Inhibition of cytokine production by cyclosporine A and G.

Cyclosporine G (CsG) is an analogue of CsA that may not have the nephrotoxicity of CsA. Not much is known about the relative immunosuppressive activity of CsG compared with CsA in humans. For this reason we compared the effects of CsA and CsG on in vitro interferon gamma production by mitogen and alloantigen-stimulated peripheral blood mononuclear cells from normal individuals. We also investigated the effects of CsA and CsG on the production of lymphotoxin (LT) and tumor necrosis factor (TNF) activity, as these cytokines have been implicated in transplant rejection. Both CsA and CsG showed very similar dose-dependent inhibition of IFN-G and LT/TNF activity (IC50 CsA for IFN-G = 8.0 ng/ml, for LT/TNF = 9.5 ng/ml; IC50 CsG for IFN-G = 13.0 ng/ml, for LT/TNF = 13.0 ng/ml). Maximum suppression was seen if the drugs were added at culture initiation and suppression was reduced if the drugs were added 24 hr later. Both CsA and CsG showed significant dose- and time-dependent inhibition of IFN-G production in 2 degrees MLC. LT/TNF activity was suppressed by CsA and CsG in 2 degrees MLC, which was also dose- and time-dependent. These results suggest that CsG has an immunosuppressive profile similar to that of CsA and may therefore be useful in clinical situations where CsA nephrotoxicity is a problem.