Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance
Allostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (F...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1162439/full |
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| author | Quanyu Chen Quanyu Chen Zhiqing Yang Heng Lin Jiejuan Lai Deyu Hu Deyu Hu Min Yan Min Yan Zhifang Wu Wei Liu Zhehai Li Yu He Zhe Sun Ling Shuai Zhiping Peng Yangyang Wang Sijin Li Youhong Cui Hongyu Zhang Leida Zhang Lianhua Bai |
| author_facet | Quanyu Chen Quanyu Chen Zhiqing Yang Heng Lin Jiejuan Lai Deyu Hu Deyu Hu Min Yan Min Yan Zhifang Wu Wei Liu Zhehai Li Yu He Zhe Sun Ling Shuai Zhiping Peng Yangyang Wang Sijin Li Youhong Cui Hongyu Zhang Leida Zhang Lianhua Bai |
| author_sort | Quanyu Chen |
| collection | DOAJ |
| description | Allostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (FK506), the most commonly used immunosuppressant (IS) in the clinic, allows tolerance induction, its use is limited because its target immune cells are unknown and it is associated with increased incidences of malignancy, infection, and nephrotoxicity, which substantially impact long-term liver transplantation (LTx) outcomes. The dark agouti (DA)-to-Lewis rat LTx model is a well-known ARJ model and was hence chosen for the present study. We show that both hepatocyte growth factor (HGF) (cHGF, containing the main form of promoting HGF production) and recombinant HGF (h-rHGF) exert immunoregulatory effects mainly on allogeneic aCD8+ T cell suppression through FAS-mediated apoptotic pathways by inhibiting cMet to FAS antagonism and Fas trimerization, leading to acute tolerance induction. We also showed that such inhibition can be abrogated by treatment with neutralizing antibodies against cMet (HGF-only receptor). In contrast, we did not observe these effects in rats treated with FK506. However, we observed that the effect of anti-rejection by FK506 was mainly on allostimulated CD4+ T cell (aCD4+ T cell) suppression and regulatory T cell (Treg) promotion, in contrast to the mechanism of HGF. In addition, the protective mechanism of HGF in FK506-mediated nephrotoxicity was addressed. Therefore, HGF as a tolerance inducer, whether used in combination with FK506 or as monotherapy, may have good clinical value. Additional roles of these T-cell subpopulations in other biological systems and studies in these fields will also be meaningful. |
| first_indexed | 2024-03-12T16:46:21Z |
| format | Article |
| id | doaj.art-393fcdbe74754031b9cda98d61cde4b7 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T16:46:21Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-393fcdbe74754031b9cda98d61cde4b72023-08-08T12:19:56ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-08-011410.3389/fimmu.2023.11624391162439Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early toleranceQuanyu Chen0Quanyu Chen1Zhiqing Yang2Heng Lin3Jiejuan Lai4Deyu Hu5Deyu Hu6Min Yan7Min Yan8Zhifang Wu9Wei Liu10Zhehai Li11Yu He12Zhe Sun13Ling Shuai14Zhiping Peng15Yangyang Wang16Sijin Li17Youhong Cui18Hongyu Zhang19Leida Zhang20Lianhua Bai21Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaKey Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaBioengineering College, Chongqing University, Chongqing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaDepartment of Special Medicine, Shanxi Medical University, Taiyuan, ChinaDepartment of Special Medicine, Shanxi Medical University, Taiyuan, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaDepartment of Orthopedics, Peking University Third Hospital, Beijing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaDepartment of Orthopedics, Peking University Third Hospital, Beijing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaDepartment of Radiological Medicine, Chongqing Medical University, Chongqing, ChinaBioengineering College, Chongqing University, Chongqing, ChinaDepartment of Special Medicine, Shanxi Medical University, Taiyuan, ChinaDepartment of Pathology, Southwest Hospital, Army Medical University, Chongqing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaHepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, ChinaAllostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (FK506), the most commonly used immunosuppressant (IS) in the clinic, allows tolerance induction, its use is limited because its target immune cells are unknown and it is associated with increased incidences of malignancy, infection, and nephrotoxicity, which substantially impact long-term liver transplantation (LTx) outcomes. The dark agouti (DA)-to-Lewis rat LTx model is a well-known ARJ model and was hence chosen for the present study. We show that both hepatocyte growth factor (HGF) (cHGF, containing the main form of promoting HGF production) and recombinant HGF (h-rHGF) exert immunoregulatory effects mainly on allogeneic aCD8+ T cell suppression through FAS-mediated apoptotic pathways by inhibiting cMet to FAS antagonism and Fas trimerization, leading to acute tolerance induction. We also showed that such inhibition can be abrogated by treatment with neutralizing antibodies against cMet (HGF-only receptor). In contrast, we did not observe these effects in rats treated with FK506. However, we observed that the effect of anti-rejection by FK506 was mainly on allostimulated CD4+ T cell (aCD4+ T cell) suppression and regulatory T cell (Treg) promotion, in contrast to the mechanism of HGF. In addition, the protective mechanism of HGF in FK506-mediated nephrotoxicity was addressed. Therefore, HGF as a tolerance inducer, whether used in combination with FK506 or as monotherapy, may have good clinical value. Additional roles of these T-cell subpopulations in other biological systems and studies in these fields will also be meaningful.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1162439/fullimmune tolerancehepatocyte growth factor (HGF)tacrolimusliver transplantationT lymphocytesimmunosuppressants |
| spellingShingle | Quanyu Chen Quanyu Chen Zhiqing Yang Heng Lin Jiejuan Lai Deyu Hu Deyu Hu Min Yan Min Yan Zhifang Wu Wei Liu Zhehai Li Yu He Zhe Sun Ling Shuai Zhiping Peng Yangyang Wang Sijin Li Youhong Cui Hongyu Zhang Leida Zhang Lianhua Bai Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance Frontiers in Immunology immune tolerance hepatocyte growth factor (HGF) tacrolimus liver transplantation T lymphocytes immunosuppressants |
| title | Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance |
| title_full | Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance |
| title_fullStr | Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance |
| title_full_unstemmed | Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance |
| title_short | Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance |
| title_sort | comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance |
| topic | immune tolerance hepatocyte growth factor (HGF) tacrolimus liver transplantation T lymphocytes immunosuppressants |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1162439/full |
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