PENTOXIFYLLINE EXERTS SYNERGISTIC IMMUNOMODULATORY EFFECTS IN COMBINATION WITH DEXAMETHASONE OR CYCLOSPORINE-A

The methylxanthine derivative pentoxifylline (PTX) is an immunomodulat ory agent with incompletely characterized effects on cytokine producti on. To analyse these effects and to delineate new combination strategi es in immunotherapy, we have investigated immunomodulatory properties of PTX in combination with dexamethasone (DEX) or cyclosporin A (CsA). Stimulated human peripheral blood mononuclear cells were treated with clinically relevant concentrations of PTX (12.5-100 mu g/ml), DEX (0. 01-10 mu M) or CsA (12.5-50 ng/ml), alone or in combination. With incr easing doses of PTX the maximum supernatant titres of tumour necrosis factor (TNF)-alpha, interleukin (IL)-2 and interferon (IFN)-gamma decr eased concomitantly, and all cultures co-treated with DEX showed syner gism. Release of IL-6 was not consistently altered under PTX treatment . Similarly, PTX and CsA synergistically inhibited the release of IL-2 , IFN-gamma and, to a lesser degree, TNF-alpha. Although PTX alone did not significantly reduce lymphoproliferation, both combinations of dr ugs synergistically inhibited this process. Furthermore, to demonstrat e that the key mechanism of PTX-induced effects is an increase in intr acellular cyclic adenosine 3':5'-monophosphate (cAMP) levels, identica l experiments were performed using dibutyryl-cAMP instead of PTX. In c ultures treated with PTX and DEX, expression of different cell recepto rs was analysed. Expression of IL-2 receptor (IL-2R) was reduced in cu ltures treated with PTX, and combination with DEX led to further reduc tion. Expression of intercellular adhesion molecule (ICAM)-1 and of le ucocyte function antigen (LFA)-1 alpha was also synergistically reduce d, though to a lesser degree. HLA-DR expression remained unchanged. In conclusion, we demonstrate that clinically relevant levels of PTX exe rt profound immunomodulatory effects in vitro, and that the combined t reatment with DEX or CsA has synergistic effects.