Theophylline and the immune response: in vitro and in vivo effects

We analyzed the in vitro and in vivo effects of theophylline on various immunological parameters including proliferation of peripheral mononuclear cells (PMNC) in response to phytohemagglutinin (PHA), anti-T3 and anti-T11 monoclonal antibodies (MAb), PHA-induced interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production by PMNC, interleukin-1 (IL-1) production by accessory cells, PHA-induced IL-2 production by T-cell clones, and PHA- and anti-T3 MAb-induced DNA synthesis by T cell clones. Results showed that theophylline inhibited PHA- and anti-T3-induced proliferation of both PMNC and T-cell clones, whereas the PMNC proliferation induced by MAb anti-T11 was not affected. The inhibition appeared to be dose-dependent and strictly related to the presence of the drug in the culture. Moreover, PHA-induced IL-2 production by both PMNC and T-cell clones also appeared to be reduced by theophylline. IL-1 production by accessory cells was not affected. These data suggest that the immunological inhibition exerted by theophylline is confined to the T-cell compartment, mainly by acting on structure(s) related to the T3/Ti complex, the primary site for T-cell activation. The alternative pathway of T-cell activation (i.e., via T11 site) seems unaffected. In addition, these results suggest possible clinical relations between the inhibition of the immune response and the plasma levels of the drug reached after a "once daily" or "twice daily" oral ingestion of slow-release theophylline products.