Chronic rejection models for vascularized composite tissue allotransplantation
Abstract Vascularized composite tissue allotransplantation (VCA) has transformed patients’ lives by enabling limb, face, abdominal wall, and penile transplants. Despite advancements in screening and immunosuppression, chronic rejection continues to limit the success of VCA. Lack of reliable preclini...
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Nature Portfolio
2025-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-01803-8 |
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| author | Daniel T. Fisher Emily Mackey Eugene Kononov Paul N. Bogner Umesh Sharma Han Yu Curtis L. Cetrulo Mukund Seshadri Pawel Kalinski Joseph J. Skitzki Elizabeth A. Repasky Minhyung Kim |
| author_facet | Daniel T. Fisher Emily Mackey Eugene Kononov Paul N. Bogner Umesh Sharma Han Yu Curtis L. Cetrulo Mukund Seshadri Pawel Kalinski Joseph J. Skitzki Elizabeth A. Repasky Minhyung Kim |
| author_sort | Daniel T. Fisher |
| collection | DOAJ |
| description | Abstract Vascularized composite tissue allotransplantation (VCA) has transformed patients’ lives by enabling limb, face, abdominal wall, and penile transplants. Despite advancements in screening and immunosuppression, chronic rejection continues to limit the success of VCA. Lack of reliable preclinical models exacerbates this challenge. Here, we report on new mouse models of chronic rejection following heterotopic hind limb VCA. We employed different levels of MHC mismatch using CD8 knockout C57BL/6 mice as recipients along with BALB/c or B6 H2-Ab1bm12 mice as donors. Transient CD4 T cell depletion was induced to allow graft maturation. Evaluation included gross findings, changes in immune status changes, production of donor-specific antibodies (DSA), C4d levels, and histopathological alterations. Two chronic rejection models displayed common features of clinical chronic graft rejection, such as skin stricture, hair loss, adnexal atrophy, extensive fibrosis and mast cell infiltration without widespread necrotic changes common in acute rejection. Similar to chronic rejection patients, large populations of activated B and plasma cells were detected in the recipient’s immune system as well as increased DSA and C4d production. Collectively, our models closely replicate the immunological and histopathological aspects of chronic graft rejection post-VCA, and could provide a new platform for evaluation of novel therapeutic interventions prior to clinical evaluation. |
| format | Article |
| id | doaj-art-9efdd05509fd4471b71f3b655fb1ddb6 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-9efdd05509fd4471b71f3b655fb1ddb62025-08-20T01:51:38ZengNature PortfolioScientific Reports2045-23222025-05-0115111610.1038/s41598-025-01803-8Chronic rejection models for vascularized composite tissue allotransplantationDaniel T. Fisher0Emily Mackey1Eugene Kononov2Paul N. Bogner3Umesh Sharma4Han Yu5Curtis L. Cetrulo6Mukund Seshadri7Pawel Kalinski8Joseph J. Skitzki9Elizabeth A. Repasky10Minhyung Kim11Department of Immunology, Roswell Park Comprehensive Cancer CenterComparative Oncology Shared Resource, Roswell Park Comprehensive Cancer CenterDepartment of Immunology, Roswell Park Comprehensive Cancer CenterDepartment of Pathology, Roswell Park Comprehensive Cancer CenterDepartment of Medicine, Division of Cardiology, University at BuffaloDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterDepartment of Surgery, Division of Plastic Surgery, Cedars-Sinai Medical CenterDepartment of Oral Oncology, Roswell Park Comprehensive Cancer CenterDepartment of Immunology, Roswell Park Comprehensive Cancer CenterDepartment of General Surgery, Cleveland ClinicDepartment of Immunology, Roswell Park Comprehensive Cancer CenterDepartment of Immunology, Roswell Park Comprehensive Cancer CenterAbstract Vascularized composite tissue allotransplantation (VCA) has transformed patients’ lives by enabling limb, face, abdominal wall, and penile transplants. Despite advancements in screening and immunosuppression, chronic rejection continues to limit the success of VCA. Lack of reliable preclinical models exacerbates this challenge. Here, we report on new mouse models of chronic rejection following heterotopic hind limb VCA. We employed different levels of MHC mismatch using CD8 knockout C57BL/6 mice as recipients along with BALB/c or B6 H2-Ab1bm12 mice as donors. Transient CD4 T cell depletion was induced to allow graft maturation. Evaluation included gross findings, changes in immune status changes, production of donor-specific antibodies (DSA), C4d levels, and histopathological alterations. Two chronic rejection models displayed common features of clinical chronic graft rejection, such as skin stricture, hair loss, adnexal atrophy, extensive fibrosis and mast cell infiltration without widespread necrotic changes common in acute rejection. Similar to chronic rejection patients, large populations of activated B and plasma cells were detected in the recipient’s immune system as well as increased DSA and C4d production. Collectively, our models closely replicate the immunological and histopathological aspects of chronic graft rejection post-VCA, and could provide a new platform for evaluation of novel therapeutic interventions prior to clinical evaluation.https://doi.org/10.1038/s41598-025-01803-8 |
| spellingShingle | Daniel T. Fisher Emily Mackey Eugene Kononov Paul N. Bogner Umesh Sharma Han Yu Curtis L. Cetrulo Mukund Seshadri Pawel Kalinski Joseph J. Skitzki Elizabeth A. Repasky Minhyung Kim Chronic rejection models for vascularized composite tissue allotransplantation Scientific Reports |
| title | Chronic rejection models for vascularized composite tissue allotransplantation |
| title_full | Chronic rejection models for vascularized composite tissue allotransplantation |
| title_fullStr | Chronic rejection models for vascularized composite tissue allotransplantation |
| title_full_unstemmed | Chronic rejection models for vascularized composite tissue allotransplantation |
| title_short | Chronic rejection models for vascularized composite tissue allotransplantation |
| title_sort | chronic rejection models for vascularized composite tissue allotransplantation |
| url | https://doi.org/10.1038/s41598-025-01803-8 |
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