The effect of novel immunosuppressants on extracellular matrix remodelling and the expression of fibrosis associated genes in an experimental model of allograft vasculopathy

Background: Chronic allograft dysfunction (CAD), the leading cause of solid organ transplant failure, is characterised by histological evidence of parenchymal extracellular matrix (ECM) accumulation (fibrosis) and allograft vasculopathy. The aim of this study was to compare the effects of rapamycin and cyclosporin therapy, individually as well as in combination, on fibrosis associated gene expression and ECM remodeling in an experimental model of allograft vasculopathy. Methods: Vascular remodeling and ECM accumulation (picrosirius red) were measured by computerised histomorphometry of F344 to Lewis rat aortic allograft sections harvested at serial time points. Expression of fibrosis associated genes was studied by means of semi-quantitative RT-PCR. Results: Rapamycin (0.5mg/kg/day) or cyclosporin (5mg/kg/day) inhibited intimal hyperplasia, medial ECM accumulation and expansive vascular remodeling (increasing vessel circumference) in rat aortic allografts. This was associated with attenuation of the graft inflammatory infiltrate and a reduction in intra-graft gelatinase, collagen III and TIMP 1 mRNA levels. At a lower dose (0.25mg/kg/day) Rapamycin inhibited intimal hyperplasia and medial ECM accumulation however there was a lesser effect on vascular remodeling compared to cyclosporin or rapamycin 0.5mg/kg/day. Combined rapamycin and cyclosporin also inhibited intimal hyperplasia however there was a lesser effect on both vascular remodeling and medial extracellular matrix accumulation. Combined treatment or rapamycin 0.25mg/kg/day monotherapy aortic allografts were also seen to have a more severe inflammatory infiltrate and larger amounts of intra-graft MMP 9, TGFp and TIMP 1 mRNA than cyclosporin or rapamycin 0.5mg/kg/day monotherapy. Conclusion: These data suggest that in addition to the tissue response to injury, the alloimmune injury itself may directly contribute to vascular and ECM remodeling. In this experimental model rapamycin inhibited vascular remodeling and ECM accumulation only in the presence of effective immunosuppression.