The effect of cyclosporin A, FK506, and rapamycin on the murine chronic graft-versus-host response--an in vivo model of Th2-like activity.
We have evaluated the effects of three potent immunosuppressive agents: cyclosporin A, FK506, and rapamycin, on a murine chronic graft-versus-host response (chronic GVHR). The chronic GVHR has previously been described to be a Th2-like response, and is characterized by a marked splenomegaly and hyper-IgE production in the early stages of the response. The effects of the immunosuppressive agents on both splenomegaly and hyper-IgE were measured 3 weeks after the induction of the chronic GVHR. Rapamycin was found to inhibit both splenomegaly and the hyper-IgE response in a dose-dependent manner. Unexpectedly cyclosporin A and FK506 were found to potentiate markedly both the splenomegaly and hyper-IgE response at low doses before exhibiting an inhibitory effect at higher doses. We propose the differences of activity seen with rapamycin compared with cyclosporin A and FK506 may be explained by their different mechanisms of action, and also by the selectivity of low dose cyclosporin A and FK506 for Th1-like lymphocytes. The implications of these observations are discussed in relation to the use of these immunosuppressives for the treatment of Th2-like diseases.
Bundick
R V
RV
Department of Biochemistry, Fisons plc--Pharmaceutical Division, Loughborough, UK.
Craggs
R I
RI
Holness
E
E
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D006087:Graft vs Host Reaction / Q000187:drug effects*; D007073:Immunoglobulin E / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011090:Polyenes / Q000494:pharmacology; D020123:Sirolimus; D013163:Splenomegaly / Q000517:prevention & control; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D011090:Polyenes; D007073:Immunoglobulin E; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus