Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantation
ObjectiveT cell-mediated rejection (TCMR) remains a significant challenge in organ transplantation. This study aimed to define a TCMR-associated cytokine gene set and identify drugs to prevent TCMR through drug repurposing.MethodsGene expression profiles from kidney, heart, and lung transplant biops...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1539645/full |
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| author | Lu Hu Lu Hu Xiaohan Zhang Xiaohan Zhang Weiqi Zhang Weiqi Zhang Shuai Jin Shuai Jin Jie Zhao Jianming Zheng Wenli Song Zhongyang Shen Zhongyang Shen Zhongyang Shen |
| author_facet | Lu Hu Lu Hu Xiaohan Zhang Xiaohan Zhang Weiqi Zhang Weiqi Zhang Shuai Jin Shuai Jin Jie Zhao Jianming Zheng Wenli Song Zhongyang Shen Zhongyang Shen Zhongyang Shen |
| author_sort | Lu Hu |
| collection | DOAJ |
| description | ObjectiveT cell-mediated rejection (TCMR) remains a significant challenge in organ transplantation. This study aimed to define a TCMR-associated cytokine gene set and identify drugs to prevent TCMR through drug repurposing.MethodsGene expression profiles from kidney, heart, and lung transplant biopsies were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between TCMR and non-TCMR groups were identified, and their intersection with cytokine-related genes yielded an 11-gene TCMR-associated cytokine gene set (TCMR-Cs). To evaluate the effectiveness of this gene set, a diagnostic predictive model was constructed using Lasso regression and multivariate logistic regression, with validation in independent datasets. Connectivity Map (CMap) analysis was employed to screen drugs targeting TCMR-Cs. Experimental validation of the identified drug was performed in vitro using T cell activation and Th1 differentiation assays, and in vivo in a mouse skin transplant model with survival analysis.ResultsThe TCMR-Cs exhibited outstanding predictive performance for TCMR, achieving an AUC of 0.99 in the training cohorts and maintaining strong performance in the test cohorts. CMap analysis identified peroxisome proliferator-activated receptor gamma (PPARγ) agonists as potential therapeutic candidates. Experimental validation showed that the PPARγ agonist rosiglitazone significantly suppressed T cell activation and reduced Th1 differentiation in vitro without cytotoxic effects. The combination of rosiglitazone and rapamycin significantly prolonged graft survival.ConclusionsThis study defined a novel TCMR-associated cytokine gene set that effectively predicts TCMR and identified PPARγ agonists, which prevent TCMR and improve graft survival when combined with rapamycin. |
| format | Article |
| id | doaj-art-992fbbcaa3b349648efc4df7b3676ae0 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-992fbbcaa3b349648efc4df7b3676ae02025-01-22T07:15:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011610.3389/fimmu.2025.15396451539645Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantationLu Hu0Lu Hu1Xiaohan Zhang2Xiaohan Zhang3Weiqi Zhang4Weiqi Zhang5Shuai Jin6Shuai Jin7Jie Zhao8Jianming Zheng9Wenli Song10Zhongyang Shen11Zhongyang Shen12Zhongyang Shen13The First Central Clinical School, Tianjin Medical University, Tianjin, ChinaResearch Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, ChinaResearch Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, ChinaSchool of Medicine, Nankai University, Tianjin, ChinaResearch Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, ChinaSchool of Medicine, Nankai University, Tianjin, ChinaThe First Central Clinical School, Tianjin Medical University, Tianjin, ChinaResearch Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, ChinaDepartment of Renal Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, ChinaDepartment of Renal Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, ChinaDepartment of Renal Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, ChinaResearch Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, ChinaNHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, ChinaKey Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, ChinaObjectiveT cell-mediated rejection (TCMR) remains a significant challenge in organ transplantation. This study aimed to define a TCMR-associated cytokine gene set and identify drugs to prevent TCMR through drug repurposing.MethodsGene expression profiles from kidney, heart, and lung transplant biopsies were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between TCMR and non-TCMR groups were identified, and their intersection with cytokine-related genes yielded an 11-gene TCMR-associated cytokine gene set (TCMR-Cs). To evaluate the effectiveness of this gene set, a diagnostic predictive model was constructed using Lasso regression and multivariate logistic regression, with validation in independent datasets. Connectivity Map (CMap) analysis was employed to screen drugs targeting TCMR-Cs. Experimental validation of the identified drug was performed in vitro using T cell activation and Th1 differentiation assays, and in vivo in a mouse skin transplant model with survival analysis.ResultsThe TCMR-Cs exhibited outstanding predictive performance for TCMR, achieving an AUC of 0.99 in the training cohorts and maintaining strong performance in the test cohorts. CMap analysis identified peroxisome proliferator-activated receptor gamma (PPARγ) agonists as potential therapeutic candidates. Experimental validation showed that the PPARγ agonist rosiglitazone significantly suppressed T cell activation and reduced Th1 differentiation in vitro without cytotoxic effects. The combination of rosiglitazone and rapamycin significantly prolonged graft survival.ConclusionsThis study defined a novel TCMR-associated cytokine gene set that effectively predicts TCMR and identified PPARγ agonists, which prevent TCMR and improve graft survival when combined with rapamycin.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1539645/fullT-cell-mediated rejectionorgan transplantationcytokine genespredictive modeldrug repurposingPPARγ agonists |
| spellingShingle | Lu Hu Lu Hu Xiaohan Zhang Xiaohan Zhang Weiqi Zhang Weiqi Zhang Shuai Jin Shuai Jin Jie Zhao Jianming Zheng Wenli Song Zhongyang Shen Zhongyang Shen Zhongyang Shen Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantation Frontiers in Immunology T-cell-mediated rejection organ transplantation cytokine genes predictive model drug repurposing PPARγ agonists |
| title | Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantation |
| title_full | Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantation |
| title_fullStr | Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantation |
| title_full_unstemmed | Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantation |
| title_short | Targeting TCMR-associated cytokine genes for drug screening identifies PPARγ agonists as novel immunomodulatory agents in transplantation |
| title_sort | targeting tcmr associated cytokine genes for drug screening identifies pparγ agonists as novel immunomodulatory agents in transplantation |
| topic | T-cell-mediated rejection organ transplantation cytokine genes predictive model drug repurposing PPARγ agonists |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1539645/full |
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