Targeting TIM-1 on CD4 T cells depresses macrophage activation and overcomes ischemia-reperfusion injury in mouse orthotopic liver transplantation

Y. Zhang, H. Ji, X. Shen, J. Cai, F. Gao, K. M. Koenig, C. M. Batikian, R. W. Busuttil, J. W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Hepatic injury due to cold storage followed by reperfusion remains a major cause of morbidity and mortality after orthotopic liver transplantation (OLT). CD4 T cell TIM-1 signaling costimulates a variety of immune responses in allograft recipients. This study analyzes mechanisms by which TIM-1 affects liver ischemia-reperfusion injury (IRI) in a murine model of prolonged cold storage followed by OLT. Livers from C57BL/6 mice, preserved at 4°C in the UW solution for 20 h, were transplanted to syngeneic recipients. There was an early (1 h) increased accumulation of TIM-1+ activated CD4 T cells in the ischemic OLTs. Disruption of TIM-1 signaling with a blocking mAb (RMT1-10) ameliorated liver damage, evidenced by reduced sALT levels and well-preserved architecture. Unlike in controls, TIM-1 blockade diminished OLT expression of Tbet/IFN-Iγ, but amplified IL-4/IL-10/IL-22; abolished neutrophil and macrophage infiltration/activation and inhibited NF-ηB while enhancing Bcl-2/Bcl-xl. Although adoptive transfer of CD4 T cells triggered liver damage in otherwise IR-resistant RAG-/- mice, adjunctive TIM-1 blockade reduced Tbet transcription and abolished macrophage activation, restoring homeostasis in IR-stressed livers. Further, transfer of TIM-1HiCD4+, but not TIM-1LoCD4+ T cells, recreated liver IRI in RAG-/- mice. Thus, TIM-1 expressing CD4 T cells are required in the mechanism of innate immune-mediated hepatic IRI in OLTs. A subpopulation of activated CD4 T cells expressing the TIM-1 receptor is required to trigger hepatic damage in mouse liver transplants subjected to prolonged periods of cold storage.

Original languageEnglish (US)
Pages (from-to)56-66
Number of pages11
JournalAmerican Journal of Transplantation
Volume13
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Innate immunity
  • ischemia-reperfusion injury
  • orthotopic liver transplantation
  • T cell costimulation
  • TIM-1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Targeting TIM-1 on CD4 T cells depresses macrophage activation and overcomes ischemia-reperfusion injury in mouse orthotopic liver transplantation'. Together they form a unique fingerprint.

Cite this