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

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. 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. 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.