Adenovirus-mediated CTLA4 immunoglobulin G gene therapy in cardiac xenotransplantation.
BACKGROUND
CTLA4 immunoglobulin (CTLA4 Ig), which binds with high affinity to B7-1 and B7-2, interrupts T-cell activation by inhibiting the costimulatory signal. CTLA4Ig has been used to achieve antigen-specific tolerance induction in cardiac allografts. On the other hand, we have shown that short-term administration of deoxyspergualin (DSG) and daily cyclosporine (CsA) induces long-term survival of cardiac xenotransplants. We hypothesized that the combination therapy of DSG and adenovirus-mediated CTLA4IgG might induce long-term, survival or tolerance in cardiac xenotransplantation.


OBJECTIVE
Syrian hamster hearts were transplanted heterotopically into Lewis rats. We compared the survival time and immunopathology of the following five groups: (1) no treatment; (2) DSG (5 mg/kg per day intramuscularly [IM], days -1 to +7) alone; (3) CsA (15 mg/kg per day IM, day 0 to rejection) plus DSG; (4) AdexLacZ (LacZ-adenovirus 1 x 10(9) (PFU intravenously [IV], day -7) plus DSG; and (5) AdexCTLA4IgG (CTLA4IgG-adenovirus 1 x 10(9) PFU IV, day -7) plus DSG.


RESULTS
The survival times were: (1) no treatment, 3.7 days; (2) DSG alone, 12.4 days; (3) CyA plus DSG, >100 days; (4) AdexLacZ plus DSG, 11.0 days; and (5) AdexCTLA4IgG plus DSG, 23.6 days. Adenovirus-mediated CTLA4IgG therapy with DSG prolonged survival time significantly compared with DSG alone or AdexLacZ plus DSG, but CTLA4IgG therapy was not as effective as CsA. Immunopathology showed the deposition of C3 and IgM on the endothelium in the AdexCTLA4IgG plus DSG group.


CONCLUSIONS
We showed that the effectiveness of adenovirus-mediated CTLA4IgG gene therapy in cardiac xenotransplantation in less than that of CsA. Combination therapy with inhibition of the B7/CD28 constimulatory signal and DSG administration might not be sufficient for long-term survival or tolerance in cardiac xenotransplantation.
Watanabe
T
T
Department of Cardiovascular Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Miyatake
T
T
Kumamoto
H
H
Mafune
N
N
Kubota
S
S
Okamoto
H
H
Murashita
T
T
Uede
T
T
Yasuda
K
K
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006224:Cricetinae; D015316:Genetic Therapy; D006085:Graft Survival / Q000187:drug effects; D006146:Guanidines / Q000627:therapeutic use; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000235:genetics*; D007165:Immunosuppression Therapy / Q000379:methods; D008647:Mesocricetus; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000276:immunology*
D006146:Guanidines; D018796:Immunoconjugates; D000069594:Abatacept; C037258:gusperimus