PENTOXIFYLLINE INHIBITS GRANZYME-B AND PERFORIN EXPRESSION FOLLOWING T-LYMPHOCYTE ACTIVATION BY ANTI-CD3 ANTIBODY

Pentoxifylline (PTX), a methylxanthine derivative, is known to inhibit the production of the Thl cytokines interleukin-2, tumour necrosis fa ctor-alpha and interferon-gamma. Because these cytokines play an impor tant role in promoting the development of cell-mediated immunity, we h ypothesized that PTX would also interfere with the generation of cytot oxic effector cells in response to an immunological stimulus. In this study we used a mouse model system to investigate the effect of PTX on the induction of non-specific killer lymphocytes by anti-CD3 monoclon al antibody. Anti-CD3-induced T-cell proliferation and the generation of anti-CD3-activated killer (AK) cells was inhibited in a dose-depend ent fashion by PTX (25-100 mu g/ml). The inhibitory effect of PTX coul d not be attributed to a defect in the recognition/adhesion phase of c ytolysis because AK cells generated in the presence of PTX conjugated normally with P815 tumour target cells. However, AK cell expression of the cytoplasmic granule-associated cytolytic effector molecules granz yme B and perforin was markedly reduced when AK cells were induced in the presence of PTX. In contrast, PTX had no effect on AK cell express ion of Fas ligand, a cell-surface cytolytic effector molecule which is involved in granule-independent cytotoxicity. PTX thus has a profound inhibitory effect in vitro on the induction of granule-dependent cyto lytic effector mechanisms in a mouse model system. (C) 1997 Internatio nal Society for Immunopharmacology.