Cargando…

Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion

Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance b...

Descripción completa

Detalles Bibliográficos
Autores principales: Koster, Eva A. S., Bonneville, Edouard F., Borne, Peter A. von dem, van Balen, Peter, Marijt, Erik W. A., Tjon, Jennifer M. L., Snijders, Tjeerd J. F., van Lammeren, Daniëlle, Veelken, Hendrik, Putter, Hein, Falkenburg, J. H. Frederik, Halkes, Constantijn J. M., de Wreede, Liesbeth C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427852/
https://www.ncbi.nlm.nih.gov/pubmed/37593737
http://dx.doi.org/10.3389/fimmu.2023.1208814
_version_ 1785090334675435520
author Koster, Eva A. S.
Bonneville, Edouard F.
Borne, Peter A. von dem
van Balen, Peter
Marijt, Erik W. A.
Tjon, Jennifer M. L.
Snijders, Tjeerd J. F.
van Lammeren, Daniëlle
Veelken, Hendrik
Putter, Hein
Falkenburg, J. H. Frederik
Halkes, Constantijn J. M.
de Wreede, Liesbeth C.
author_facet Koster, Eva A. S.
Bonneville, Edouard F.
Borne, Peter A. von dem
van Balen, Peter
Marijt, Erik W. A.
Tjon, Jennifer M. L.
Snijders, Tjeerd J. F.
van Lammeren, Daniëlle
Veelken, Hendrik
Putter, Hein
Falkenburg, J. H. Frederik
Halkes, Constantijn J. M.
de Wreede, Liesbeth C.
author_sort Koster, Eva A. S.
collection PubMed
description Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance between GvL and GvHD can be shifted by removing T-cells via T-cell depletion (TCD) to reduce the risk of GvHD, and by introducing additional donor T-cells (donor lymphocyte infusions [DLI]) to boost the GvL effect. However, the association between T-cell kinetics and the occurrence of allo-immunological events has not been clearly demonstrated yet. Therefore, we investigated the complex associations between the T-cell kinetics and alloimmune responses in a cohort of 166 acute leukemia patients receiving alemtuzumab-based TCD alloSCT. Of these patients, 62 with an anticipated high risk of relapse were scheduled to receive a prophylactic DLI at 3 months after transplant. In this setting, we applied joint modelling which allowed us to better capture the complex interplay between DLI, T-cell kinetics, GvHD and relapse than traditional statistical methods. We demonstrate that DLI can induce detectable T-cell expansion, leading to an increase in total, CD4+ and CD8+ T-cell counts starting at 3 months after alloSCT. CD4+ T-cells showed the strongest association with the development of alloimmune responses: higher CD4 counts increased the risk of GvHD (hazard ratio 2.44, 95% confidence interval 1.45-4.12) and decreased the risk of relapse (hazard ratio 0.65, 95% confidence interval 0.45-0.92). Similar models showed that natural killer cells recovered rapidly after alloSCT and were associated with a lower risk of relapse (HR 0.62, 95%-CI 0.41-0.93). The results of this study advocate the use of joint models to further study immune cell kinetics in different settings.
format Online
Article
Text
id pubmed-10427852
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-104278522023-08-17 Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion Koster, Eva A. S. Bonneville, Edouard F. Borne, Peter A. von dem van Balen, Peter Marijt, Erik W. A. Tjon, Jennifer M. L. Snijders, Tjeerd J. F. van Lammeren, Daniëlle Veelken, Hendrik Putter, Hein Falkenburg, J. H. Frederik Halkes, Constantijn J. M. de Wreede, Liesbeth C. Front Immunol Immunology Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance between GvL and GvHD can be shifted by removing T-cells via T-cell depletion (TCD) to reduce the risk of GvHD, and by introducing additional donor T-cells (donor lymphocyte infusions [DLI]) to boost the GvL effect. However, the association between T-cell kinetics and the occurrence of allo-immunological events has not been clearly demonstrated yet. Therefore, we investigated the complex associations between the T-cell kinetics and alloimmune responses in a cohort of 166 acute leukemia patients receiving alemtuzumab-based TCD alloSCT. Of these patients, 62 with an anticipated high risk of relapse were scheduled to receive a prophylactic DLI at 3 months after transplant. In this setting, we applied joint modelling which allowed us to better capture the complex interplay between DLI, T-cell kinetics, GvHD and relapse than traditional statistical methods. We demonstrate that DLI can induce detectable T-cell expansion, leading to an increase in total, CD4+ and CD8+ T-cell counts starting at 3 months after alloSCT. CD4+ T-cells showed the strongest association with the development of alloimmune responses: higher CD4 counts increased the risk of GvHD (hazard ratio 2.44, 95% confidence interval 1.45-4.12) and decreased the risk of relapse (hazard ratio 0.65, 95% confidence interval 0.45-0.92). Similar models showed that natural killer cells recovered rapidly after alloSCT and were associated with a lower risk of relapse (HR 0.62, 95%-CI 0.41-0.93). The results of this study advocate the use of joint models to further study immune cell kinetics in different settings. Frontiers Media S.A. 2023-08-01 /pmc/articles/PMC10427852/ /pubmed/37593737 http://dx.doi.org/10.3389/fimmu.2023.1208814 Text en Copyright © 2023 Koster, Bonneville, Borne, van Balen, Marijt, Tjon, Snijders, van Lammeren, Veelken, Putter, Falkenburg, Halkes and de Wreede https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Koster, Eva A. S.
Bonneville, Edouard F.
Borne, Peter A. von dem
van Balen, Peter
Marijt, Erik W. A.
Tjon, Jennifer M. L.
Snijders, Tjeerd J. F.
van Lammeren, Daniëlle
Veelken, Hendrik
Putter, Hein
Falkenburg, J. H. Frederik
Halkes, Constantijn J. M.
de Wreede, Liesbeth C.
Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion
title Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion
title_full Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion
title_fullStr Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion
title_full_unstemmed Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion
title_short Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion
title_sort joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427852/
https://www.ncbi.nlm.nih.gov/pubmed/37593737
http://dx.doi.org/10.3389/fimmu.2023.1208814
work_keys_str_mv AT kosterevaas jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT bonnevilleedouardf jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT bornepeteravondem jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT vanbalenpeter jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT marijterikwa jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT tjonjenniferml jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT snijderstjeerdjf jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT vanlammerendanielle jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT veelkenhendrik jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT putterhein jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT falkenburgjhfrederik jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT halkesconstantijnjm jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion
AT dewreedeliesbethc jointmodelsquantifyassociationsbetweenimmunecellkineticsandalloimmunologicaleventsafterallogeneicstemcelltransplantationandsubsequentdonorlymphocyteinfusion