Alpha interferon combined with ribavirin potentiates proliferative suppression but not cytokine production in mitogenically stimulated human lymphocytes

The improved clinical outcome observed among patients with hepatitis C trea ted with the combination of alpha interferon (IFN) and ribavirin (RBV) is p resumed to result from immunomodulation and viral inhibition. However, the impact of the drug combination upon lymphocyte activity is unknown. The pre sent study evaluated the effects of IFN and RBV, singly and in combination, upon proliferation, cell cycle sensitivity and cytokine elaboration follow ing PHA stimulation of lymphocytes. Two formulations of IFN, interferon-a-2 b (IFN-2b) and interferon-a-con-1 (CIFN), were included. Titration of each drug over a wide range of concentrations showed dose dependent proliferativ e suppression without cytotoxicity. Proliferation was suppressed 57-99% (P < 0.001) by IFN-2b (10(5)-10(7) IU/ml), 41-74% (P < 0.001) by CIFN (1.5-150 ng/ml), and 10-94% (P < 0.001) by RBV (0.5-50 <mu>g/ml). Isobologram analy sis showed that the interaction between IFN-2b and RBV on proliferative sup pression was additive. In contrast, the interaction between CIFN and RBV wa s weakly antagonistic. Proliferative suppression by both the IFNs was cell cycle restricted. IFN-2b and CIFN added at the onset of PHA stimulation (G0 /G1) versus 24 h later (S phase) inhibited proliferation by 50 versus 5%, r espectively (P < 0.05). The onset of IFN resistance correlated with a 50% r eduction (P < 0.05) in IFN receptors on the cell surface. In contrast, RBV caused equivalent proliferative suppression (P = NS) when added at any time during PHA activation. Cytokine secretion after 24 h of PHA stimulation sh owed that IFN-2b versus CIFN increased the secretion of IL2, TNF and gamma IFN by 4.5-, 4.1- and 8.3-fold (P < 0.005) versus 1-, 1.9- and 1.9-fold (P < 0.05), respectively, above control levels. Neither IFN affected IL10 secr etion. RBV, singly and in combination with IFN, had no impact on cytokine e xpression (P = NS). This study identifies several potential mechanisms by w hich the combination of IFN and RBV may exert a more potent effect upon cel lular immunity than either agent alone and shows that different formulation s of IFN may have non-identical effects upon lymphocyte responses. (C) 1999 Elsevier Science B.V. All rights reserved.