Long-term survival of xenografted neonatal cardiomyocytes by adenovirus-mediated CTLA4-Ig expression and CD40 blockade

Circulation. 2003 Oct 7;108(14):1760-5. doi: 10.1161/01.CIR.0000091086.54107.49. Epub 2003 Sep 22.

Abstract

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).

Methods and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Adenoviridae / genetics*
  • Animals
  • Animals, Newborn
  • Antibodies, Monoclonal
  • CD40 Antigens / metabolism*
  • CD40 Ligand / immunology
  • Cell Differentiation
  • Cell Movement
  • Cells, Cultured
  • Connexin 43 / analysis
  • Follow-Up Studies
  • Gene Expression
  • Genetic Vectors
  • Graft Survival
  • Heart / growth & development
  • Immunoconjugates / genetics*
  • Immunoconjugates / metabolism
  • Intercellular Junctions / chemistry
  • Lymphocytes / immunology
  • Mice
  • Mice, Inbred C3H
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / transplantation*
  • Rats
  • Transplantation, Heterologous

Substances

  • Antibodies, Monoclonal
  • CD40 Antigens
  • Connexin 43
  • Immunoconjugates
  • CD40 Ligand
  • Abatacept