Substantially Altered Local and Systemic Immunity in Ischemia-Free Versus Conventional Liver Transplantation

Tao Luo; Shuai He; Shirui Chen; Dongmei Ye; Shibo Zhang; Di Liu; Dawei Zou; Linhe Wang; Huadi Chen; Jinghong Xu; Huanjie Liu; Ruiting Liu; Xi Tan; Yitong Wang; Jiayi Zeng; Runbing Mo; Yuexin Li; Yuyi Zhang; Tanyiyang Ruan; Tielong Wang; Zehua Jia; Yu Jia; Tongdi Fang; Yimou Lin; Xiaorui Liu; Yunhua Tang; Maogen Chen; Qiang Zhao; Anbin Hu; Weiqiang Ju; Yi Ma; Dongping Wang; Xiaofeng Zhu; Schlegel Andrea; Yuan Zhai; Kwan Man; Tullius G. Stefan; Yifang Gao; Jinxin Bei; Xiaoshun He; Zhiyong Guo

doi:10.1002/advs.202502854

Substantially Altered Local and Systemic Immunity in Ischemia-Free Versus Conventional Liver Transplantation

Tao Luo, Shuai He, Shirui Chen, Dongmei Ye, Shibo Zhang, Di Liu, Dawei Zou, Linhe Wang, Huadi Chen, Jinghong Xu, Huanjie Liu, Ruiting Liu, Xi Tan, Yitong Wang, Jiayi Zeng, Runbing Mo, Yuexin Li, Yuyi Zhang, Tanyiyang Ruan, Tielong WangZehua Jia, Yu Jia, Tongdi Fang, Yimou Lin, Xiaorui Liu, Yunhua Tang, Maogen Chen, Qiang Zhao, Anbin Hu, Weiqiang Ju, Yi Ma, Dongping Wang, Xiaofeng Zhu, Schlegel Andrea, Yuan Zhai, Kwan Man, Tullius G. Stefan, Yifang Gao, Jinxin Bei, Xiaoshun He, Zhiyong Guo

Research output: Contribution to journal › Article › peer-review

Abstract

Ischemia-free liver transplant (IFLT) has been developed to reduce ischemia-reperfusion injury (IRI). This study aims to investigate how this procedure impacts local and systemic immunity compared to conventional liver transplantation (CLT). Immunohistochemistry, immunofluorescence staining, single-cell RNA sequencing (scRNA-seq), and multiplex cytokine are used to illustrate distinct local and systemic immunity. In contrast to CLT, IFLT reduces neutrophil infiltration and neutrophil extracellular trap formation in grafts. By constructing an immune cell chimerism atlas, we reveal that IFLT reduces recipient-derived monocyte infiltration by suppressing ANXA1-FPR1 signaling through the STAT3-HIF-1α pathway, thereby attenuating inflammatory responses in graft monocytes. Additionally, IFLT confers graft protection by upregulating HMOX1 expression in monocytes and macrophages. Peripherally, IFLT significantly reduces the expression of MHC II molecules in circulating monocytes. Accordingly, CD8⁺ effector T cell composition, T helper 1 (Th1) and Th17 cytokine levels are reduced, while regulatory T cell (Treg) composition and Th2 cytokine levels are increased in IFLT versus CLT recipients. These results show that IFLT profoundly affects local and systemic immunity in liver transplantation. Recipient-circulating monocytes might play a key role in the interaction between graft IRI and allograft rejection.

Original language	English (US)
Journal	Advanced Science
DOIs	https://doi.org/10.1002/advs.202502854
State	Accepted/In press - 2026

Keywords

allograft rejection
ischemia-free liver transplantation
ischemia-reperfusion injury
macrophages
monocytes
neutrophils
single-cell sequencing

ASJC Scopus subject areas

Medicine (miscellaneous)
General Chemical Engineering
Biochemistry, Genetics and Molecular Biology (miscellaneous)
General Materials Science
General Engineering
General Physics and Astronomy

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10.1002/advs.202502854

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Luo, T., He, S., Chen, S., Ye, D., Zhang, S., Liu, D., Zou, D., Wang, L., Chen, H., Xu, J., Liu, H., Liu, R., Tan, X., Wang, Y., Zeng, J., Mo, R., Li, Y., Zhang, Y., Ruan, T., ... Guo, Z. (Accepted/In press). Substantially Altered Local and Systemic Immunity in Ischemia-Free Versus Conventional Liver Transplantation. Advanced Science. https://doi.org/10.1002/advs.202502854

Luo, T, He, S, Chen, S, Ye, D, Zhang, S, Liu, D, Zou, D, Wang, L, Chen, H, Xu, J, Liu, H, Liu, R, Tan, X, Wang, Y, Zeng, J, Mo, R, Li, Y, Zhang, Y, Ruan, T, Wang, T, Jia, Z, Jia, Y, Fang, T, Lin, Y, Liu, X, Tang, Y, Chen, M, Zhao, Q, Hu, A, Ju, W, Ma, Y, Wang, D, Zhu, X, Andrea, S, Zhai, Y, Man, K, Stefan, TG, Gao, Y, Bei, J, He, X & Guo, Z 2026, 'Substantially Altered Local and Systemic Immunity in Ischemia-Free Versus Conventional Liver Transplantation', Advanced Science. https://doi.org/10.1002/advs.202502854

@article{db71f897e6614d93b81cc9c57df34460,

title = "Substantially Altered Local and Systemic Immunity in Ischemia-Free Versus Conventional Liver Transplantation",

abstract = "Ischemia-free liver transplant (IFLT) has been developed to reduce ischemia-reperfusion injury (IRI). This study aims to investigate how this procedure impacts local and systemic immunity compared to conventional liver transplantation (CLT). Immunohistochemistry, immunofluorescence staining, single-cell RNA sequencing (scRNA-seq), and multiplex cytokine are used to illustrate distinct local and systemic immunity. In contrast to CLT, IFLT reduces neutrophil infiltration and neutrophil extracellular trap formation in grafts. By constructing an immune cell chimerism atlas, we reveal that IFLT reduces recipient-derived monocyte infiltration by suppressing ANXA1-FPR1 signaling through the STAT3-HIF-1α pathway, thereby attenuating inflammatory responses in graft monocytes. Additionally, IFLT confers graft protection by upregulating HMOX1 expression in monocytes and macrophages. Peripherally, IFLT significantly reduces the expression of MHC II molecules in circulating monocytes. Accordingly, CD8+ effector T cell composition, T helper 1 (Th1) and Th17 cytokine levels are reduced, while regulatory T cell (Treg) composition and Th2 cytokine levels are increased in IFLT versus CLT recipients. These results show that IFLT profoundly affects local and systemic immunity in liver transplantation. Recipient-circulating monocytes might play a key role in the interaction between graft IRI and allograft rejection.",

keywords = "allograft rejection, ischemia-free liver transplantation, ischemia-reperfusion injury, macrophages, monocytes, neutrophils, single-cell sequencing",

author = "Tao Luo and Shuai He and Shirui Chen and Dongmei Ye and Shibo Zhang and Di Liu and Dawei Zou and Linhe Wang and Huadi Chen and Jinghong Xu and Huanjie Liu and Ruiting Liu and Xi Tan and Yitong Wang and Jiayi Zeng and Runbing Mo and Yuexin Li and Yuyi Zhang and Tanyiyang Ruan and Tielong Wang and Zehua Jia and Yu Jia and Tongdi Fang and Yimou Lin and Xiaorui Liu and Yunhua Tang and Maogen Chen and Qiang Zhao and Anbin Hu and Weiqiang Ju and Yi Ma and Dongping Wang and Xiaofeng Zhu and Schlegel Andrea and Yuan Zhai and Kwan Man and Stefan, \{Tullius G.\} and Yifang Gao and Jinxin Bei and Xiaoshun He and Zhiyong Guo",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s). Advanced Science published by Wiley-VCH GmbH.",

year = "2026",

doi = "10.1002/advs.202502854",

language = "English (US)",

journal = "Advanced Science",

issn = "2198-3844",

publisher = "Wiley",

}

TY - JOUR

T1 - Substantially Altered Local and Systemic Immunity in Ischemia-Free Versus Conventional Liver Transplantation

AU - Luo, Tao

AU - He, Shuai

AU - Chen, Shirui

AU - Ye, Dongmei

AU - Zhang, Shibo

AU - Liu, Di

AU - Zou, Dawei

AU - Wang, Linhe

AU - Chen, Huadi

AU - Xu, Jinghong

AU - Liu, Huanjie

AU - Liu, Ruiting

AU - Tan, Xi

AU - Wang, Yitong

AU - Zeng, Jiayi

AU - Mo, Runbing

AU - Li, Yuexin

AU - Zhang, Yuyi

AU - Ruan, Tanyiyang

AU - Wang, Tielong

AU - Jia, Zehua

AU - Jia, Yu

AU - Fang, Tongdi

AU - Lin, Yimou

AU - Liu, Xiaorui

AU - Tang, Yunhua

AU - Chen, Maogen

AU - Zhao, Qiang

AU - Hu, Anbin

AU - Ju, Weiqiang

AU - Ma, Yi

AU - Wang, Dongping

AU - Zhu, Xiaofeng

AU - Andrea, Schlegel

AU - Zhai, Yuan

AU - Man, Kwan

AU - Stefan, Tullius G.

AU - Gao, Yifang

AU - Bei, Jinxin

AU - He, Xiaoshun

AU - Guo, Zhiyong

PY - 2026

Y1 - 2026

N2 - Ischemia-free liver transplant (IFLT) has been developed to reduce ischemia-reperfusion injury (IRI). This study aims to investigate how this procedure impacts local and systemic immunity compared to conventional liver transplantation (CLT). Immunohistochemistry, immunofluorescence staining, single-cell RNA sequencing (scRNA-seq), and multiplex cytokine are used to illustrate distinct local and systemic immunity. In contrast to CLT, IFLT reduces neutrophil infiltration and neutrophil extracellular trap formation in grafts. By constructing an immune cell chimerism atlas, we reveal that IFLT reduces recipient-derived monocyte infiltration by suppressing ANXA1-FPR1 signaling through the STAT3-HIF-1α pathway, thereby attenuating inflammatory responses in graft monocytes. Additionally, IFLT confers graft protection by upregulating HMOX1 expression in monocytes and macrophages. Peripherally, IFLT significantly reduces the expression of MHC II molecules in circulating monocytes. Accordingly, CD8+ effector T cell composition, T helper 1 (Th1) and Th17 cytokine levels are reduced, while regulatory T cell (Treg) composition and Th2 cytokine levels are increased in IFLT versus CLT recipients. These results show that IFLT profoundly affects local and systemic immunity in liver transplantation. Recipient-circulating monocytes might play a key role in the interaction between graft IRI and allograft rejection.

AB - Ischemia-free liver transplant (IFLT) has been developed to reduce ischemia-reperfusion injury (IRI). This study aims to investigate how this procedure impacts local and systemic immunity compared to conventional liver transplantation (CLT). Immunohistochemistry, immunofluorescence staining, single-cell RNA sequencing (scRNA-seq), and multiplex cytokine are used to illustrate distinct local and systemic immunity. In contrast to CLT, IFLT reduces neutrophil infiltration and neutrophil extracellular trap formation in grafts. By constructing an immune cell chimerism atlas, we reveal that IFLT reduces recipient-derived monocyte infiltration by suppressing ANXA1-FPR1 signaling through the STAT3-HIF-1α pathway, thereby attenuating inflammatory responses in graft monocytes. Additionally, IFLT confers graft protection by upregulating HMOX1 expression in monocytes and macrophages. Peripherally, IFLT significantly reduces the expression of MHC II molecules in circulating monocytes. Accordingly, CD8+ effector T cell composition, T helper 1 (Th1) and Th17 cytokine levels are reduced, while regulatory T cell (Treg) composition and Th2 cytokine levels are increased in IFLT versus CLT recipients. These results show that IFLT profoundly affects local and systemic immunity in liver transplantation. Recipient-circulating monocytes might play a key role in the interaction between graft IRI and allograft rejection.

KW - allograft rejection

KW - ischemia-free liver transplantation

KW - ischemia-reperfusion injury

KW - macrophages

KW - monocytes

KW - neutrophils

KW - single-cell sequencing

UR - https://www.scopus.com/pages/publications/105029014319

UR - https://www.scopus.com/inward/citedby.url?scp=105029014319&partnerID=8YFLogxK

U2 - 10.1002/advs.202502854

DO - 10.1002/advs.202502854

M3 - Article

AN - SCOPUS:105029014319

SN - 2198-3844

JO - Advanced Science

JF - Advanced Science

ER -

Substantially Altered Local and Systemic Immunity in Ischemia-Free Versus Conventional Liver Transplantation

Abstract

Keywords

ASJC Scopus subject areas

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