The significance of timing of additional short-term immunosuppression in the donor-specific transfusion/cyclosporine-treated rat.

It is hypothesized that the mechanism, or mechanisms, responsible for donor-specific transfusion (DST)/cyclosporine (CsA) immunosuppression is generated by an active immune response that is most dynamic in the immediate peritransplant period and thus might be at the peak of vulnerability to the influences of added immunosuppression. To better define this concept, four immunosuppressive drugs were combined with a d-1 DST and 14-day course of CsA in the ACl-to-Lewis cardiac transplant model. A 5-day course of antithymocyte globulin (ATG) initiated at d-1 or d+4 with DST/CsA reduced survival vs. DST/CsA alone (27.0 +/- 2.6 days and 24.6 +/- 5.7 days vs. 95.3 +/- 16.3 days, P<.05). Delay of initiation to d+7 improved survival to 39.5 +/- 8.9 days. A 5-day course of methylprednisolone (MP) begun at d-1 with DST/CsA decreased survival vs. DST/CsA alone, 59.2 +/- l0.0 days vs. 95.3 +/- 16.3 days, but delay to d+4 improved survival to 110 +/- l8 days, P<.05 vs d-1. A 3-day course of brequinar (Breq) begun at d-1 with DST/CsA increased survival to 244 +/- 48.6 days, while delay to d+4 reduced survival to 49.0 +/- 6.7 days, P<.05 vs. d-1. Finally, a 5-day course of rapamycin (Rapa), was given with d-1 DST/CsA treatment beginning on d-1, d0, d+l, d+3, d+5, and d+7. In this instance, no significant differences in survival were found between timing groups or DST/CsA control. Together, these data support the hypothesis that DST/CsA treatment generates an active immune response that is inhibited by early initiation of ATG or MP, enhanced by early administration of Breq, and unchanged by early administration of Rapa.