Patient-Derived Avatar Mouse Model to Predict the Liver Immune Homeostasis of Long-Term Stable Liver Transplant Patients

Soon Kyu Lee, Min Jung Park, Jeong Won Choi, Jin Ah Baek, Se Young Kim, Ho Joong Choi, Young Kyoung You, Jeong Won Jang, Pil Soo Sung, Si Hyun Bae, Seung Kew Yoon, Jong Young Choi, Mi La Cho

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3 Scopus citations

Abstract

Although rejection or tolerance can occur in liver transplantation (LT) patients, there are no reliable non-invasive methods for predicting immune homeostasis. In this study, we developed a humanized mouse model to predict liver immune homeostasis in patients who underwent LT. The patient-derived avatar model was developed by injecting peripheral blood mononuclear cells from healthy controls (HCs) or LT patients with stable, rejection, or tolerance into NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJ (NSG) mice, followed by injection of human hepatic stellate cells and Carbone tetrachloride (CCl4). After 7 weeks, the patient’s T-cell engraftment and liver inflammation in the avatar model were evaluated and compared with the liver histology of LT patients. Changes in liver inflammation following treatment with tacrolimus and/or biguanide derivatives were also examined. The C-X-C Motif Chemokine Receptor 3 (CXCR3)-dependently engrafted patient T cells led to differences in liver inflammation in our model according to the status of LT patients. The livers of avatar models from rejection patients had severe inflammation with more T helper 17 cells and fewer regulatory T cells compared to those of models from tolerance and HCs showing only mild inflammation. Moreover, our model classified stable post-LT patients into severe and mild inflammation groups, which correlated well with liver immunity in these patients. Our models revealed alleviation of inflammation after combination treatment with tacrolimus and biguanide derivatives or monotherapy. Consequently, using our new patient-derived avatar model, we predicted liver immune homeostasis in patients with stable LT without biopsy. Moreover, our avatar model may be useful for preclinical analysis to evaluate treatment responses while reducing risks to patients.

Original languageEnglish
Article number817006
JournalFrontiers in Immunology
Volume13
DOIs
StatePublished - 28 Mar 2022

Bibliographical note

Funding Information:
This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C3062). This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1F1A1075816) and was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2021R1I1A1A01050954).

Publisher Copyright:
Copyright © 2022 Lee, Park, Choi, Baek, Kim, Choi, You, Jang, Sung, Bae, Yoon, Choi and Cho.

Keywords

  • avatar model
  • fibrosis
  • immune homeostasis
  • inflammation
  • liver transplantation

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