Intrathymic immune modulation prevents acute rejection but not the development of graft arteriosclerosis (chronic rejection)

Background. We showed previously that our intrathymic immune modulation pro tocol induces virtually permanent graft survival of simultaneously transpla nted cardiac allografts in MHC-incompatible rat strain combinations. It is, however, unknown whether this procedure prevents the development of graft arterial disease (GAD). Methods. Male AO recipient rats were intrathymically inoculated with 2.5 x 10(7) PVG splenocytes immediately followed by heterotopic transplantation o f a PVG cardiac allograft (day 0). Immunosuppression consisted of 1 mi of a ntilymphocyte serum i.p. (day 0) and cyclosporine i.m. (15 mg/kg body weigh t) on days 1, 2, and 3 posttransplantation. Histological analysis, mixed ly mphocyte reactions, and intragraft cytokine mRNA expression were performed at several time points after engraftment. Results. Histological analysis revealed that GAD was already present 14 day s after transplantation. At 200 days, virtually all vessels were affected a nd over 80% of the vessels showed severe intimal lesions, Infiltrate analys is displayed massive parenchymatous infiltrates (CD8(+) cells and ED1(+) ma crophages) 2 weeks after transplantation. At later time points, infiltrates became epicardial and/or blood vessel associated and mainly consisted of C D4(+), CD8(+), and B cells. Mixed lymphocyte reactions showed nonspecifical ly decreased responses at 60 days but complete restoration of these respons es at later time points (120 to 280 days). Intragraft cytokine mRNA express ion showed decreased interleukin-2/interferon-gamma and sustained interleuk in-10 expression 2 weeks after transplantation. Transforming growth factor- p mRNA expression was increased >200 days after transplantation. Conclusions. Intrathymic immune modulation does not abolish alloreactivity, and despite induction of long-lasting graft survival, this procedure does not prevent and may even facilitate the development of GAD.