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Adenovirus-Mediated CTLA4Ig or CD40Ig Gene Transfer Delays Pancreatic Islet Rejection in a Rat-to-Mouse Xenotransplantation Model After Systemic But Not Local Expression

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Abstract:

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 (IM) or intravenous (IV) 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, IM AdCTLA4Ig and IV 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 IV 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, IM or IV 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.

Keywords: Adenovirus; CD40Ig; CTLA4Ig; Costimulation; Gene transfer; Islet transplantation; Xenotransplantation

Document Type: Review Article

DOI: http://dx.doi.org/10.3727/000000005783983052

Affiliations: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR643 and Institut de Transplantation et de Recherche en Transplantation, Centre Hospitalo-Universitaire, 30 boulevard Jean Monnet, 44093 Nantes Cedex 01, France

Publication date: May 1, 2005

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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