The CD154-CD40 T-cell co-stimulation pathway in liver ischemia and reperfusion inflammatory responses.
BACKGROUND
Ischemia-reperfusion (I/R) injury is a prime antigen-independent inflammatory factor in the dysfunction of liver transplants. The precise contribution of T cells in the mechanism of I/R injury remains to be elucidated. As the CD154-CD40 co-stimulation pathway provides essential second signal in the initiation and maintenance of T-cell-dependent immune responses, this study was designed to assess the role of CD154 signaling in the pathophysiology of liver I/R injury.


METHODS
A mouse model of partial 90-min warm hepatic ischemia followed by 6 hr of reperfusion was used. Three animal groups were studied: (1) wild-type (WT) mice treated with Ad-(-gal versus Ad-CD40 immunoglobulin; (2) untreated WT versus CD154 (MR1) monoclonal antibody-treated WT mice; and (3) untreated WT versus CD154 knockout mice.


RESULTS
The disruption of CD154 signaling in all three animal groups ameliorated otherwise fulminant liver injury, as evidenced by depressed serum glutamic oxaloacetic transaminase levels, compared with controls. These beneficial effects were accompanied by depressed hepatic T-cell sequestration, local decrease of vascular endothelial growth factor expression, inhibition of tumor necrosis factor-(and T-helper type 1 cytokine production, and induction of antiapoptotic (Bcl-2/Bcl-xl) but depression of proapoptotic (caspase-3) proteins.


CONCLUSIONS
By using in parallel a gene therapy approach, pharmacologic blockade, and genetically targeted mice, these findings document the benefits of disrupting CD154 to selectively modulate inflammatory responses in liver I/R injury. This study reinforces the key role of CD154-CD40 T-cell co-stimulation in the pathophysiology of liver I/R injury.
Ke
Bibo
B
The Dumont-University of California, Los Angeles Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
Shen
Xiu-Da
XD
Gao
Feng
F
Tsuchihashi
Seiichiro
S
Farmer
Douglas G
DG
Briscoe
David
D
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D007511:Ischemia; D008099:Liver / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D008102:Liver Circulation / Q000276:immunology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D012313:RNA / Q000302:isolation & purification; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D019013:CD40 Antigens; D016207:Cytokines; D023201:CD40 Ligand; D012313:RNA