Targeted gene therapy with CD40Ig to induce long-term acceptance of liver allografts.
BACKGROUND
The purpose of this study was to modulate the immune response of rat liver transplant recipients by adenovirus-mediated gene transfer of CD40Ig, a secretable fusion protein designed to block the CD40-CD154 T-cell costimulation pathway.


METHODS
CD40Ig complementary DNA was created by joining the reverse transcriptase-polymerase chain reaction complementary DNA products for the extracellular domain of murine CD40 to the Fc portion of murine IgG2a. AdCD40Ig and AdSIg (IgG2a-Fc control) recombinant adenoviruses were used to transduce donor liver grafts before nonarterialized orthotopic rat liver transplantation. Donor specific unresponsiveness was examined with skin transplants.


RESULTS
All rats (n = 6) that received liver allografts transduced with AdCD40Ig survived >100 days with normal liver histology. Serum levels of CD40Ig at 10, 30, 60, and 100 days after transplantation ranged from 100 to 500, 100 to 250, 5 to 40, and 2 to 10 microg/mL, respectively. Mean survival of rats (n = 4) that received liver allografts transduced with AdSIg control adenovirus was 9.25 +/- 2.9 days. Long-term survivors were rechallenged with skin grafts 100 days after liver transplantations. Survival was 72, >100 (x4) days for donor specific allogeneic skin grafts and 14, 14, 18, 19, and 21 days for third-party allogeneic skin grafts.


CONCLUSIONS
Adenovirus-mediated gene transfer of CD40Ig into cold-preserved liver allografts before transplantation results in high levels of transgene expression with resultant long-term survival of hepatic allografts and donor specific unresponsiveness.
Chang
George J
GJ
Division of Transplantation Surgery, Department of Surgery, University of California, San Francisco School of Medicine, 94143, USA.
Liu
Tao
T
Feng
Sandy
S
Bedolli
Melanie
M
O'rourke
Robert W
RW
Schmidt
Gregory
G
Roberts
John P
JP
Stock
Peter G
PG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019013:CD40 Antigens / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D006084:Graft Rejection / Q000276:immunology / Q000628:therapy*; D006085:Graft Survival / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics* / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods; D016031:Liver Transplantation; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016038:Skin Transplantation; D019076:Transgenes / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous
D019013:CD40 Antigens; D007074:Immunoglobulin G