Bicistronic adenovirus-mediated gene transfer of CTLA4Ig gene and CD40Ig gene result in indefinite survival of islet xenograft

• DOI: 10.1016/j.transproceed.2003.10.064
• Publication Date: 2003-12-22T17:58:38Z
• Authors: Y.-Z Jin; S.-S Xie
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; 0303 health sciences; Immunoconjugates; CD40 Ligand; Graft Survival; Transplantation, Heterologous; Gene Transfer Techniques; Islets of Langerhans Transplantation; Antibodies, Monoclonal; Genetic Therapy; Rats; 3. Good health; Abatacept; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Rats, Inbred Lew; Animals; CD40 Antigens

Blockade of CD40-CD154 costimulatory pathway in mice and primates with anti-CD154 monoclonal antibodies results in prolonged survival of vascularized organs and islet grafts. CD40Ig, a recombinant fusion protein comprised of the extracellular domain of human CD40 molecule in frame fused with the site-mutated human IgG1 Fc region, abrogated the cognate interaction of CD40-CD154 pathway by binding the CD154 molecule. In this study, replication-defective adenovirus containing the CD40Ig gene was prepared by homologous recombination and used to infect freshly isolated islets from LEW rats (RT-1(1)) in vitro using a titered dose. The islet transfectants (500 per recipient) were transplanted under the left kidney capsule of streptozocin-rendered diabetic C57BL/6 mouse recipient (H-2(b)). The mean survival time of AdCD40Ig-transfected islet grafts was significantly prolonged, while mock-infected grafts and AdEGFP-transfected grafts were rejected in normal fashion. Additionally, dose-dependent prolongation of islet graft survival was observed in mice receiving AdCD40Ig-transfected grafts. In conclusion, local production of Cd40Ig via adenoviral-mediated gene transfer induced dose-dependent prolongation of LEW --> Balb-c islet xenografts.