Immune repertoire diversity in allogeneic stem cell transplantation and its implications for infections and the graft versus leukemia effect
Author: Björklund, Andreas
Date: 2014-09-19
Location: Föreläsningssal 4V, Alfred Nobels allé 8, Campus Huddinge
Time: 09.00
Department: Inst för medicin, Huddinge / Dept of Medicine, Huddinge
View/ Open:
Thesis (2.176Mb)
Abstract
The beneficial graft versus leukemia effect (GVL) and its detrimental counterparts, graft versus
host disease (GVHD) and susceptibility to infections, are all coupled to a multitude of events
during the immune reconstitution (IR) after hematopoietic stem cell transplantation (HSCT).
The general aim of this thesis has been to learn more about the IR in HSCT with a particular
focus on the impact of infections, natural killer (NK) cell mediated GVL effects and the
possibility to apply GVL effects in adoptive cell therapy.
In paper I, we identified factors interfering with the IR, thereby making the patients susceptible to late lethal infections. We found that cytomegalovirus (CMV) was an independent risk factor for death in late infections. NK cells are important for controlling CMV infections and patients lacking NK cells suffer from cyclic herpes virus reactivations.1-3 NK cells are also known to mediate GVL-effects and have been coupled to reduced relapse rates after HSCT. The results of paper I thus prompted us to study NK cell-mediated GVL effects and the interaction between CMV and NK cell repertoire dynamics.
In paper II we examined NK cell-mediated alloreactivityin 105 patients with myeloid malignancies undergoing human leukocyte antigen (HLA )-identicalsibling transplantation. A longitudinal analysis revealed maintained NK cell tolerance at all timepoints during the IR. In agreement with these experimental data, no clinically evident GVL effect was observed based on stratification of missing ligands to killer cell immunoglobulin-like receptors (KIRs ) in the recipients.
In paper III we determined the size of the alloreactive subset and graded the ability of different donors to deliver GVL effects in HLA -mismatched transplantation. The educated subsets expressing KIRs in presence of a corresponding HLA - receptor ligand varied between 12-68% (mean 33%) resulting in 0-62% (mean 8%) alloreactive NK cells depending on recipient HLA -ligands. This algorithm served as a template for studies conducted in paper IV, where we further dissected the role of pre-transplant NK cell repertoires in the donor and post-transplant repertoires developing after 9-12 months. Unsupervised hierarchical clustering was used to group donors and recipients based on their NK cell receptor repertoires. The result showed that donors with naïve receptor repertoires had less relapse and recipients with a tendency to reset their repertoires towards naivety had less relapse and better overall survival.
In summary this thesis shed new light on the relationships between early and late infections and the recovery of the immune system after HSCT, linking specific NK cell repertoires to protection from relapse and increased overall survival. This knowledge may be useful for the development of new strategies utilizing NK cells in cellular therapies against hematological malignancies.
In paper I, we identified factors interfering with the IR, thereby making the patients susceptible to late lethal infections. We found that cytomegalovirus (CMV) was an independent risk factor for death in late infections. NK cells are important for controlling CMV infections and patients lacking NK cells suffer from cyclic herpes virus reactivations.1-3 NK cells are also known to mediate GVL-effects and have been coupled to reduced relapse rates after HSCT. The results of paper I thus prompted us to study NK cell-mediated GVL effects and the interaction between CMV and NK cell repertoire dynamics.
In paper II we examined NK cell-mediated alloreactivityin 105 patients with myeloid malignancies undergoing human leukocyte antigen (HLA )-identicalsibling transplantation. A longitudinal analysis revealed maintained NK cell tolerance at all timepoints during the IR. In agreement with these experimental data, no clinically evident GVL effect was observed based on stratification of missing ligands to killer cell immunoglobulin-like receptors (KIRs ) in the recipients.
In paper III we determined the size of the alloreactive subset and graded the ability of different donors to deliver GVL effects in HLA -mismatched transplantation. The educated subsets expressing KIRs in presence of a corresponding HLA - receptor ligand varied between 12-68% (mean 33%) resulting in 0-62% (mean 8%) alloreactive NK cells depending on recipient HLA -ligands. This algorithm served as a template for studies conducted in paper IV, where we further dissected the role of pre-transplant NK cell repertoires in the donor and post-transplant repertoires developing after 9-12 months. Unsupervised hierarchical clustering was used to group donors and recipients based on their NK cell receptor repertoires. The result showed that donors with naïve receptor repertoires had less relapse and recipients with a tendency to reset their repertoires towards naivety had less relapse and better overall survival.
In summary this thesis shed new light on the relationships between early and late infections and the recovery of the immune system after HSCT, linking specific NK cell repertoires to protection from relapse and increased overall survival. This knowledge may be useful for the development of new strategies utilizing NK cells in cellular therapies against hematological malignancies.
List of papers:
I. Risk Factors for Fatal Infectious Complications Developing Late after Allogeneic Stem Cell Transplantation ANDREAS BJÖRKLUND, Johan Aschan, Myriam Labopin, Mats Remberger, Olle Ringden, Jacek Winiarski and Per Ljungman Bone Marrow Transplantation, 2007, 40: 1055-1062
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. NK Cells Expressing Inhibitory KIR for Non–Self-Ligands Remain Tolerant in HLA -Matched Sibling Stem Cell Transplantation ANDREAS T BJÖRKLUND, Marie Schaffer, Cyril Fauriat, Olle Ringdén, Mats Remberger, Christina Hammarstedt, A. John Barrett, Per Ljungman, Hans-Gustaf Ljunggren and Karl-Johan Malmberg. Blood, 2010, 115: 2686-2694
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Estimation of the Size of the Alloreactive NK Cell Repertoire: Studies in Individuals Homozygous for the Group A KIR Haplotype Cyril Fauriat, Sandra Andersson, ANDREAS T BJÖRKLUND, Mattias Carlsten, Marie Schaffer, Niklas K. Björkström, Bettina C. Baumann, Jakob Michaélsson, Hans- Gustaf Ljunggren, and Karl-Johan Malmberg The Journal of Immunology, 2008, 181: 6010–6019
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Integrative Profiling of Natural Killer Cell Repertoires Reveal a Role for Less Differentiated NK cells in Protection from Leukemia Relapse ANDREAS T BJÖRKLUND, Trevor Clancy, Jodie Goodridge, Vivien Beziat, Marie Schaffer, Eivind Hovig, Hans-Gustaf Ljunggren, Per Ljungman, Karl- Johan Malmberg [Manuscript]
I. Risk Factors for Fatal Infectious Complications Developing Late after Allogeneic Stem Cell Transplantation ANDREAS BJÖRKLUND, Johan Aschan, Myriam Labopin, Mats Remberger, Olle Ringden, Jacek Winiarski and Per Ljungman Bone Marrow Transplantation, 2007, 40: 1055-1062
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. NK Cells Expressing Inhibitory KIR for Non–Self-Ligands Remain Tolerant in HLA -Matched Sibling Stem Cell Transplantation ANDREAS T BJÖRKLUND, Marie Schaffer, Cyril Fauriat, Olle Ringdén, Mats Remberger, Christina Hammarstedt, A. John Barrett, Per Ljungman, Hans-Gustaf Ljunggren and Karl-Johan Malmberg. Blood, 2010, 115: 2686-2694
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Estimation of the Size of the Alloreactive NK Cell Repertoire: Studies in Individuals Homozygous for the Group A KIR Haplotype Cyril Fauriat, Sandra Andersson, ANDREAS T BJÖRKLUND, Mattias Carlsten, Marie Schaffer, Niklas K. Björkström, Bettina C. Baumann, Jakob Michaélsson, Hans- Gustaf Ljunggren, and Karl-Johan Malmberg The Journal of Immunology, 2008, 181: 6010–6019
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Integrative Profiling of Natural Killer Cell Repertoires Reveal a Role for Less Differentiated NK cells in Protection from Leukemia Relapse ANDREAS T BJÖRKLUND, Trevor Clancy, Jodie Goodridge, Vivien Beziat, Marie Schaffer, Eivind Hovig, Hans-Gustaf Ljunggren, Per Ljungman, Karl- Johan Malmberg [Manuscript]
Institution: Karolinska Institutet
Supervisor: Ljungman, Per
Issue date: 2014-08-29
Rights:
Publication year: 2014
ISBN: 978-91-7549-631-3
Statistics
Total Visits
Views | |
---|---|
Immune ...(legacy) | 1027 |
Immune ... | 199 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Immune ... | 0 | 0 | 0 | 0 | 2 | 2 | 4 |
File Visits
Views | |
---|---|
Thesis_Andreas_Björklund.pdf | 470 |
Thesis_Andreas_Björklund.pdf(legacy) | 446 |
Top country views
Views | |
---|---|
United States | 314 |
China | 219 |
Sweden | 158 |
Germany | 105 |
South Korea | 45 |
Russia | 18 |
France | 15 |
Switzerland | 12 |
United Kingdom | 11 |
India | 11 |
Top cities views
Views | |
---|---|
Shenzhen | 90 |
Sunnyvale | 59 |
Ashburn | 49 |
Stockholm | 47 |
Seoul | 40 |
Kiez | 39 |
Beijing | 33 |
Dublin | 14 |
Göteborg | 11 |
Geneva | 8 |