CD154-CD40 T-cell costimulation pathway is required in the mechanism of hepatic ischemia/reperfusion injury, and its blockade facilitates and depends on heme oxygenase-1 mediated cytoprotection.
BACKGROUND
Ischemia/reperfusion (I/R) injury remains an important clinical problem that affects both early and later allograft outcome. This study was designed to analyze the role of T cells and CD154-CD40 T- cell costimulation pathway in a mouse liver I/R model.


RESULTS
Ninety minutes of warm ischemia followed by 4 h of reperfusion in wild-type (WT) mice resulted in a significant hepatic damage, as assessed by liver function (serum alanine aminotransferase [sALT] levels), local neutrophil accumulation (myeloperoxidase activity), and histology (Suzuki's score). In contrast, T-cell deficiency (in T-cell deficient [nu/nu] mice), disruption of the CD154 signaling (in knockout [KO] mice), or its blockade in WT recipients (after MR1 monoclonal antibody [mAb] treatment), virtually prevented hepatic I/R insult. Unlike CD154-deficient T cells, adoptive transfer of WT spleen cells fully restored hepatic I/R injury in nu/nu mice. Finally, the improved hepatic function in CD154 KO recipients, WT mice treated with CD154 mAb, or nu/nu mice infused with CD154-deficient cells resulted in consistently enhanced expression of heme oxygenase-1 (HO-1), a heat-shock protein with cytoprotective functions.


CONCLUSIONS
This study confirms the importance of T cells, and documents for the first time the role of CD154 costimulation signals in the mechanism of hepatic I/R injury. We also show that CD154 blockade-mediated cytoprotection results and depends on HO-1 overexpression. Our data provide the rationale for human trials to target CD154-CD40 costimulation in hepatic I/R injury, particularly in the transplant patient.
Shen
Xiu-Da
XD
Ke
Bibo
B
Zhai
Yuan
Y
Amersi
Farin
F
Gao
Feng
F
Anselmo
Dean M
DM
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D019264:Adoptive Transfer; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology*; D006419:Heme Oxygenase (Decyclizing) / Q000276:immunology*; D051547:Heme Oxygenase-1; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000098:blood supply*; D008213:Lymphocyte Activation; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology*
D019013:CD40 Antigens; D008565:Membrane Proteins; D023201:CD40 Ligand; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000410:Alanine Transaminase