Combined gene therapy with adenovirus vectors containing CTLA4Ig and CD40Ig prolongs survival of composite tissue allografts in rat model.
BACKGROUND
The blockade of costimulatory signal pathway by anti-CD40 ligand antibody or cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) prolongs allograft survival in various vascularized organ transplantations. Because of the short half life of these agents, repeated administration of proteins is required to achieve significant graft survival. Furthermore, there is limited information regarding the effect of cosimulatory blockade on the survival of composite tissue allografts. Therefore, we examined the effect of adenovirus-mediated gene transfer of CTLA4Ig or CD40Ig gene or both in composite tissue allotransplantation.


METHODS
The hind limbs removed from male ACI rats (RT1 ) were transplanted into female Lewis rats (RT1 ) heterotopically. The recombinant adenovirus carrying CTLA4Ig (AxCTLA4Ig) or CD40Ig (AxCD40Ig) was intravenously administered after limb transplantation.


RESULTS
Limb allograft survival was significantly prolonged by either AxCTLA4Ig or AxCD40Ig treatment at 1 x 10 plaque forming unit (mean survival time [MST] of 39.4+/-6.0 and 13.0+/-2.9, respectively) compared with the adenovirus vector containing beta-galactosidase-treated group (MST of 4.8+/-0.8). Combination of AxCTLA4Ig and AxCD40Ig led to significant prolongation of graft survival (MST of 49.2+/-6.6). Serum levels of CD40Ig were higher in rats treated with combination therapy than those treated with AxCD40Ig alone, whereas the serum levels of CTLA4Ig in rats treated with AxCTLA4Ig alone and AxCTLA4Ig and AxCD40Ig combined were very similar.


CONCLUSIONS
This study indicates that an adenovirus-mediated gene therapy of CTLA4Ig or CD40Ig has a therapeutic potential for preventing rejection in composite tissue transplantation. Furthermore, a combination therapy of AxCTLA4Ig and AxCD40Ig was even more effective in preventing acute rejection and prolonging the survival of allografted limbs without apparent complication.
Kanaya
Kohei
K
Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Tsuchida
Yoshihiko
Y
Inobe
Manabu
M
Murakami
Masaaki
M
Hirose
Toshiaki
T
Kon
Shigeyuki
S
Kawaguchi
Satoshi
S
Wada
Takuro
T
Yamashita
Toshihiko
T
Ishii
Seiichi
S
Uede
Toshimitsu
T
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019013:CD40 Antigens / Q000235:genetics* / Q000276:immunology; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006084:Graft Rejection / Q000276:immunology / Q000628:therapy; D006085:Graft Survival / Q000276:immunology*; D006614:Hindlimb / Q000637:transplantation*; D018796:Immunoconjugates / Q000235:genetics* / Q000276:immunology; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D019076:Transgenes / Q000276:immunology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous
D019013:CD40 Antigens; D018796:Immunoconjugates; D000069594:Abatacept