Gene therapy for liver transplantation using adenoviral vectors: CD40-CD154 blockade by gene transfer of CD40Ig protects rat livers from cold ischemia and reperfusion injury.

Abstract

Liver injury induced by ischemia/reperfusion (I/R) is the prime factor in delayed or loss graft function following transplantation. CD4+ T lymphocytes are key cellular mediators of antigen-independent inflammatory response triggered by I/R. We attempted to modulate rat liver I/R injury by targeted gene therapy with CD40Ig, which blocks the CD40-CD154 costimulation pathway. One hundred percent of Ad-CD40Ig-pretreated orthotopic liver transplants (OLTs) subjected to 24 h of cold (4 degrees C) ischemia survived > 14 days (vs 50% in untreated/Ad-beta-gal groups). Ad-CD40Ig treatment decreased sGOT levels and depressed neutrophil infiltration, compared with controls. These functional data correlated with histological Suzuki's grading of hepatic injury, which in untreated/Ad-beta-gal groups showed severe necrosis (> 60%) and moderate to severe sinusoidal congestion; the Ad-CD40Ig-pretreated group revealed minimal sinusoidal congestion/necrosis. Unlike in controls, OLT expression of mRNA coding for IL-2/IFN-gamma remained depressed, whereas that of IL-4/IL-13 reciprocally increased in the Ad-CD40Ig group. Ad-CD40Ig reduced frequency of TUNEL+ cells and pro-apoptotic Caspase-3, but enhanced antioxidant HO-1 and anti-apoptotic Bcl-2/Bcl-xl expression. Thus, prolonged blockade of CD40-CD154 by CD40Ig exerts potent cytoprotection against hepatic I/R injury. These results provide the rationale for a novel gene therapy approach to maximize the organ donor pool through the safer use of liver transplants exposed to prolonged cold ischemia.

• Authors: Bibo Ke, Xiu-Da Shen, Feng Gao, Ronald W Busuttil, Pedro R Löwenstein, Maria G Castro, Jerzy W Kupiec-Weglinski
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 9 Issue 1 Pg. 38-45 (Jan 2004) ISSN: 1525-0016 [Print] United States
• PMID: 14741776 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CD40 Antigens
• Cytokines
• Immunoglobulins
• CD40 Ligand

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis
• CD40 Antigens (genetics)
• CD40 Ligand (physiology)
• Cold Temperature
• Cytokines (genetics, metabolism)
• Gene Expression
• Genetic Therapy
• Genetic Vectors
• Immunoglobulins (genetics)
• Liver Diseases (etiology, pathology, prevention & control)
• Liver Transplantation (methods, pathology)
• Male
• Neutrophil Infiltration
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (etiology, pathology, prevention & control)