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Natural killer cell function after liver resection: the role of extracellular ATP

English title Natural killer cell function after liver resection: the role of extracellular ATP
Applicant Beldi Guido
Number 130816
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 01.04.2010 - 31.03.2013
Approved amount 307'194.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (7)

Purinergic signaling; Liver regeneration; NTPDase1/CD39; liver resection; natural killer cell; extracellular ATP; NTPDase

Lay Summary (English)

Lead
Lay summary
Surgery offers the only potential cure in many patients with primary or metastatic liver cancer. Extending the limits and improving safety of liver resection would allow more patients to benefit from surgery and to decrease morbidity. The prerequisite for successful and safe liver surgery is the optimal regeneration of the remaining hepatic tissue in order to fulfill the metabolic demands of the patient. Liver regeneration is closely coordinated by paracrine mechanisms. Natural killer (NK) cells are the dominant lymphocyte population in the human liver and have been shown to modulate hepatocellular regeneration and injury after partial liver resection in mice. However, mechanisms that regulate important NK cell functions such as cytotoxicity or cytokine secretion during liver regeneration remain unknown. Extracellular nucleotides such as ATP activate specific purinergic (P2) receptors that are present on a variety of immune cells including NK cells. Levels of extracellular ATP are regulated by enzymatic hydrolysis by ectonucleotidases (mainly CD39/ENTPDase1). Preliminary data reveal that after liver resection, cytotoxicity of wild type NK cells is modulated by extracellular ATP. Alterations of pericellular ATP levels in NK cells null for CD39 was associated with increased proliferation and decreased liver injury after partial liver resection. The purinergic receptor P2Y1 and P2Y2 seem to be involved. Interestingly, cytotoxicity was increased in NK cells with genetic deletion of CD39 compared to wild type NK cells, possibly in response to P2Y receptor desensitization. The general aim of the study is to explore the role of purinergic receptors on NK cell derived cytotoxicity in a mouse model of partial liver resection. Specifically we explore the impact of interactions of extracellular ATP, CD39 and and P2Y receptors on NK cell cytotoxicity in a model of partial liver resection. 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 its 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 to extend boarders of hepatic resection and to improve patient's outcome for advanced primary and metastatic liver tumors
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Promotion of liver regeneration by natural killer cells in a murine model is dependent on extracellular adenosine triphosphate phosphohydrolysis.
Graubardt Nadine, Fahrner René, Trochsler Markus, Keogh Adrian, Breu Karin, Furer Cynthia, Stroka Deborah, Robson Simon C, Slack Emma, Candinas Daniel, Beldi Guido (2013), Promotion of liver regeneration by natural killer cells in a murine model is dependent on extracellular adenosine triphosphate phosphohydrolysis., in Hepatology (Baltimore, Md.), 57(5), 1969-79.
Deletion of CD39 on Natural Killer Cells Attenuates Hepatic Ischemia/Reperfusion Injury in Mice
Beldi Guido, Banz Yara, Kroemer Alexander, Sun Xiaofeng, Wu Yan, Graubardt Nadine, Rellstab Alyssa, Nowak Martina, Enjyoji Keiichi, Li Xian, Junger Wolfgang G., Candinas Daniel, Robson Simon C. (2010), Deletion of CD39 on Natural Killer Cells Attenuates Hepatic Ischemia/Reperfusion Injury in Mice, in HEPATOLOGY, 51(5), 1702-1711.

Collaboration

Group / person Country
Types of collaboration
Harvard Medcial School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Vortrag Sonderforschungsbereich Talk given at a conference Impact of extracellular ATP on heptic inflammation and regeneration 29.03.2012 Homburg, Germany Beldi Guido; Graubardt Nadine;
The International Liver Meeting Poster Terlipressin improves liver regeneration after extended liver resection in a mouse model of partial hepatectomy 31.03.2011 Berlin, Germany Beldi Guido;
AASLD Liver Meeting Poster Extracellular ATP and CD39 regulate natural killer cell activation and cytotoxicity during liver regeneration 29.10.2010 Boston, United States of America Graubardt Nadine; Beldi Guido;


Knowledge transfer events



Self-organised

Title Date Place
Annual research retreat Universitätsklinik für Viszerale Chirurgie und Medizin Bern 25.11.2011 Gerzensee, Switzerland

Awards

Title Year
Young investigator bursary award 2011
Best Poster Prize 2010
Young investigator bursary award 2010

Associated projects

Number Title Start Funding scheme
115700 CD39/NTPDase1 expression by Natural Killer T cells modulates hepatic inflammation and oncogenesis 01.01.2007 SFGBM Fellowships for advanced researchers
166594 Purinergic control of innate lymphoid cells in liver injury and repair 01.04.2016 Project funding
146986 NTPDase1/CD39 and innate lymphoid cells in liver injury and repair 01.04.2013 Project funding
112764 Modulation of hepatocyte and sinusoidal endothelial cell responses by ectonucleotidase during liver regeneration 01.01.2006 Fellowships for prospective researchers
145003 A new Zeiss LSM 710 laser scanning microscope for the DCR LCI Core Facility 01.12.2012 R'EQUIP

Abstract

BackgroundSurgery offers the only potential cure in many patients with primary or metastatic liver cancer. Extending the limits and improving safety of liver resection would allow more patients to benefit from surgery and to in-crease their survival. The prerequisite for successful and safe liver surgery is the optimal regeneration of the remaining hepatic tissue in order to fulfill the metabolic demands of the patient.Liver regeneration is closely coordinated by paracrine mechanisms. Natural killer (NK) cells are the dominant lymphocyte population in the human liver and have been shown to modulate hepatocellular regeneration and injury after partial liver resection in mice. However, mechanisms that regulate important NK cell functions such as cytotoxicity or cytokine secretion during liver regeneration remain unknown. Extracellular nucleotides such as ATP activate specific purinergic (P2) receptors that are present on a variety of immune cells including NK cells. Levels of extracellular ATP are regulated by cellular release and enzymatic hydrolysis by ectonucleotidases (mainly CD39/ENTPDase1). Preliminary results show a significant decrease of cytotoxicity of purified wild type NK cells by extracellular ATP. Pharmacological profiling reveals P2Y1 and P2Y2 as the receptors involved. Interestingly, cytotoxicity was increased in NK cells with genetic deletion of CD39 compared to wild type NK cells, possibly in response to P2Y receptor desensitization. In vivo, alterations of pericellular ATP levels in NK cells null for CD39 was associated with increased proliferation and decreased liver injury after partial liver resection. Aim: To explore the role of purinergic receptors on NK cell derived cytotoxicity in a mouse model of partial liver resection.Specific aims1. To determine the role of extracellular ATP on NK cell cytotoxicity in a model of partial liver resection. 2. To explore the specific role of P2Y receptor activation on NK cell cytotoxicity in vitro and in a model of partial liver resection. 3. To determine the presence of P2Y receptor desensitization in response to deletion of CD39.SignificanceAspects 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 its 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 to extend boarders of hepatic resection and to improve patient’s outcome for advanced primary and metastatic liver tumors.
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