Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance

Quanyu Chen; Zhiqing Yang; Heng Lin; Jiejuan Lai; Deyu Hu; 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

doi:10.3389/fimmu.2023.1162439

Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance

Front Immunol. 2023 Aug 8:14:1162439. doi: 10.3389/fimmu.2023.1162439. eCollection 2023.

Authors

Quanyu Chen^{1

2}, Zhiqing Yang¹, Heng Lin¹, Jiejuan Lai¹, Deyu Hu^{1

3}, Min Yan^{1

4}, Zhifang Wu⁴, Wei Liu¹, Zhehai Li⁵, Yu He¹, Zhe Sun⁵, Ling Shuai¹, Zhiping Peng⁶, Yangyang Wang³, Sijin Li⁴, Youhong Cui⁷, Hongyu Zhang¹, Leida Zhang¹, Lianhua Bai¹

Affiliations

¹ Hepatobiliary Institute, Southwest Hospital, Army Medical University, Chongqing, China.
² Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China.
³ Bioengineering College, Chongqing University, Chongqing, China.
⁴ Department of Special Medicine, Shanxi Medical University, Taiyuan, China.
⁵ Department of Orthopedics, Peking University Third Hospital, Beijing, China.
⁶ Department of Radiological Medicine, Chongqing Medical University, Chongqing, China.
⁷ Department of Pathology, Southwest Hospital, Army Medical University, Chongqing, China.

Abstract

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.

Keywords: T lymphocytes; hepatocyte growth factor (HGF); immune tolerance; immunosuppressants; liver transplantation; tacrolimus.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Animals
CD8-Positive T-Lymphocytes
Hepatocyte Growth Factor*
Liver
Rats
Rats, Inbred Lew
Tacrolimus* / pharmacology

Substances

Hepatocyte Growth Factor
Tacrolimus

Grants and funding

This work was supported by the National Natural Science Foundation of China (LB; no. 81873586; HZ: no. 81571566), Beijing, China, and the Stem Cell Pioneer Project (LB, no. 2021-20180-052) from the Army Medical University of China.