A COMPARISON OF THE IMMUNOSUPPRESSIVE EFFECTS OF CYCLOSPORINE A AND CYCLOSPORINE G IN VIVO AND IN VITRO

Abstract

In this study we compared the immunosuppressive effects of cyclosporine (Cs) A and G, both in vitro (human and rabbit) and in vivo (rabbit). The 50% inhibitory concentration (IC50) of CsG was up to three times greater than that of CsA for mitogen and alloantigen-induced lymphocyte proliferation (IC50 CsA 1 degree MLC = 19 +/- 4 micrograms/L vs. IC50 CsG = 60 +/- 7 micrograms/L; P < 0.01). Kinetic studies in both human and rabbit systems showed that the effectiveness of both drugs was similarly reduced when added at later times after culture initiation. The effects of CsA and CsG in combination on immune responses appeared to be antagonistic at higher and additive at lower drug doses. We also compared the ability of CsA and CsG to displace 3H-CsA from PBMC. The 50% displacement concentration (DC50) for CsG was up to three times greater than that for CsA (DC50 CsA = 1.44 +/- 2.49 x 10(-7) M vs. DC50 CsG = 3.9 +/- 5.4 x 10(-7) M; P < 0.05), suggesting that CsG does not bind as well to PBMC as CsA. In vivo studies using skin allografts confirmed in vitro findings. Both CsA and CsG at 5 and 10 mg/kg/day significantly (P < 0.01) prolonged graft survival compared with control animals. However, at these doses and even at 15 mg/kg/day CsG, CsA was more efficacious at prolonging skin graft survival in rabbits (P < 0.01), e.g., mean survival time (MST, days) 10 mg/kg/day CsA = > 20.5 vs. MST 15 mg/kg/day CsG = 15.0. These results suggest that both in vitro and in vivo in rabbits CsG is less immunosuppressive than CsA.