Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells
Summary: Graft-versus-host disease (GVHD) remains a serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). While post-transplant administration of cyclophosphamide (PTCy) is increasingly used as GVHD prophylaxis, its precise mechanisms of action and its impact on graft-versu...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223001621 |
| _version_ | 1811166115737370624 |
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| author | Caroline Ritacco Murat Cem Köse Justine Courtois Lorenzo Canti Charline Beguin Sophie Dubois Benoît Vandenhove Sophie Servais Jo Caers Yves Beguin Grégory Ehx Frédéric Baron |
| author_facet | Caroline Ritacco Murat Cem Köse Justine Courtois Lorenzo Canti Charline Beguin Sophie Dubois Benoît Vandenhove Sophie Servais Jo Caers Yves Beguin Grégory Ehx Frédéric Baron |
| author_sort | Caroline Ritacco |
| collection | DOAJ |
| description | Summary: Graft-versus-host disease (GVHD) remains a serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). While post-transplant administration of cyclophosphamide (PTCy) is increasingly used as GVHD prophylaxis, its precise mechanisms of action and its impact on graft-versus-leukemia effects have remained debated. Here, we studied the mechanisms of xenogeneic GVHD (xGVHD) prevention by PTCy in different humanized mouse models. We observed that PTCy attenuated xGVHD. Using flow cytometry and single-cell RNA-sequencing, we demonstrated that PTCy depleted proliferative CD8+ and conventional CD4+ T cells but also proliferative regulatory T cells (Treg). Further, T-cell receptor β variable region sequencing (TCRVB) analyses demonstrated that highly xenoreactive T-cell clones were depleted by PTCy. Although Treg frequencies were significantly higher in PTCy-treated than in control mice on day 21, xGVHD attenuation by PTCy was not abrogated by Treg depletion. Finally, we observed that PTCy did not abrogate graft-versus-leukemia effects. |
| first_indexed | 2024-04-10T15:47:18Z |
| format | Article |
| id | doaj.art-464d71e83f13405492f07b9d3cfb0e29 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-10T15:47:18Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-464d71e83f13405492f07b9d3cfb0e292023-02-12T04:15:29ZengElsevieriScience2589-00422023-03-01263106085Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cellsCaroline Ritacco0Murat Cem Köse1Justine Courtois2Lorenzo Canti3Charline Beguin4Sophie Dubois5Benoît Vandenhove6Sophie Servais7Jo Caers8Yves Beguin9Grégory Ehx10Frédéric Baron11Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium; Department of Medicine, Division of Hematology, CHU of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium; Department of Medicine, Division of Hematology, CHU of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium; Department of Medicine, Division of Hematology, CHU of Liège, Liège 4000, BelgiumHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium; Corresponding authorHematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium; Department of Medicine, Division of Hematology, CHU of Liège, Liège 4000, Belgium; Corresponding authorSummary: Graft-versus-host disease (GVHD) remains a serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). While post-transplant administration of cyclophosphamide (PTCy) is increasingly used as GVHD prophylaxis, its precise mechanisms of action and its impact on graft-versus-leukemia effects have remained debated. Here, we studied the mechanisms of xenogeneic GVHD (xGVHD) prevention by PTCy in different humanized mouse models. We observed that PTCy attenuated xGVHD. Using flow cytometry and single-cell RNA-sequencing, we demonstrated that PTCy depleted proliferative CD8+ and conventional CD4+ T cells but also proliferative regulatory T cells (Treg). Further, T-cell receptor β variable region sequencing (TCRVB) analyses demonstrated that highly xenoreactive T-cell clones were depleted by PTCy. Although Treg frequencies were significantly higher in PTCy-treated than in control mice on day 21, xGVHD attenuation by PTCy was not abrogated by Treg depletion. Finally, we observed that PTCy did not abrogate graft-versus-leukemia effects.http://www.sciencedirect.com/science/article/pii/S2589004223001621MedicineMolecular biologyImmunology |
| spellingShingle | Caroline Ritacco Murat Cem Köse Justine Courtois Lorenzo Canti Charline Beguin Sophie Dubois Benoît Vandenhove Sophie Servais Jo Caers Yves Beguin Grégory Ehx Frédéric Baron Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells iScience Medicine Molecular biology Immunology |
| title | Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells |
| title_full | Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells |
| title_fullStr | Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells |
| title_full_unstemmed | Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells |
| title_short | Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells |
| title_sort | post transplant cyclophosphamide prevents xenogeneic graft versus host disease while depleting proliferating regulatory t cells |
| topic | Medicine Molecular biology Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223001621 |
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