Long-term survival of xenografted neonatal cardiomyocytes by adenovirus-mediated CTLA4-Ig expression and CD40 blockade.
BACKGROUND
Prolonged survival of xenografted neonatal cardiomyocytes was achieved by blocking the CD28/B7 costimulatory pathway via CTLA4-Ig gene transfer. We examined the long-term survival of xenografted neonatal cardiomyocytes by adenovirus-mediated CTLA4-Ig expression and transient CD40 blockade with anti-CD40L monoclonal antibody (MR1).


RESULTS
Neonatal cardiomyocytes derived from Dark Agouti rats were infected with CTLA4-Ig-expressing adenovirus vectors and injected directly into the normal myocardium of C3H/He mice. Mice were also given an intraperitoneal injection of 500 microg MR1 (CTLA+MR group, n=30) or control immunoglobulin (CTLA group, n=30) 1 hour before and 1, 3, and 7 days after cardiomyocyte implantation. As a control, cells infected with beta-Gal-expressing adenovirus vector (RL group, n=15) and cells without infection (control group, n=15) were injected into additional mice. Mice from all groups were killed 2, 4, and 8 weeks after xenotransplantation, and mice from the CTLA+MR and CTLA groups were killed 4 and 6 months after xenotransplantation. Neonatal cardiomyocytes were successfully infected by adenovirus vectors. Immunohistochemical analysis showed that the xenografted cardiomyocytes survived and expressed CTLA4-Ig for 6 months in all mice from the CTLA+MR and CTLA groups. A gap junction between the xenografted and host cardiomyocytes was also confirmed. Conversely, neonatal cardiomyocytes did not survive for even 2 weeks after xenotransplantation in the mice from the RL and control groups.


CONCLUSIONS
Long-term survival of xenografted neonatal cardiomyocytes was achieved by adenovirus-mediated CTLA4-Ig expression and transient CD40 blockade.
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000276:immunology; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D018031:Connexin 43 / Q000032:analysis; D005500:Follow-Up Studies; D015870:Gene Expression; D005822:Genetic Vectors; D006085:Graft Survival; D006321:Heart / Q000254:growth & development; D018796:Immunoconjugates / Q000235:genetics* / Q000378:metabolism; D007365:Intercellular Junctions / Q000737:chemistry; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D018031:Connexin 43; D018796:Immunoconjugates; D023201:CD40 Ligand; D000069594:Abatacept