Adenovirus-mediated CTLA4Ig or CD40Ig gene transfer delays pancreatic islet rejection in a rat-to-mouse xenotransplantation model after systemic but not local expression.
Transient costimulation signal blockade of either CD28/CD80-86 interactions and/or CD40/CD154 interactions can prevent islet rejection in some models of both allo- and xenotransplantation. We have used adenoviruses coding for CTLA4Ig or CD40Ig and compared the efficacy of genetic modification of islets to systemic production through either intramuscular (i.m.) or intravenous (i.v.) injection of these vectors in a rat-to-mouse islet transplantation model. When gene transfer was performed into islets, a high level of primary nonfunction was induced. Furthermore, transduced functional grafts were rejected with the same kinetics as nontransduced islets. In contrast, i.m. AdCTLA4Ig and i.v. AdCD40Ig significantly delayed rejection (mean survival time of 54 +/- 26.9 and 67.6 +/- 44.9 days, respectively, vs. 24.3 +/- 9.7 days for unmodified islets, p < 0.05). Combination of ex vivo AdCTLA4Ig islet transduction and i.v. AdCD40Ig did not improve graft survival further. In conclusion, islet graft transduction with adenoviruses coding for costimulation inhibitors resulted in local expression with low serum concentrations of CTLA4Ig or CD40Ig and was unable to protect islet xenografts from rejection. In contrast, i.m. or i.v. gene transfer resulted in high serum concentrations of these molecules and was highly efficient in prolonging xenograft survival. These results contrast with the efficacy of AdCTLA4Ig we observed in a rat islet allotransplantation model and suggest that islet xenograft rejection might be more difficult to control.
Potiron
Nicolas
N
Institut National de la Santé et de la Recherche Médicale (INSERM) UMR643, Centre Hospitalo-Universitaire, 30 boulevard Jean Monnet, 44093 Nantes 01, France.
Chagneau
Carine
C
Boeffard
Françoise
F
Soulillou
Jean-Paul
JP
Anegon
Ignacio
I
Le Mauff
Brigitte
B
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D018796:Immunoconjugates / Q000235:genetics* / Q000276:immunology; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000276:immunology / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000276:immunology / Q000502:physiology; D051381:Rats; D011920:Rats, Inbred WF; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D014161:Transduction, Genetic; D023001:Transplantation Tolerance; D014183:Transplantation, Heterologous
C499839:CD40Ig protein, recombinant; D018796:Immunoconjugates; D011993:Recombinant Fusion Proteins; D000069594:Abatacept