Potential immunomodulatory activity of phenylphosphonothioates

In the course of immunotoxicological studies of several organophosphorous compounds, it was noted that some phenylphosphonothioates enhanced the activation of rat splenocytes by concanavalin A. In the present study some of these compounds were compared to the well-characterized immunomodulatory thiol, 2-mercaptoethanol (2-ME). Two of the compounds are able to substitute for 2-ME and allow near maximal growth of a strictly 2-ME-dependent lymphocyte cell line (CTLL-2). These compounds exhibit essentially additive effects with 2-ME on CTLL-2 cells and rat splenocytes. In agreement with previous results with 2-ME, the phosphonothioates have essentially no effect on interleukin-2 production in mitogen-stimulated splenocyte cultures. One phosphonothioate, as well as its possible thiol hydrolysis product, supports cell survival and enhanced cystine incorporation by CTLL-2 cells. However, 2-ME was more effective in stimulation of enhanced generation of extracellular thiols than were the other agents. These results suggest very similar modes of action for phosphonothionates and 2-ME. Finally, a phosphonothioate selected for low neurotoxic potential was examined and found to effectively support lymphocyte growth in vitro and to exhibit relatively low acute toxicity in mice.