Induction of donor-specific tolerance by adenovirus-mediated CD40Ig gene therapy in rat liver transplantation.
BACKGROUND
Blockade of CD40-CD40 ligand (CD154) costimulatory pathway with anti-CD154 antibody (Ab) prolongs allograft survival in experimental organ transplantations; however, repeated agent administration is needed to provide an adequate immunosuppression. Seeking for simple and effective approach to interfere this signaling, we applied adenovirus-mediated gene therapy by encoding CD40Ig gene (AdCD40Ig).


METHODS
Liver graft from ACI (RT1av1) rat was transplanted orthotopically into LEW (RT1l) rat, and AdCD40Ig was given to animals via the penile vein immediately after grafting (n=6).


RESULTS
A single treatment with AdCD40Ig at 1x10(9) plaque forming units induced specific expression of CD40Ig gene on allograft liver, produced substantial amount of the protein in the sera, and allowed indefinite graft survival. Whereas, LEW recipients given no treatment or control adenovirus vector (AdLacZ) promptly rejected ACI liver. In addition, AdCD40Ig-treated, long-term survivors accepted skin graft from the donor strain but not the third party graft. Histopathology revealed that liver structure of the long-term surviving animals was completely preserved in normal with no infiltration of mononuclear cells.


CONCLUSIONS
Blockade of CD40-CD154 pathway by CD40Ig gene therapy is a potent alloantigen-specific immunosuppressive strategy to induce permanent acceptance of liver allograft and would be a new therapeutic candidate in a clinical liver transplantation.
Nomura
Masaru
M
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
Yamashita
Kenichiro
K
Murakami
Masaaki
M
Takehara
Megumi
M
Echizenya
Hayato
H
Sunahara
Masao
M
Kitagawa
Norihiko
N
Fujita
Miri
M
Furukawa
Hiroyuki
H
Uede
Toshimistu
T
Todo
Satoru
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019013:CD40 Antigens / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006085:Graft Survival; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics*; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D019076:Transgenes / Q000235:genetics; D023001:Transplantation Tolerance
D019013:CD40 Antigens; D007074:Immunoglobulin G