Prof. Sacha Sergio Zeerleder (MD PhD) received is MD from the University of Berne (Switzerland) in 1997. He completed his training as internist hematologist at the University hospital Bern, Switzerland, and at the Academic Medical Center AMC in Amsterdam, the Netherlands. From 2010 to July 2018 Prof. Zeerleder worked as staff hematologist at the Academic Medical Centre AMC and as principle investigator at Sanquin Research in Amsterdam. At the AMC, he was the director of the stem cell transplantation program, medical head of the special hematology laboratory and the transfusion laboratory. In 2016, he was appointed full professor for Immunohematology at the University of Amsterdam. Since August 2018 is chief physician at the University Hospital in Bern (Switzerland) and is responsible for the transfusion service, apheresis unit, is director of the program cellular therapies and vice director of the Center of Hemato-oncology as a part of the University Cancer Center Inselspital (UCI). In July 2019, he received the “Venia docendi” and his “associate professorship” at the medical faculty at the University of Bern. The main interest of the research of Prof. Sacha Zeerleder lies in the role of innate immunity in hematological diseases.
Since more than 20 years, Prof. Sacha Zeerleder’s research is dedicated to the role of innate immunity in human disease, with a special interest in damage-associated molecular patterns (DAMPs) and complement. In the recent years there was a focus on innate immunity in hematological diseases, including hemolytic diseases (sickle cell disease, paroxysmal nocturnal hemoglobinuria (PNH), thrombotic microangiopathy (TMA), autoimmune hemolytic anemia (AIHA)), Graft-vs-host disease, hematopoietic and immune reconstitution after stem cell transplantation (allogeneic and autologous) as well as conditions defined by systemic inflammation (e.g. sepsis). The approach of Prof. Sacha Zeerleder is mainly TRANSLATIONAL including basic research, preclinical models and clinical research.
In 2003 together with Prof. Eric Hack (Sanquin Research, Amsterdam) Prof. Sacha Zeerleder was among the first to describe cell-free DNA in the form of nucleosomes - a classical DAMP- to be released from dead cells in sepsis patients and that this cell-free DNA is a reliable marker for severity of inflammation and outcome (1). Zeerleder’s group demonstrated that the release of DAMPs from dead cells is a highly structured and regulated process including plasma proteases (e.g. factor VII-activating protease (FSAP)) and its inhibitors (C1-inhibitor, alpha2-antiplasmin, and tissue-factor pathway inhibitor (TFPI)). Zeerleder’s group demonstrated the proinflammatory effects of cell-free DNA and DNA-binding proteins and identified FSAP as an efficient neutralizer of cytotoxicity of DNA-binding proteins, such as histones. They also showed cell-free DNA and DNA-binding proteins to play a crucial role in the pathogenesis of systemic inflammation (e.g. sepsis, GvHD) and that therapeutic neutralization of DAMPs may attenuate inflammation and improve outcome in these clinical situations. To date his group investigates the efficacy of plasma-purified or recombinant FSAP for therapeutic application to neutralize the harmful effects of DAMPs released during systemic inflammation.
The recent years the mechanism red blood cell (RBC) membrane disintegration with subsequent release of DAMPs (e.g. cell-free hemoglobin and heme) became a new focus of his research. Zeerleder’s group demonstrated complement activation to contribute significantly to RBC destruction in AIHA and that therapeutic complement inhibition halts and prevent RBC lysis in these patients. Interestingly in AIHA as well as in other hemolytic diseases (e.g. sickle cell disease) neutrophil activation in the form of neutrophil extracellular traps is significantly present contributing to systemic inflammation and poor outcome of these diseases. Interestingly, there growing evidence that DAMPs in the form of hemoproteins induce systemic inflammation also in the absence of hemolysis.
The Zeerleder group demonstrated that
- Serine protease activity plays an indispensable step in the release of nuclear DAMPs from dead cells. Factor VII-activation protease (FSAP) cleaves histone-1 with a subsequent release of nucleosomes. FSAP is activated by histones released upon cell death and in turn proteolytically degrades histones, neutralizes cytotoxicity and attenuates systemic inflammation
- Complement activation plays a crucial role in red blood cell (RBC) destruction in autoimmune hemolytic anemia (AHIA) and therapeutic complement targeting different complement proteases is effective to halt hemolysis, to inhibit systemic inflammation, to reduce fatality and to improve recovery of RBC transfusion.
- Neutrophil activation in the form of neutrophil extracellular traps (NETs) is a hallmark of systemic inflammation as observed in many different form of sepsis as well in hemolytic diseases (e.g. AHIA, sickle cell disease, paroxysmal nocturnal hemoglobinuria). The presence of NETs in these diseases is associated with severe inflammation, microvascular complications and fatality. Among others, complement activation, the release of hemoproteins (cell-free hemoglobin and heme) and iron play an indispensable role in this process
- Plasma protein inhibitors, such as the SERPIN C1-inhibitor, can successfully be applied in a variety of diseases, such as hereditary angioedema, AIHA, ischemic reperfusion injury and sepsis. Besides the protease-inhibiting domain, specific glycosylation pattern of the non-protease inhibiting domain of these serpins do have anti-inflammatory effects. In addition, contamination of plasma-derived C1-inhibitor products with highly glycosylated plasma inhibitors, e.g. alpha1-antichymotrypsin, significantly contribute to the anti-inflammatory properties of therapeutic C1-inhibitor plasma products.
The ongoing projects of the Zeerleder group focus on the role of the innate immune system in hematological diseases using a translational approach. In 2 competitive programs in transfusion research financed by Sanquin Research Amsterdam, Zeerleder focuses on the role of the innate immune response in the formation of alloantibodies. One project investigates the role of innate immunity, especially heme, complement and neutrophil activation on alloantibody formation in sickle cell disease. In the second project, we study the role of innate immunity in the formation of anti-platelet antibodies with subsequent refractoriness to platelet transfusion. Another research line of the Zeerleder group investigates the role of complement and neutrophil activation in neutrophil activation in the form of neutrophil extracellular traps (NETs) in the pathogenesis of thrombosis with a special focus on hemolytic diseases (e.g. autoimmune hemolytic anemia, AIHA), antibody-mediated acquired thrombophilia and COVID-19. Finally, the Zeerleder group investigates the role of innate immunity in the development of (allogenic) T-cell responses in acute graft-vs-host disease and adoptive T-cell therapy.
- Prof. D. Ricklin, Department Pharmazeutische Wissenschaften, University of Basel, Switzerland
- Prof. W.A. Wuillemin, Department of Hematology, Kantonsspital Lucerne, Switzerland
- Prof. W. Korte, Center for Laboratory Medicine and Hemostasis and Hemophilia Center St. Gallen, Frohbergstrasse 3, 9001 St. Gallen, Switzerland.
- Prof. R. Rieben, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Prof. M. Neerman-Arbez, Department of Genetic Medicine and Development, University Medical Centre, Geneva, Switzerland
- Dr. C. Voermans, Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
- Dr. M. Hazenberg, Department of Hematology, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands
- Dr. E. Nur, Department of Hematology, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands
- Prof. T. Kuipers, Emma Children's Hospital, Amsterdam UMC location AMC, University of Amsterdam, 1105AZ Amsterdam, The Netherlands; Department of Blood Cell Research, Sanquin Research, 1066 CX Amsterdam, The Netherlands.
- Prof. M. de Haas, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, The Netherlands
- Dr. I. Jongerius, department of Immunopathology, Sanquin Research, Amsterdam, The Netherland
- Prof. J. Lambris, Department of Pathology & Laboratory Medicine, University of Pennsylvania, USA
- Prof. T. van der Poll, Division of Infectious Diseases, Amsterdam University Medical Centers - Location AMC, University of Amsterdam, Amsterdam, Netherlands
- Prof. F. Cognasse, Faculté de Médecine Jacques Lisfranc, Université de Lyon, GIMAP-EA3064, 42270 Saint-Etienne, France
Cumulative support: 01/2009-present 10.798 kEuro
- Landsteiner Foundation for Blood Transfusion, Amsterdam, The Netherlands
- Product and Process Development Cellular Products Sanquin (PPOC) program Sanquin Amsterdam, The Netherlands
- Dutch Thrombosis Foundation, The Netherlands
- Jazz Pharma
- SNF NRP78 “COVID-19” (2020)
- Jazz Pharma