INVITRO AND INVIVO COMPARATIVE-STUDIES ON IMMUNOSUPPRESSIVE PROPERTIES OF CYCLOSPORINE-A, CYCLOSPORINE-C, CYCLOSPORINE-D AND METABOLITE-M1,METABOLITE-M17, AND METABOLITE-M21

Cyclosporine A (CsA) and its major metabolites : M1, M17 and M21 and t wo analogues : cyclosporines C (CsC) and D (CsD), were studied for the ir capacity to interfer with different in vitro activation pathways. T heir inhibition potentials against the reaction of Graft-versus-Host ( GvH) were also studied. The results showed : CsA, CsC and metabolite M 17 were the most active compounds upon the inhibition of lymphocyte pr oliferation induced by different mitogens (ConA, PHA, PWM) and also on the proliferation of mixed lymphocyte cultures (MLC). The same result s were observed concerning the direct activation by protein kinase C u sing a combined action of phorbol ester + calcium ionophore. In vivo u sing local GvH reaction, CsA and CsC proved more active than M17 in th e two different combinations : H-2d --> (H-2b x H-2d)F1 and H-2k --> ( H-2b x H-2k)F1 CsD and two metabolites M1 and M21 showed no or weak im munosuppressive effects. Overall, the immunosuppressive potency of six compounds could be schematized as : CsA greater-than-or-equal-to CsC > M17 > M1 greater-than-or-equal-to CsD > M21