Background-Sirolimus reduces acute rejection in renal transplant recipients and prevents vasculopathy in nonhuman primates and in-stent restenosis in humans. Its effects on rejection and transplant vasculopathy in human heart transplant recipients are unknown. Methods and Results-In a randomized, open-label study, sirolimus was compared with azathioprine in combination with cyclosporine and steroids administered from the time of cardiac transplantation. We report 6-month rejection rates (primary end point), 12-month safety and efficacy data, and 6-and 24-month graft vasculopathy data in 136 cardiac allograft recipients randomly assigned (2:1) to sirolimus (nϭ92) or azathioprine (nϭ44). At 6 months, the proportion of patients with grade 3a or greater acute rejection was 32.4% for sirolimus 3 mg/d (Pϭ0.027), 32.8% for sirolimus 5 mg/d (Pϭ0.013), and 56.8% for azathioprine. Patient survival at 12 months was comparable among groups. Intracoronary ultrasound at 6 weeks, 6 months, and 2 years demonstrated highly significant progression of transplant vasculopathy in azathioprine-treated patients. At 6 months, a highly significant absence of progression in intimal plus medial proliferation and significant protection against luminal encroachment was evident in sirolimus-treated patients, and these effects were sustained at 2 years. Conclusions-Sirolimus use from the time of transplantation approximately halved the number of patients experiencing acute rejection. The measurable development of transplant vasculopathy at 6 months and 2 years in patients receiving azathioprine was not observed in patients receiving sirolimus.

The treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (PTLD) in EBV seronegative solid organ transplant recipients who acquire their EBV infection after engraftment poses a considerable challenge because of underlying immunosuppression that inhibits the virus-specific cytotoxic T cell (CTL) response in vivo. We have developed a protocol for activating autologous EBVspecific CTL lines from these patients and show their potential use for immunotherapy against PTLD in solid organ transplant patients. Peripheral blood mononuclear cells from a panel of solid organ transplant recipients with and without active PTLD were used to assess EBV-specific memory CTL responses. The activation protocol involved cocultivation of peripheral blood mononuclear cells with an autologous lymphoblastoid cell line under conditions that favored expansion of virus-specific CTL and hindered the proliferation of allospecific T cells. These CTL consistently showed (i) strong EBV-specificity, including reactivity through defined epitopes in spite of concurrent immunosuppressive therapy, and (ii) no alloreactivity toward donor alloantigens. More importantly, adoptive transfer of these autologous CTLs into a single patient with active PTLD was coincident with a very significant regression of the PTLD. These results demonstrate that a potent EBV-specific memory response can be expanded from solid organ recipients who have acquired their primary EBV infection under high levels of immunosuppressive therapy and that these T cells may have therapeutic potential against PTLD.