Recurrent infections are common features in patients affected by propionic acidaemia (McKusick 232000) and methylmalonic acidaemia (McKusick 251000). Since these disorders are biochemically characterized by tissue accumulation of propionic acid and methylmalonic acid respectively, it is possible that these compounds may act as immunosuppressants. We therefore investigated the effect of propionate and methylmalonate on cellular growth of human peripheral lymphocytes stimulated in vitro by phytohaemagglutinin, concanavalin A and pokeweed mitogen, a recognized test of cellular immunocompetence. Lymphocytes were cultured in flat-bottomed 96-well microplates at 37 ;°C for 96 ;h (phytohaemagglutinin and concanavalin A) or 144 ;h (pokeweed mitogen) in the presence of one mitogen at different concentrations and of one acid added at doses of 1.0, 2.5 or 5.0 ;mM. Cell blastogenesis was measured by the incorporation of tritiated thymidine into cellular DNA and compared with that of identical cultures with no acid added (controls). A consistent and progressive inhibitory effect of propionic acid with increasing concentrations in culture was identified with all mitogens and was more pronounced 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. The viability of lymphocytes after treatment with the drug, as assessed by the Trypan Blue exclusion test, revealed no change when compared with the same untreated lymphocytes, indicating no lymphocytotoxic activity. In conclusion, propionic acid, which accumulates in tissues of patients with propionic acidaemia, causes ‘ in vitro ’ immunosuppression, which may be related to the recurrent infections characteristic of these patients.

1. The effects of a variety of fatty acids on human peripheral blood lymphocyte proliferation stimulated by concanavalin A or purified protein derivative of Mycobacterium tuberculosis were studied. 2. The proliferative response to concanavalin A was inhibited by all of the polyunsaturated fatty acids tested (eicosapentaenoate, arachidonate, docosahexaenoate, linoleate and α-linolenate) and also by the saturated fatty acid, stearate. The greatest inhibition of proliferation (approximately 85%) was caused by eicosapentaenoate. 3. The proliferative response to the purified protein derivative of Mycobacterium tuberculosis was inhibited by all of the polyunsaturated fatty acids tested, except α-linolenate, and also by stearate. The greatest inhibition of proliferation (approximately 75%) was caused by eicosapentaenoate. 4. The pattern of inhibition of proliferation by fatty acids was similar to that previously reported for rat lymphocytes with one exception: oleate did not inhibit human lymphocyte proliferation. 5. The proliferation of T-lymphocytes is dependent upon their ability to synthesize and secrete the cytokine, interleukin-2. In the presence of mitogen the concentration of interleukin-2 in the culture medium increased markedly above that in the medium of non-stimulated cells. 6. All polyunsaturated fatty acids tested caused a decrease in the concentration of interleukin-2; the greatest decrease (approximately 90%) was caused by eicosapentaenoate. 7. There was a good correlation between lymphocyte proliferation in the presence of fatty acids and interleukin-2 concentration. However, stearate did not decrease the interleukin-2 concentration but did inhibit lymphocyte proliferation. 8. These observations suggest that, although fatty acid suppression of interleukin-2 production may play a role in the inhibition of proliferation, it is not the sole mechanism by which fatty acids act.