Long-term kidney graft survival by delayed T cell ablative treatment in rhesus monkeys.
Jonker M., Ringers J., Ossevoort MA., Slingerland W., van den Hout Y., Haanstra K., Wubben J., Kuhn E., Friend P., Calne R.
BACKGROUND: Tolerance to organ allografts in primates including man has been elusive, although in rodents and pigs tolerance can be achieved to organ allografts with relatively short courses of immunosuppressive treatment. In all varieties of graft acceptance that do not require full-dose maintenance immunosuppression, immunological engagement of donor and recipient and an early unstable period have been observed. On the basis of the hypothesis that elimination of aggressive T cell function should tip the balance in favor of an operationally tolerant state, experiments have been performed in monkeys allowing recipient-donor interaction before T-cell ablation and a short course of immunosuppression. METHODS: Rhesus monkeys received an allogeneic kidney graft from a MHC-mismatched donor. The animals either received anti-CD3 immunotoxin (FN18-CRM9) alone, started 2 days after transplantation, or in combination with a short course of cyclosporine (CsA) and/or rapamycin (RAPA), started at 5 days after transplantation. Kidney function was followed by monitoring serum creatinine levels and regular biopsies. Humoral and cellular antidonor immunity was tested in vitro before and at several time points after transplantation. RESULTS: Graft survival of monkeys that received CsA alone (mean survival time (MST)=29.3) was significantly prolonged compared with the controls (MST=6). FN18-CRM9 treatment alone also resulted in prolonged graft survival (MST=29.4). The combined treatment of FN18-CRM9 and CsA and/or RAPA resulted in prolonged graft survival after all immunosuppression was stopped (MST=207.8). CONCLUSIONS: It seems feasible to postpone immunosuppression posttransplantation and yet prevent allograft rejection without the need of permanent immunosuppression.