PCP and analogs prevent the proliferative response of T lymphocytes by lowering IL2 production. An effect related to the blockade of mitogen-triggered enhancement of free cytosolic calcium concentration

Abstract

The psychotomimetic drug PCP displays a vast array of known pharmacological effects, among them its capacity to affect cation transport in nervous and myocardiac tissues. Since increased movements of cations are essential for the immune responses, it has been mentioned that PCP could also depress immune functions by this mechanism. In order to check this hypothesis, we have investigated the effects of PCP and of many other structural derivatives on the blastogenic response of murine or human T lymphocytes. We find that all the drugs block an early event of T lymphocyte activation and prevent their further proliferation; conversely they do not affect primed lymphocytes. The compounds, which do not inhibit interleukin-1 (IL-1) production in stimulated macrophages, lower interleukin-2 (IL-2) synthesis in activated T helper cells. This negative action appears to be related to the inhibition of the rise of free cytosolic calcium concentration [Ca2+]i observed soon after the T receptor triggering and which is an essential message for IL-2 production. The lymphocyte membrane depolarization induced by the drugs could explain the blockade of the lectin-induced [Ca2+]i changes. The study of the structure-activity relationship shows that the PCP analogs which possess a quasi-rigid conformational structure express an inhibitory capacity of T lymphocyte proliferation higher than that of PCP (200 times for some products). Since these compounds interact poorly with the CNS tissues and have few behavioral effects, we suggest that PCP exerts its negative action on lymphocytes on cell components different from its receptor(s) in the CNS.