IL-2-INDUCED GVHD PROTECTION IS NOT INHIBITED BY CYCLOSPORINE AND IS MAXIMAL WHEN IL-2 IS GIVES OVER A 25-H PERIOD BEGINNING ON THE DAY FOLLOWING BONE-MARROW TRANSPLANTATION

We have recently demonstrated, in a fully MHC-mismatched murine bone m arrow transplantation (BMT) model, that administration of a short cour se of high-dose interleukin 2 (IL-2) markedly delays the onset of graf t-versus-host disease (GVHD) without compromising alloengraftment or t he graft-versus-leukemia (GVL) effect of allogeneic T cells, Early tim ing of IL-2 administration and high dose were shown to be critical to achieve this protective effect, Although a 2.5 day course of IL-2, beg un on the day of BMT, was found to confer marked protection without ob servable toxicity, shorter courses and a higher dose of IL-2 than 5 x 10(4) Cetus units per treatment have not been previously evaluated in this model, We now demonstrate that administration of a three-treatmen t course of IL-2 over a 25 h period beginning 15 h following BMT is su fficient to provide maximal GVHD protection, that increasing the IL-2 dose beyond 5 x 10(4) units per treatment does not further improve the level of GVHD protection, and that further division of IL-2 treatment s to achieve more constant tissue levels does not result in improved G VHD protection, We also demonstrate that IL-2 is still protective when administered in combination with cyclosporine, These results suggest that IL-2 administered in a sufficient short course to avoid toxicity might have the potential to achieve effective GVHD prophylaxis in huma ns, even if given in combination with cyclosporine.