Project

Back to overview

NTPDase1/CD39 and innate lymphoid cells in liver injury and repair

English title NTPDase1/CD39 and innate lymphoid cells in liver injury and repair
Applicant Beldi Guido
Number 146986
Funding scheme Project funding
Research institution Klinik und Poliklinik für Viszerale und Transplantationschirurgie Inselspital
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.04.2013 - 31.03.2016
Approved amount 337'235.00
Show all

All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (5)

Interleukin-22; Liver regeneration; P2 receptor ; NTPDase1/CD39; Innate lymphoid cells

Lay Summary (German)

Lead
Chirurgie bietet die einzige Möglichkeit auf Heilung bei Patienten mit Lebermetastasen oder primären Lebertumoren. Grenzen der Leberchirurgie zu erweitern würde es ermöglichen, mehr Patienten mit kurativer Absicht chirurgisch zu behandeln.Mit diesem Projekt wird untersucht, ob Adenosin-triphosphat (ATP) welches durch gestresste Zellen in die Umgebung freigesetzt wird, relevante immunologische Funktionen der Leber beeinflusst und somit für Resultat nach Leberchirurgie von Relevanz sein könnten.
Lay summary

Chirurgie bietet die einzige Möglichkeit auf langfristige Heilung bei Patienten mit Lebermetastasen oder primären Lebertumoren. Die Grenzen der Leberchirurgie zuerweitern und die Sicherheit zu erhöhen würde es ermöglichen mehr Patienten mit kurativer Absicht zu behandeln. Die Voraussetzung für eine erfolgreiche Leberchirurgie ist die optimale Regeneration der Leber. Nach der Entfernung eines Grossteils der Leber kann die restliche Leber bis zur ursprünglichen Grösse nachwachsen.

Neben den primären Leberzellen wird die Leberregeneration durch eine Vielzahl von anderen Zellen zum Beispiel speziellen Immunzellen der Leber beeinflusst. Wie diese Zellen durch Adenosin-triphosphat (ATP) reguliert wird, wird in diesem Projekt untersucht. ATP ist der universelle Energieträger der menschlichen Zelle. Bei zellulärem Stress, wie er zum Beispiel während einem chirurgischen Eingriff vorkommt, wird ATP aus der Zelle freigesetzt. Eine zunehmende Evidenz zeigt, dass dieses freigesetzte und sogar in der Blutbahn zirkulierende ATP relevante immunologische und nicht-immunologische Prozesse im Körper reguliert.

In dem vorliegenden Projekt untersuchen wir primär, wie ATP sich auf die Funktion von Immunzellen der Leber auswirkt. In einem zweiten Schritt wird untersucht ob die veränderte Funktion dieser Immunzellen den Ausgang einer Leber-Operation beeinflusst.

Ausdiesen Erkenntnissen würden sich neue therapeutische Optionen ergeben da ATPDerivate bereits synthetisiert wurden und für therapeutische Zwecke getestetwerden könnten.

Direct link to Lay Summary Last update: 15.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Endothelial- and Platelet-Derived Microparticles Are Generated During Liver Resection in Humans
Banz Y (2016), Endothelial- and Platelet-Derived Microparticles Are Generated During Liver Resection in Humans, in J invest surg, 29(1), 20-31.
P2X1 regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration
Kudira Ramesh, Malinka Thomas, Kohler Andreas, Dosch Michel, Gomez de Agüero Mercedes, Melin Nicolas, Haegele Stefanie, Starlinger Patrick, Maharjan Niran, Saxena Smita, Keogh Adrian, Stroka Deborah, Candinas Daniel, Beldi Guido (2016), P2X1 regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration, in Hepatology, n/a-n/a.
Elevated Liver Regeneration in Response to Pharmacological Reduction of Elevated Portal Venous Pressure by Terlipressin After Partial Hepatectomy
Fahrner René, Patsenker Eleonora, Gottardi Andrea de, Stickel Felix, Montani Matteo, Stroka Deborah, Candinas Daniel, Beldi Guido (2014), Elevated Liver Regeneration in Response to Pharmacological Reduction of Elevated Portal Venous Pressure by Terlipressin After Partial Hepatectomy, in Transplantation, 97(9), 892-900.
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand on NK Cells Protects From Hepatic Ischemia-Reperfusion Injury
Fahrner René, Trochsler Markus, Corazza Nadia, Graubardt Nadine, Keogh Adrian, Candinas Daniel, Brunner Thomas, Stroka Deborah, Beldi Guido (2014), Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand on NK Cells Protects From Hepatic Ischemia-Reperfusion Injury, in Transplantation, 97(11), 1102-1109.

Collaboration

Group / person Country
Types of collaboration
Prof. Andrew Macpherson, Department of Clinical Research, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Dr. Patrick Starlinger, Universität Wien Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Smita Saxena, Universität Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Simon C. Robson, Liver and Transplant Centers, BIDMC, Harvard Medical School, Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Keystone Symposium Talk given at a conference P2X1 regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration 29.01.2016 Vancouver, Canada Beldi Guido; Kudira Ramesh;
Annual Congress EASL Talk given at a conference IL-22 secretion is required for liver regeneration and is modulated by extracellular nucleotides 25.04.2015 Vienna, Austria Kudira Ramesh; Beldi Guido;
Annual Meeting EASL Poster LIVER REGENERATION IS NOT IMPACTED IN THE ABSENCE OF MICROBIOTA 23.04.2015 Wien, Austria Beldi Guido; Kudira Ramesh;
EASL Basic School of Hepatology Course 9 Talk given at a conference Extracellular nucleotides modulate the secretion of IL-22 by hepatic innate lymphoid cells 25.01.2014 Milan, Italy Kudira Ramesh;


Awards

Title Year
SGG-SGC-ARS award for best oral presentation 2015
Travel Award, schweizerische Gesellschaft für Viszeralchirurgie 2014
Travel grant: EASL Basic School of Hepatology Course 9; Epithelial and mesenchymal interactions in liver development, diseases and cancer. Milan, Italy 2014

Associated projects

Number Title Start Funding scheme
112764 Modulation of hepatocyte and sinusoidal endothelial cell responses by ectonucleotidase during liver regeneration 01.01.2006 Fellowships for prospective researchers
130816 Natural killer cell function after liver resection: the role of extracellular ATP 01.04.2010 Project funding
166594 Purinergic control of innate lymphoid cells in liver injury and repair 01.04.2016 Project funding

Abstract

The prerequisite for successful and safe liver surgery is the optimal regeneration of the remaining hepatic tissue, sufficient to fulfill the metabolic demands of the patient. Liver regeneration is closely coordinated by paracrine mechanisms. We have shown that cellular subsets of the innate immune system such as natural killer cells critically modulate hepatocellular regeneration after partial liver resection in mice. Recently, novel subsets of innate immune cells have been described mainly in the gut with potent effector functions, including interleukin (IL)-22 secretion. IL-22 has been shown to be of crucial relevance in various models of liver inflammation and repair. Interestingly, the source and regulation of IL-22 secretion in the liver remains largely unexplored. Extracellular nucleotides such as ATP activate specific purinergic (P2) receptors that are present on a variety of immune cells. Levels of extracellular ATP are regulated by cellular release and enzymatic hydrolysis by ectonucleotidases (mainly ENTPDase1/CD39). We have shown that CD39 is expressed not just on the vasculature but also on several immune cells modulating potent effector functions. Preliminary results show a differential distribution of IL-22 producing cell subsets in the liver compared to other lymphoid organs. Thus, the general hypothesis of this project is that hepatic IL-22 dependent functions impact upon liver regeneration and are modulated by CD39. The aim of the study is to explore the impact of CD39 on function and differentiation of IL-22 secreting subsets of innate lymphoid cells in a mouse model of liver injury and repair.Significance: Aspects of innate immunity that contribute to liver injury and hepatocellular proliferation during liver regeneration will be investigated in this proposal. Future therapeutic options may result as nucleotides and their derivatives have already been synthesized as small and stable compounds. Their administration could potentially improve hepatic regeneration after major liver resection. This could, ultimately, allow extending boarders of hepatic resection and improving patient outcome for advanced primary and metastatic liver tumors. Furthermore, the results of this proposal may reveal novel mechanisms of the regulation of innate lymphoid cells by purinergic signaling and are therefore of potential relevance for other organs than the liver as well.
-