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

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  • 1Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
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PubMed
Summary

Ischemia-free liver transplant (IFLT) significantly improves outcomes by modulating local and systemic immunity. This novel approach reduces inflammatory cell infiltration and promotes immune tolerance compared to conventional liver transplantation (CLT).

Keywords:
allograft rejectionischemia‐free liver transplantationischemia‐reperfusion injurymacrophagesmonocytesneutrophilssingle‐cell sequencing

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Area of Science:

  • Immunology
  • Transplantation Science
  • Surgical Innovation

Background:

  • Ischemia-reperfusion injury (IRI) remains a significant challenge in liver transplantation.
  • Ischemia-free liver transplantation (IFLT) was developed to mitigate IRI.
  • Understanding IFLT's impact on immune responses is crucial for optimizing transplant outcomes.

Purpose of the Study:

  • To compare the local and systemic immune effects of IFLT versus conventional liver transplantation (CLT).
  • To elucidate the mechanisms by which IFLT influences immune cell infiltration and function.
  • To assess the role of recipient-derived monocytes in IFLT-mediated immune modulation.

Main Methods:

  • Immunohistochemistry and immunofluorescence staining to analyze graft immune cell infiltration.
  • Single-cell RNA sequencing (scRNA-seq) to profile immune cell populations and gene expression.
  • Multiplex cytokine analysis to quantify systemic inflammatory markers.
  • Construction of an immune cell chimerism atlas to track recipient-derived cells.

Main Results:

  • IFLT reduced neutrophil infiltration and neutrophil extracellular trap formation in liver grafts compared to CLT.
  • IFLT suppressed recipient monocyte infiltration via ANXA1-FPR1/STAT3-HIF-1α pathway, attenuating graft inflammation.
  • IFLT upregulated HMOX1 in monocytes/macrophages, conferring graft protection.
  • IFLT decreased circulating monocyte MHC II expression, reduced CD8+ effector T cells, Th1/Th17 cytokines, and increased regulatory T cells (Tregs) and Th2 cytokines.

Conclusions:

  • IFLT profoundly alters local and systemic immunity in liver transplantation.
  • IFLT mitigates IRI and promotes a more tolerogenic immune environment.
  • Recipient-circulating monocytes are key mediators in the interplay between graft IRI and allograft rejection, with IFLT modulating their activity.