Inhibition of mitogen-activated proliferation of human peripheral lymphocytes in vitro by propionic acid

Recurrent infections are com mon features in patients affected by propionic acidaemia (McKusick 232000) and methylmalonic acidaemia (McKusick 251000). Since these disorders are biochemically characterized by tissue accumulati on of propionic acid and methylmalonic acid respectively, it is possible th at these compounds may act as immunosuppressants. We therefore investigated the effect of propionate and methylmatonate on cellular growth of human pe ripheral lymphocytes stimulated in vitro by phytohaemagglutinin, concanaval in A and pokeweed mitogen, a recognized test of cellular immunocompetence. Lymphocytes were cultured in flat-bottomed 96-well microplates at 37 degree s C for 96 h (phytohaemagglutinin and concanavalin A) or 144 h (pokeweed mi togen) in the presence of one mitogen at different concentrations and of on e acid added at doses of 1.0, 2.5 or 5.0 mM. Cell blastogenesis was measure d by the incorporation of tritiated thymidine into cellular DNA and compare d with that of identical cultures with no acid added (controls). A consiste nt and progressive inhibitory effect of propionic acid with increasing conc entrations in culture was identified with all mitogens and was more pronoun ced with pokeweed mitogen. Lymphocyte blastogenesis was not altered in the presence of methylmalonic acid. The effect of propionate was observed only when the drug was added at the beginning (phytohaemagglutinin-activated) or until 24 h (concanavalin A- and pokeweed mitogen-activated) of culture. Th e viability of lymphocytes after treatment with the drug, as assessed by th e Trypan Blue exclusion test, revealed no change when compared with the sam e untreated lymphocytes, indicating no lymphocytotoxic activity. In conclus ion, propionic acid, which accumulates in tissues of patients with propioni c acidaemia, causes 'in vitro' immunosuppression, which may be related to t he recurrent infections characteristic of these patients.