TY - JOUR
T1 - Targeting TIM-1 on CD4 T cells depresses macrophage activation and overcomes ischemia-reperfusion injury in mouse orthotopic liver transplantation
AU - Zhang, Y.
AU - Ji, H.
AU - Shen, X.
AU - Cai, J.
AU - Gao, F.
AU - Koenig, K. M.
AU - Batikian, C. M.
AU - Busuttil, R. W.
AU - Kupiec-Weglinski, J. W.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
KW - Innate immunity
KW - ischemia-reperfusion injury
KW - orthotopic liver transplantation
KW - T cell costimulation
KW - TIM-1
UR - http://www.scopus.com/inward/record.url?scp=84871714144&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871714144&partnerID=8YFLogxK
U2 - 10.1111/j.1600-6143.2012.04316.x
DO - 10.1111/j.1600-6143.2012.04316.x
M3 - Article
C2 - 23137033
AN - SCOPUS:84871714144
VL - 13
SP - 56
EP - 66
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 1
ER -