece (ITHACA) in which AMY-101 treatment greatly inhibited systemic complement activation and attenuated markers of thromboinflammation in severe COVID-19 patients. This study also documented the safety and tolerability of AMY-101 following systemic application (see publications below). These results are encouraging for future complement-modulating clinical studies in which the Institute of Clinical and Experimental Trauma Immunology will take a central role.
Complement C3 inhibition in severe COVID-19 using compstatin AMY-101.
Skendros P, Germanidis G, Mastellos DC, Antoniadou C, Gavriilidis E, Kalopitas G, Samakidou A, Liontos A, Chrysanthopoulou A, Ntinopoulou M, Kogias D, Karanika I, Smyrlis A, Cepaityte D, Fotiadou I, Zioga N, Mitroulis I, Gatselis NK, Papagoras C, Metallidis S, Milionis H, Dalekos GN, Willems L, Persson B, Manivel VA, Nilsson B, Connolly ES, Iacobelli S, Papadopoulos V, Calado RT, Huber-Lang M, Risitano AM, Yancopoulou D, Ritis K, Lambris JD. Sci Adv. 2022 Aug 19;8(33):eabo2341. doi: 10.1126/sciadv.abo2341. Epub 2022 Aug 17. PMID: 35977025
Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy.
Mastellos DC, Pires da Silva BGP, Fonseca BAL, Fonseca NP, Auxiliadora-Martins M, Mastaglio S, Ruggeri A, Sironi M, Radermacher P, Chrysanthopoulou A, Skendros P, Ritis K, Manfra I, Iacobelli S, Huber-Lang M, Nilsson B, Yancopoulou D, Connolly ES, Garlanda C, Ciceri F, Risitano AM, Calado RT, Lambris JD. Clin Immunol. 2020 Nov;220:108598. doi: 10.1016/j.clim.2020.108598. Epub 2020 Sep 19.
Complement as a target in COVID-19?
Risitano AM, Mastellos DC, Huber-Lang M, Yancopoulou D, Garlanda C, Ciceri F, Lambris JD. Nat Rev Immunol. 2020 Jun;20(6):343-344. doi: 10.1038/s41577-020-0320-7.
The first case of COVID-19 treated with the complement C3 inhibitor AMY-101.
Mastaglio S, Ruggeri A, Risitano AM, Angelillo P, Yancopoulou D, Mastellos DC, Huber-Lang M, Piemontese S, Assanelli A, Garlanda C, Lambris JD, Ciceri F. Clin Immunol. 2020 Jun;215:108450.
Hemodialysis is a method to clean blood in patients suffering from an acute or chronic kidney disease. Hereby, blood is redirected in an extracorporal circuit, passes a dialyzer, and enters the body in a cleaned version again. However, contact of blood with artificial surfaces induces an inflammatory state, mainly driven by the intravascular fluid phase cascade system, which can significantly contribute to therapy-associated complications such as an increased risk of cardiovascular disease. In this study, we want to investigate the effects of different anticoagulation protocols on cascade activation in hemodialysis patients. Prospectively, the findings shall form a rationale for a future interventional study. This study is performed in cooperation with Dr. med. Martin Kächele, Department of Internal Medicine I, Section Nephrology of the University Hospital of Ulm.
The ITI's C3 defense research group is highly interested in conducting tailored complement analysis on patients suffering from diseases with hidden pathophysiological backgrounds. In these patients, we aim to elucidate and assess the involvement and contribution of the complement system. For this, we perform highly sophisticated in vitro and ex vivo complement analyses to aid patients and their attending physicians in comprehending and possibly addressing the role of complement within their specific diseases. Currently, we are providing support to two patients depicting complex features of autoimmune diseases. Additionally, a case report of a third patient was recently published (please see below).
Combined Heterozygous Genetic Variations in Complement C2 and C8B: An Explanation for Multidimensional Immune Imbalance?
Mannes M, Halbgebauer R, Wohlgemuth L, Messerer DAC, Savukoski S, Schultze A, Berger B, Knapp CL, Schmidt CQ, Fürst D, Hillmer M, Siebert R, Eriksson O, Persson B, Nilsson B, Nilsson Ekdahl K, Huber-Lang M. J Innate Immun. 2023 Mar 1;15(1):412-427. doi: 10.1159/000528607. Online ahead of print.PMID: 36858027