| 1. |
- Remberger, Mats, et al.
(författare)
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Improved survival after allogeneic hematopoietic stem cell transplantation in recent years : A single-center study
- 2011
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 17:11, s. 1688-1697
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
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| 2. |
- Beziat, Vivien, et al.
(författare)
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NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:14, s. 2678-2688
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Tidskriftsartikel (refereegranskat)abstract
- Human natural killer (NK) cells are functionally regulated by killer cell immunoglobulin-like receptors (KIRs) and their interactions with HLA class I molecules. As KIR expression in a given NK cell is genetically hard-wired, we hypothesized that KIR repertoire perturbations reflect expansions of unique NK-cell subsets and may be used to trace adaptation of the NK-cell compartment to virus infections. By determining the human KIR-ome at a single-cell level in more than 200 donors, we were able to analyze the magnitude of NK cell adaptation to virus infections in healthy individuals. Strikingly, infection with human cytomegalovirus (CMV), but not with other common herpesviruses, induced expansion and differentiation of KIR-expressing NK cells, visible as stable imprints in the repertoire. Education by inhibitory KIRs promoted the clonal-like expansion of NK cells, causing a bias for self-specific inhibitory KIRs. Furthermore, our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human NK cells. These results provide new insight into the diversity of KIR repertoire and its adaptation to virus infection, suggesting a role for both activating and inhibitory KIRs in immunity to CMV infection.
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| 3. |
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| 4. |
- Enqvist, Monika, et al.
(författare)
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Systemic and Intra-Nodal Activation of NK Cells After Rituximab Monotherapy for Follicular Lymphoma.
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Monotherapy with the anti-CD20 monoclonal antibody rituximab can induce complete responses (CR) in patients with follicular lymphoma (FL). Resting FcRγIII+ (CD16+) natural killer (NK) cells respond strongly to rituximab-coated target cells in vitro. Yet, the contribution of NK cells in the therapeutic effect in vivo remains unknown. Here, we followed the NK cell repertoire dynamics in the lymph node and systemically during rituximab monotherapy in patients with FL. At baseline, NK cells in the tumor lymph node had a naïve phenotype albeit they were more differentiated than NK cells derived from control tonsils as determined by the frequency of CD56dim NK cells and the expression of killer cell immunoglobulin-like receptors (KIR), CD57 and CD16. Rituximab therapy induced a rapid drop in NK cell numbers coinciding with a relative increase in the frequency of Ki67+ NK cells both in the lymph node and peripheral blood. The Ki67+ NK cells had slightly increased expression of CD16, CD57 and higher levels of granzyme A and perforin. The in vivo activation of NK cells was paralleled by a temporary loss of in vitro functionality, primarily manifested as decreased IFNγ production in response to rituximab-coated targets. However, patients with pre-existing NKG2C+ adaptive NK cell subsets showed less Ki67 upregulation and were refractory to the loss of functionality. These data reveal variable imprints of rituximab monotherapy on the NK cell repertoire, which may depend on pre-existing repertoire diversity.
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| 5. |
- Liu, Lisa L., et al.
(författare)
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Ex Vivo Expanded Adaptive NK Cells Effectively Kill Primary Acute Lymphoblastic Leukemia Cells
- 2017
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Ingår i: CANCER IMMUNOLOGY RESEARCH. - 2326-6066 .- 2326-6074. ; 5:8, s. 654-665
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Tidskriftsartikel (refereegranskat)abstract
- Manipulation of human natural killer (NK) cell repertoires promises more effective strategies for NK cell-based cancer immunotherapy. A subset of highly differentiated NK cells, termed adaptive NK cells, expands naturally in vivo in response to human cytomegalovirus (HCMV) infection, carries unique repertoires of inhibitory killer cell immunoglobulin-like receptors (KIR), and displays strong cytotoxicity against tumor cells. Here, we established a robust and scalable protocol for ex vivo generation and expansion of adaptive NK cells for cell therapy against pediatric acute lymphoblastic leukemia (ALL). Culture of polyclonal NK cells together with feeder cells expressing HLA-E, the ligand for the activating NKG2C receptor, led to selective expansion of adaptive NK cells with enhanced allor-eactivity against HLA-mismatched targets. The ex vivo expanded adaptive NK cells gradually obtained a more differentiated phenotype and were specific and highly efficient killers of allogeneic pediatric T-and precursor B-cell acute lymphoblastic leukemia (ALL) blasts, previously shown to be refractory to killing by autologous NK cells and the NK-cell line NK92 currently in clinical testing. Selective expansion of NK cells that express one single inhibitory KIR for self-HLA class I would allow exploitation of the full potential of NK-cell alloreactivity in cancer immunotherapy. In summary, our data suggest that adaptive NK cells may hold utility for therapy of refractory ALL, either as a bridge to transplant or for patients that lack stem cell donors.
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| 6. |
- Philippon, Camille, et al.
(författare)
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Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires
- 2023
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:16, s. 4492-4504
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Tidskriftsartikel (refereegranskat)abstract
- The functionality of natural killer (NK) cells is tuned during education and is associated with remodeling of the lysosomal compartment. We hypothesized that genetic variation in killer cell immunoglobulin-like receptor (KIR) and HLA, which is known to influence the functional strength of NK cells, fine-tunes the payload of effector molecules stored in secretory lysosomes. To address this possibility, we performed a high-resolution analysis of KIR and HLA class I genes in 365 blood donors and linked genotypes to granzyme B loading and functional phenotypes. We found that granzyme B levels varied across individuals but were stable over time in each individual and genetically determined by allelic variation in HLA class I genes. A broad mapping of surface receptors and lysosomal effector molecules revealed that DNAM-1 and granzyme B levels served as robust metric of the functional state in NK cells. Variation in granzyme B levels at rest was tightly linked to the lytic hit and downstream killing of major histocompatibility complex-deficient target cells. Together, these data provide insights into how variation in genetically hardwired receptor pairs tunes the releasable granzyme B pool in NK cells, resulting in predictable hierarchies in global NK cell function.
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| 7. |
- Schaffer, Marie
(författare)
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HLA and KIR gene polymorphism in hematopoietic stem cell transplantation
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The major histocompatibility complex (MHC) in humans known as the Human Leukocyte Antigens (HLA) is localised to the short arm of chromosome six. The HLA class 1 antigens, HLA-A, -B and -C are highly polymorphic glycoproteins expressed on the cell surface of most nucleated cells in the body. The HLA class 11 antigens HLA-DR, -DQ and -DIP are expressed on the cells of the immune system, mainly B-cells, macrophages, activated T-cells and dendritic cells. Processed foreign antigens and self-antigens are presented to T-cells by the class 1 and class 11 molecules. The class 1 molecules interact with CD8 molecules on T-cells and the class 11 molecules with CD4. Matching for HLA class 1 and class 11 alleles is known to be important for the clinical outcome of hematopoietic stem cell transplantation (HSCT). However, the exact level of matching required to minimize the risk for immunological complications when using an unrelated donor is still not known. Natural killer (NK) cells interact with MHC class 1 molecules on target cells. In humans, NK cells are negatively regulated by killer cell immunoglobulin-like receptors (KIR) recognizing HLA class 1 antigens. Transplantation across HLA barriers may trigger donor cell alloreactivity, which can influence the result of the treatment. Until recently serological typing has been the primary technique used for HLA class 1 analysis. It has been assumed that HLA class 1 serological typing was more accurate than serological HLA-DR typing. However, several studies have shown that serological HLA-A, -B typing is poorer than expected. The first paper describes a systematic investigation of the accuracy of class 1 serological typing in all the groups of patients and healthy individuals that are routinely typed at our laboratory. Class 1 typing using PCR-SSP was more accurate and also gave a higher resolution, especially when typing patients with hematological disorders. We have retrospectively performed allele level typing for HLA class 1 and class 11 in unrelated donor/recipient pairs and correlated the degree of matching to the clinical outcome. We found that patients that had a donor with, at the time of transplantation, an unknown HLA-B allele level mismatch had a very poor transplant outcome with severe graft versus host disease (GVHD) and a high mortality rate. In addition we found that pairs mismatched for HLA-C but matched for the KIR ligand epitope had increased survival and disease free survival. The role of matching for HLA-DPB1 and -DPA1 is still unclear and debated. We found inferior survival and increased transplantationrelated mortality (TRM) in patients with an HLA-DPA1 incompatible donor. Extending the study, analysing a larger patient cohort, we found that the results are in concordance with our previous findings and that incompatibility for HLA-DPA1 is associated with inferior survival, increased infection related mortality and TRM. We also further investigated the role of KIR ligand incompatibility in unrelated HSCT. A total of 190 patients with hematological malignancies, transplanted with an unrelated donor were included in the study. We observed that KIR ligand mismatch was associated with increased TRM. The increased TRM was due to a higher rate of infections. The KIR genes located on human chromosome 19 and the HLA genes on chromosome 6 segregate independently. Thus HLA identical siblings are not KIR identical. Two recent studies have shown an impact of KIRHLA mismatch in HLA-identical HSCT, where no missing-self recognition can be expected. In paper V we present our results, of these effects in a single centre setting. A total of 80 patients with myeloid malignancies transplanted with an HLA-identical sibling donor were investigated. HLA and KIR genotypes were determined for the donor-recipient sibling pairs. We investigated if the combination of donor-inhibitory KIR and recipient HLA-C type could influence transplant outcome. Missing KIR-ligand was found for 51 of the 80 patients (63.7%). Lack of HLA ligand for donor inhibitory KIR had no effect on transplant outcome regarding disease free survival, overall survival, relapse or GVHD. In conclusion, the use of genomic typing techniques for HLA class 1 and 11 and KIR genes results in improved typing quality giving the opportunity to obtain a more precise matching in transplantation. Using these techniques, we here show a negative influence of HLA-B, HLA-DPA1 and KIR-ligand incompatibilities in allogeneic hematopoietic stem cell transplantation.
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