TY - JOUR
T1 - Gene therapy for liver transplantation using adenoviral vectors
T2 - CD40-CD154 blockade by gene transfer of CD40Ig protects rat livers from cold ischemia and reperfusion injury
AU - Ke, Bibo
AU - Shen, Xiu Da
AU - Gao, Feng
AU - Busuttil, Ronald W.
AU - Löwenstein, Pedro R.
AU - Castro, Maria G.
AU - Kupiec-Weglinski, Jerzy W.
N1 - Funding Information:
This work was supported by NIH Grants RO1 AI23847, AI42223, and DK062357 (J.W.K.W.) and The Dumont Research Foundation. J.W.K.W. is holder of the Ralph and Joan Goldwyn Chair in Transplantation Immunobiology. Work at the GTRI (P.R.L. and M.G.C.) is funded in part by the Board of Governors at Cedars–Sinai Medical Center. P.R.L. is holder of the Bram and Elaine Goldsmith Chair in Gene Therapeutics.
PY - 2004/1
Y1 - 2004/1
N2 - 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°C) ischemia survived >14 days (vs 50% in untreated/Ad-β-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-β-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-γ remained depressed, whereas that of IL-4/IL-13 reciprocally increased in the Ad-CD40Ig group. Ad-CD40Ig reduced frequency of TUNEL+ cells and proapoptotic Caspase-3, but enhanced antioxidant HO-1 and antiapoptotic 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.
AB - 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°C) ischemia survived >14 days (vs 50% in untreated/Ad-β-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-β-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-γ remained depressed, whereas that of IL-4/IL-13 reciprocally increased in the Ad-CD40Ig group. Ad-CD40Ig reduced frequency of TUNEL+ cells and proapoptotic Caspase-3, but enhanced antioxidant HO-1 and antiapoptotic 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.
KW - CD40Ig
KW - Gene therapy
KW - Ischemia/reperfusion injury
KW - Liver
KW - Transplantation
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U2 - 10.1016/j.ymthe.2003.10.011
DO - 10.1016/j.ymthe.2003.10.011
M3 - Article
C2 - 14741776
AN - SCOPUS:1142287429
VL - 9
SP - 38
EP - 45
JO - Molecular therapy : the journal of the American Society of Gene Therapy
JF - Molecular therapy : the journal of the American Society of Gene Therapy
SN - 1525-0016
IS - 1
ER -