Project

Back to overview

Killer cell Immunoglobulin-like Receptors (KIR) in the recognition of tumor- and virus-transformed target cells

English title Killer cell Immunoglobulin-like Receptors (KIR) in the recognition of tumor- and virus-transformed target cells
Applicant Stern Martin
Number 128461
Funding scheme SNSF Professorships
Research institution
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.10.2010 - 30.09.2014
Approved amount 1'331'067.00
Show all

Keywords (11)

Hematopoietic stem cell transplantation; Natural killer cells; Killer cell immunoglobulin-like receptors; Graft-versus-host disease; Cytomegalovirus; Cord blood transplantation; Human leukocyte antigens; Multiple Myeloma; Stem cell transplantation; Immune reconstitution; Leukemia

Lay Summary (German)

Lead
Lay summary
Natürliche Killer- (NK)-Zellen sind eine Untergruppe von weissen Blutkörperchen, welche in der Abwehr von Virus-Infekten oder bösartigen Tumoren wichtig sind. Eine zentrale Gruppe von Oberflächen-Eiweissen auf NK-Zellen sind die "Killer-cell Immunoglobulin-like receptors" (KIR). Aus Populations-Studien ist bekannt, dass Menschen Gene für ganz verschiedene Rezeptoren aus der Gruppe der KIR tragen können. Das Vorhandensein oder Fehlen von einzelnen KIR-Genen prädisponiert zu oder schützt vor verschiedenen Krankheiten. Dies insbesondere bei Individuen nach Transplantation von Organen oder Stammzellen, da bei diesen Patienten andere Teile der Immunabwehr nur reduziert funktionsfähig sind. Die biologischen Mechanismen, welche hierfür verantwortlich sind, bleiben bisher weitgehend ungeklärt. Ziel unseres Projektes ist es aufzuklären, bei welchen Arten der Stammzell-Transplantation NK-Zellen eine Antitumorwirkung ausüben können und zu charakterisieren, auf welchen Mechanismen dies beruht. Dies geschieht, indem wir die NK-Zellen von Patienten, welche mit einer Stammzell-Transplantation behandelt werden, untersuchen. In einem zweiten Teil benützen wir schon bekannte Eigenschaften von NK-Zellen zur Behandlung von Patienten, welche an Multiplem Myelom, einer bösartigen Knochenmarkskrankheit leiden. Zusätzlich zur Standardbehandlung mit Chemotherapie erhalten die Patienten mehrere Infusionen mit im Labor vermehrten NK-Zellen. Die Absicht hierbei ist, dass die infundierten NK-Zellen vereinzelte Tumorzellen - welche trotz Chemotherapie nicht abgestorben sind - erkennen und zerstören können. Die langfristigen Hoffnung hierbei ist, die heute noch unbefriedigende Therapie des Multiplen Myeloms zu verbessern. Im dritten Teil des Projektes geht es um den Beitrag von NK-Zellen in der Abwehr von Cytomegalie-Virus- (CMV-)Infekten. Infektionen mit CMV sind eine gefürchtete Komplikation nach Transplantation von Stammzellen oder soliden Organen. Menschen welche die Gene für gewisse aktivierende KIR-Rezeptoren tragen sind vor CMV-Infekten geschützt, wobei der Mechanismus dieses Schutzes noch völlig unbekannt ist. Ziel dieses Projektes ist, die molekulare Mechanismen der CMV-Erkennung durch NK-Zellen aufzuschlüsseln.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Cytomegalovirus Serology and Replication Remain Associated With Solid Organ Graft Rejection and Graft Loss in the Era of Prophylactic Treatment.
Stern Martin, Hirsch Hans, Cusini Alexia, van Delden Christian, Manuel Oriol, Meylan Pascal, Boggian Katia, Mueller Nicolas J, Dickenmann Michael, on behalf of all members of the Swiss Transplant Cohort Study (2014), Cytomegalovirus Serology and Replication Remain Associated With Solid Organ Graft Rejection and Graft Loss in the Era of Prophylactic Treatment., in Transplantation, epub ahead of print(epub ahead), epub ahead-epub ahead.
KIR/HLA interactions negatively affect rituximab- but not GA101 (obinutuzumab)-induced antibody-dependent cellular cytotoxicity.
Terszowski Grzegorz, Klein Christian, Stern Martin (2014), KIR/HLA interactions negatively affect rituximab- but not GA101 (obinutuzumab)-induced antibody-dependent cellular cytotoxicity., in Journal of immunology (Baltimore, Md. : 1950), 192(12), 5618-24.
KIR-associated protection from CMV replication requires pre-existing immunity: a prospective study in solid organ transplant recipients.
Gonzalez A, Schmitter K, Hirsch H H, Garzoni C, van Delden C, Boggian K, Mueller N J, Berger C, Villard J, Manuel O, Meylan P, Stern M, Hess C (2014), KIR-associated protection from CMV replication requires pre-existing immunity: a prospective study in solid organ transplant recipients., in Genes and immunity, epub ahead of print(epub ahead), epub ahead-epub ahead.
Lymphocyte subset recovery and outcome after autologous hematopoietic stem cell transplantation for plasma cell myeloma.
Rueff Jessica, Medinger Michael, Heim Dominik, Passweg Jakob, Stern Martin (2014), Lymphocyte subset recovery and outcome after autologous hematopoietic stem cell transplantation for plasma cell myeloma., in Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow T, 20(6), 896-9.
Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis.
Stern M, de Wreede L C, Brand R, van Biezen A, Dreger P, Mohty M, de Witte T M, Kröger N, Ruutu T (2014), Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis., in Leukemia, epub ahead of print(epub ahead), epub ahead-epub ahead.
Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol
Koehl Ulrike, Brehm Claudia, Huenecke Sabine, Zimmermann Stenfanie-Yvonne, Kloess Stephan, Bremm Melanie, Ullrich Evelyn, Soerensen Jan, Quaiser Andrea, Erben Stephanie, Wunram Claudia, Gardlowski Tanja, Auth Eileen, Tonn Torsten, Seidl Christine, Meyer-Monard Sandrine, Stern Martin, Passweg Jakob, Klingebiel Thomas, Bader Peter, Schwabe Dirk, Esser Ruth (2013), Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol, in Frontiers in Oncology, 118.
A polymorphism affecting HLA-C surface expression associates with herpes simplex virus and cytomegalovirus immunoglobulin G seropositivity
Charoudeh HN, Schmitter K, Buser A, Gonzalez A, Stern M (2012), A polymorphism affecting HLA-C surface expression associates with herpes simplex virus and cytomegalovirus immunoglobulin G seropositivity, in TISSUE ANTIGENS, 80(3), 263-264.
HLA-Bw4 identifies a population of HIV-infected patients with an increased capacity to control viral replication after structured treatment interruption.
Stern M, Czaja K, Rauch A, Rickenbach M, Günthard H F, Battegay M, Fellay J, Hirschel B, Hess C, the Swiss HIV Cohort Study Group (2012), HLA-Bw4 identifies a population of HIV-infected patients with an increased capacity to control viral replication after structured treatment interruption., in HIV medicine, 13(10), 589-595.
Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers.
Stern M, Passweg J R, Meyer-Monard S, Esser R, Tonn T, Soerensen J, Paulussen M, Gratwohl A, Klingebiel T, Bader P, Tichelli A, Schwabe D, Koehl U (2012), Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers., in Bone marrow transplantation, e pub(e pub), e pub-epub.
Quantity of HLA-C surface expression and licensing of KIR2DL+ natural killer cells
Charoudeh HN, Schmied L, Gonzalez A, Terszowski G, Czaja K, Schmitter K, Infanti L, Buser A, Stern M (2012), Quantity of HLA-C surface expression and licensing of KIR2DL+ natural killer cells, in IMMUNOGENETICS, 64(10), 739-745.
Expansion of CD56-negative, CD16-positive, KIR-expressing natural killer cells after T cell-depleted haploidentical hematopoietic stem cell transplantation
De Angelis C, Mancusi A, Ruggeri L, Capanni M, Urbani E, Velardi A, Stern M (2011), Expansion of CD56-negative, CD16-positive, KIR-expressing natural killer cells after T cell-depleted haploidentical hematopoietic stem cell transplantation, in Acta Haematologica, 126(1), 13-20.
Telomeric rather than centromeric activating KIR genes protect from cytomegalovirus infection after kidney transplantation.
Stern M, Hadaya K, Hönger G, Martin P-Y, Steiger J, Hess C, Villard J (2011), Telomeric rather than centromeric activating KIR genes protect from cytomegalovirus infection after kidney transplantation., in American journal of transplantation : official journal of the American Society of Transplantation an, 11(6), 1302-7.
Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT.
Bühlmann L, Buser A S, Cantoni N, Gerull S, Tichelli A, Gratwohl A, Stern M (2010), Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT., in Bone marrow transplantation, 46(10), 1357-62.
A comprehensive analysis of the binding of anti-KIR antibodies to activating KIR
Czaja Karol, Borer Aline, Schmied Laurent, Terszowski Grzegorz, Stern Martin, Gonzalez Asensio, A comprehensive analysis of the binding of anti-KIR antibodies to activating KIR, in Genes & Immunity.
Modulation of Natural Killer Cell KIR Repertoire by Cytomegalovirus Infection
Charoudeh Hojjat, Terszowski Greg, Czaja Karol, Gonzalez Asensio, Schmitter Karin, Stern Martin, Modulation of Natural Killer Cell KIR Repertoire by Cytomegalovirus Infection, in European Journal of Immunology, in press(in press), in press-in press.
Natural Killer Cell Immunity after Transplantation
Terszowski Grzegorz, Passweg Jakob, Stern Martin, Natural Killer Cell Immunity after Transplantation, in Swiss Medical Weekly.

Collaboration

Group / person Country
Types of collaboration
Swiss Transplant Cohort Study Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Biozentrum, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Paul Scherrer Institut Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Swiss HIV Cohort Study Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EBMT Immunobiology Working Party Talk given at a conference Quantifying graft-versus-leukemia effects 27.09.2013 Perugia, Italy Stern Martin;
NK2013 Poster KIR/HLA interactions differentially affect NK cell activation by the CD20 antibodies rituximab and GA101 (obinutuzumab) 17.09.2013 Heidelberg, Germany Terszowski Grzegorz; Stern Martin;


Associated projects

Number Title Start Funding scheme
149647 Immunotherapy with NK cells: adoptive transfer of ex vivo expanded and activated NK cells in elderly patients with acute myeloid leukemia 01.01.2015 Project funding (Div. I-III)
152992 Killer cell Immunoglobulin-like Receptors (KIR) in the recognition of tumor- and virus-transformed target cells 01.10.2014 SNSF Professorships

Abstract

As an extension of work previously funded by SNF on the significance of NK cells and KIR after haploidentical stem cell transplantation we propose in this project to study the biological significance of KIR after cord blood transplantation, a potential role for NK cells in autologous HSCT, and to identify ligands for activating KIR receptors. In the translational part of the project, patients with multiple myeloma will be treated with ex vivo expanded allogeneic NK cells.
-