Effect of p53 gene therapy combined with CTLA4Ig selective immunosuppression on prolonged neointima formation reduction in a rat model

In a previous study, we have demonstrated a significant reduction of neoint imal formation following adenovirus-mediated gene transfer of p53 to the in jured rat carotid artery. The purpose of this study was to determine if the effect of p53 gene in reducing neointimal formation would still be present up to 8 weeks after arterial injury and whether it could be enhanced by ad ding immunosuppression. Cytotoxic T lymphocyte-associated antigen-4 Ig (CTL A4Ig), a novel immunosuppressive agent, is a recombinant soluble protein th at blocks T cell-dependent immune response. Animals were divided into eight groups (n = 6 in each). In vivo gene transfer was used in isolated segment s of balloon-injured rat carotid arteries. Genetically modified adenovirus encoding for wild-type p53 protein was applied at 8 x 10(10) pfu/ml. Contro l rats received adenovirus null at the same concentration. A daily dose of 300 mu g of CTLA4Ig was given intraperitoneally, either once, twice, or thr ee times. Expression of p53 was determined by Western blot analysis. Neoint imal formation was assessed at 4 or 8 weeks by harvesting carotid arteries and determining the intima/media (I/M) ratio cross-sectional area measureme nts. p53 expression was confirmed by Western blot analysis. We concluded th at adenovirus-mediated p53 gene transfer significantly decreases the format ion of neointima up to 8 weeks following rat carotid injury. However, there is loss of effectiveness on neointimal formation inhibition as time elapse s. When CTLA4Ig is added, there is significant improvement in results, with sustained neointimal formation inhibition at 8 weeks after the procedure. DOI: 10.1007/s100169910077.