Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanized mouse model
| Autor: | Katrina M. Bird, Sam R. Adhikary, Leigh Nicholson, Ronald Sluyter, Peter Cuthbertson, Chloe Sligar, Philip J. O'Connell, Stephen I. Alexander, Min Hu, Debbie Watson |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
CD3 Immunology Graft vs Host Disease Mice SCID T-Lymphocytes Regulatory Peripheral blood mononuclear cell Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Mice Inbred NOD Animals Humans Transplantation Homologous Immunology and Allergy Medicine Cyclophosphamide Cells Cultured biology business.industry Hematopoietic Stem Cell Transplantation Carboxyfluorescein succinimidyl ester Original Articles medicine.disease Tissue Donors Transplantation Disease Models Animal Haematopoiesis surgical procedures operative 030104 developmental biology Graft-versus-host disease chemistry Humanized mouse Leukocytes Mononuclear biology.protein Female Stem cell business 030215 immunology |
| Zdroj: | Immunology |
| ISSN: | 1365-2567 0019-2805 |
| Popis: | Graft‐versus‐host disease (GVHD) is a major complication of allogeneic haematopoietic stem cell transplantation (allo‐HSCT) that develops when donor T cells in the graft become reactive against the host. Post‐transplant cyclophosphamide (PTCy) is increasingly used in mismatched allo‐HSCT, but how PTCy impacts donor T cells and reduces GVHD is unclear. This study aimed to determine the effect of PTCy on reactive human donor T cells and GVHD development in a preclinical humanized mouse model. Immunodeficient NOD‐scid‐IL2Rγ(null) mice were injected intraperitoneally (i.p.) with 20 × 10(6) human peripheral blood mononuclear cells stained with carboxyfluorescein succinimidyl ester (CFSE) (day 0). Mice were subsequently injected (i.p.) with PTCy (33 mg kg(−1)) (PTCy‐mice) or saline (saline‐mice) (days 3 and 4). Mice were assessed for T‐cell depletion on day 6 and monitored for GVHD for up to 10 weeks. Flow cytometric analysis of livers at day 6 revealed lower proportions of reactive (CFSE(low)) human (h) CD3(+) T cells in PTCy‐mice compared with saline‐mice. Over 10 weeks, PTCy‐mice showed reduced weight loss and clinical GVHD, with prolonged survival and reduced histological liver GVHD compared with saline‐mice. PTCy‐mice also demonstrated increased splenic hCD4(+):hCD8(+) T‐cell ratios and reduced splenic Tregs (hCD4(+) hCD25(+) hCD127(lo)) compared with saline‐mice. This study demonstrates that PTCy reduces GVHD in a preclinical humanized mouse model. This corresponded to depletion of reactive human donor T cells, but fewer human Tregs. |
| Databáze: | OpenAIRE |
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