Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory Cells
<b>Background/Objectives</b>: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and mali...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/13/7/1757 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849407480511070208 |
|---|---|
| author | Alvin Man Lung Chan Rajalingham Sakthiswary Yogeswaran Lokanathan |
| author_facet | Alvin Man Lung Chan Rajalingham Sakthiswary Yogeswaran Lokanathan |
| author_sort | Alvin Man Lung Chan |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). <b>Methods:</b> A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. <b>Results:</b> CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. <b>Conclusions:</b> CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials. |
| format | Article |
| id | doaj-art-e893d60843a545e0921093ba4d8e794a |
| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj-art-e893d60843a545e0921093ba4d8e794a2025-08-20T03:36:03ZengMDPI AGBiomedicines2227-90592025-07-01137175710.3390/biomedicines13071757Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory CellsAlvin Man Lung Chan0Rajalingham Sakthiswary1Yogeswaran Lokanathan2My CytoHealth Sdn. Bhd, 5th Floor, Plaza Hamodal, Lot No. 15, Jalan 13/2, Section 13, Petaling Jaya 46200, Selangor, MalaysiaDepartment of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, MalaysiaDepartment of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia<b>Background/Objectives</b>: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). <b>Methods:</b> A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. <b>Results:</b> CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. <b>Conclusions:</b> CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials.https://www.mdpi.com/2227-9059/13/7/1757chimeric antigen receptorT regulatory cellsimmunosuppressive therapysolid organ transplantallograft |
| spellingShingle | Alvin Man Lung Chan Rajalingham Sakthiswary Yogeswaran Lokanathan Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory Cells Biomedicines chimeric antigen receptor T regulatory cells immunosuppressive therapy solid organ transplant allograft |
| title | Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory Cells |
| title_full | Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory Cells |
| title_fullStr | Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory Cells |
| title_full_unstemmed | Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory Cells |
| title_short | Revolutionizing Allogeneic Graft Tolerance Through Chimeric Antigen Receptor-T Regulatory Cells |
| title_sort | revolutionizing allogeneic graft tolerance through chimeric antigen receptor t regulatory cells |
| topic | chimeric antigen receptor T regulatory cells immunosuppressive therapy solid organ transplant allograft |
| url | https://www.mdpi.com/2227-9059/13/7/1757 |
| work_keys_str_mv | AT alvinmanlungchan revolutionizingallogeneicgrafttolerancethroughchimericantigenreceptortregulatorycells AT rajalinghamsakthiswary revolutionizingallogeneicgrafttolerancethroughchimericantigenreceptortregulatorycells AT yogeswaranlokanathan revolutionizingallogeneicgrafttolerancethroughchimericantigenreceptortregulatorycells |