Comparative evaluation of in vitro and in vivo immunosuppressive potential of cyclosporin G with cyclosporin A and FK-506.
Cyclosporin G (CsG), a promising cyclosporin A (CsA) analogue, was examined and compared with two reference immunosuppressive drugs: CsA and FK-506, regarding their inhibitory effects on different lymphocyte activation pathways as well as on graft-versus-host reaction (GvHR) across differences at major or minor histocompatibility loci. The results showed that, at different concentrations, CsG efficiently inhibited proliferation induced by alloantigens (mixed lymphocyte culture), mitogens (concanavalin A, pokeweed mitogen) and the combination of phorbol myristate acetate + ionomycin, to the same extent as observed with CsA and FK-506. It was also shown that CsG exhibited the same strong inhibitory effects as the two other immunosuppressants upon stimulation triggered by viral (MLs-1a) or bacterial (staphylococcal enterotoxin B) superantigen. Determination of IL-2 activity in the supernatant of MLC also confirmed similar strong inhibitory effects, exerted by CsG compared to CsA and FK-506. In systemic and local GvHR across major or minor histocompatibility barriers, CsG as well as CsA and FK-506 presented an equivalent immunosuppressive potential. In conclusion, from various experiments involving different modes of activation, it was shown that CsG was as strongly immunosuppressive as CsA and FK-506.
Saada
V
V
Laboratoire de Toxicologie (EA207), Faculté de Pharmacie, Paris, France.
Pham-Huy
C
C
Voisin
J
J
Righenzi
S
S
Rucay
P
P
Claude
J R
JR
Duc
H T
HT
D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D006087:Graft vs Host Reaction / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D007376:Interleukin-2; C045571:cyclosporin G; D016572:Cyclosporine; D016559:Tacrolimus