Permissive immunosuppression facilitates the expansion of ex vivo administered regulatory T cells in the lung allograft
Abstract In lung transplantation (LT), alloreactive T cell priming begins in the graft, a process that can be inhibited by seeding the graft with recipient-derived expanded polyclonal regulatory T cells (Tregs) using ex vivo lung perfusion (EVLP) prior to transplantation. However, this therapy alone...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-06835-8 |
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| author | Akihiro Takahagi Ei Miyamoto Christina Lam Mingyao Liu Betty Joe Xiaomin Wang David Hwang Tereza Martinu Marcelo Cypel Shaf Keshavjee Stephen Juvet |
| author_facet | Akihiro Takahagi Ei Miyamoto Christina Lam Mingyao Liu Betty Joe Xiaomin Wang David Hwang Tereza Martinu Marcelo Cypel Shaf Keshavjee Stephen Juvet |
| author_sort | Akihiro Takahagi |
| collection | DOAJ |
| description | Abstract In lung transplantation (LT), alloreactive T cell priming begins in the graft, a process that can be inhibited by seeding the graft with recipient-derived expanded polyclonal regulatory T cells (Tregs) using ex vivo lung perfusion (EVLP) prior to transplantation. However, this therapy alone cannot attenuate acute rejection in non-immunosuppressed animals. Interleukin 2 (IL-2)-anti-IL-2 antibody complexes (IL-2 C) promote Treg expansion in vivo with concomitant tacrolimus (Tac) administration. We combined IL-2 C and Tac with pre-transplant Treg administration during EVLP in a Fischer 344 to Wistar Kyoto rat LT model, to test the hypothesis that this strategy would facilitate intragraft Treg expansion and function. Recipients were given no treatment, Tac alone, IL-2 C/Tac alone, Treg alone, or Treg/IL-2 C/Tac. After 7 days, graft CD25highFoxp3+ content increased as a result of Treg therapy, and cellular rejection was attenuated in the IL-2 C/Tac and Treg/IL-2 C/Tac groups. Graft Treg content and Treg-to-effector T cell ratio (Treg/Teff) at day 7 was highest in animals receiving Treg/IL-2 C/Tac, which has important implications for long-term immunomodulation. Our data suggest that pre-transplant administration of graft-directed Treg cell therapy combined with Treg-permissive immunosuppression may be a viable therapeutic approach to modulate rejection in LT. |
| format | Article |
| id | doaj-art-0e47f1b9b6f54342802ee7a2aaa8ed92 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-0e47f1b9b6f54342802ee7a2aaa8ed922025-08-20T03:38:16ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-06835-8Permissive immunosuppression facilitates the expansion of ex vivo administered regulatory T cells in the lung allograftAkihiro Takahagi0Ei Miyamoto1Christina Lam2Mingyao Liu3Betty Joe4Xiaomin Wang5David Hwang6Tereza Martinu7Marcelo Cypel8Shaf Keshavjee9Stephen Juvet10Latner Thoracic Research Laboratories, Toronto General Hospital Research InstituteLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteDepartment of Laboratory Medicine and Pathobiology, Sunnybrook Health Sciences CentreLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteLatner Thoracic Research Laboratories, Toronto General Hospital Research InstituteAbstract In lung transplantation (LT), alloreactive T cell priming begins in the graft, a process that can be inhibited by seeding the graft with recipient-derived expanded polyclonal regulatory T cells (Tregs) using ex vivo lung perfusion (EVLP) prior to transplantation. However, this therapy alone cannot attenuate acute rejection in non-immunosuppressed animals. Interleukin 2 (IL-2)-anti-IL-2 antibody complexes (IL-2 C) promote Treg expansion in vivo with concomitant tacrolimus (Tac) administration. We combined IL-2 C and Tac with pre-transplant Treg administration during EVLP in a Fischer 344 to Wistar Kyoto rat LT model, to test the hypothesis that this strategy would facilitate intragraft Treg expansion and function. Recipients were given no treatment, Tac alone, IL-2 C/Tac alone, Treg alone, or Treg/IL-2 C/Tac. After 7 days, graft CD25highFoxp3+ content increased as a result of Treg therapy, and cellular rejection was attenuated in the IL-2 C/Tac and Treg/IL-2 C/Tac groups. Graft Treg content and Treg-to-effector T cell ratio (Treg/Teff) at day 7 was highest in animals receiving Treg/IL-2 C/Tac, which has important implications for long-term immunomodulation. Our data suggest that pre-transplant administration of graft-directed Treg cell therapy combined with Treg-permissive immunosuppression may be a viable therapeutic approach to modulate rejection in LT.https://doi.org/10.1038/s41598-025-06835-8 |
| spellingShingle | Akihiro Takahagi Ei Miyamoto Christina Lam Mingyao Liu Betty Joe Xiaomin Wang David Hwang Tereza Martinu Marcelo Cypel Shaf Keshavjee Stephen Juvet Permissive immunosuppression facilitates the expansion of ex vivo administered regulatory T cells in the lung allograft Scientific Reports |
| title | Permissive immunosuppression facilitates the expansion of ex vivo administered regulatory T cells in the lung allograft |
| title_full | Permissive immunosuppression facilitates the expansion of ex vivo administered regulatory T cells in the lung allograft |
| title_fullStr | Permissive immunosuppression facilitates the expansion of ex vivo administered regulatory T cells in the lung allograft |
| title_full_unstemmed | Permissive immunosuppression facilitates the expansion of ex vivo administered regulatory T cells in the lung allograft |
| title_short | Permissive immunosuppression facilitates the expansion of ex vivo administered regulatory T cells in the lung allograft |
| title_sort | permissive immunosuppression facilitates the expansion of ex vivo administered regulatory t cells in the lung allograft |
| url | https://doi.org/10.1038/s41598-025-06835-8 |
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