Decreased macrophage-mediated suppression of lymphocyte activation in chronic renal failure

Prostaglandin-dependent adherent cell suppressor activity was assessed in patients with end-stage renal insufficiency. Proliferative responses of uremic peripheral blood mononuclear cells to optimal concentrations of phytohemagglutinin and concanavalin A were impaired. Responses to the galactosyl-directed lectins, soybean agglutinin and peanut agglutinin, were, however, normal or supranormal. The addition of 1 μg/ml of indomethacin, to cell cultures resulted in relatively less potentiation of blastogenic responses to the galactosyl-directed lectins in cells from uremic patients (soybean agglutinin, p < 0.02; peanut agglutinin, p < 0.05). Similarly, depletion of adherent cells markedly enhanced blastogenesis induced by the galactosyl-directed lectins in normal cell cultures, whereas the effect was much less pronounced (soybean agglutinin, p < 0.02; peanut agglutinin, p < 0.02) in uremic cells. Reduced activity of the adherent cell suppressor system in patients with renal failure might be associated with altered sensitivity of uremic lymphocytes to soluble mediators of suppression. The lymphocytes of uremic patients, depleted of adherent cells, were relatively resistant to the inhibitory action of prostaglandin E 1 (0.001 μg/ml, p < 0.05, and 0.01 μg/ml, p < 0.02) on galactosyl-directed, lectin-induced mitogenesis. In contrast, dibutyryl cyclic AMP (10 −4 M), 8-bromo cyclic AMP (10 −5 M), and 3-isobutyl-1-methyl xanthine (20 μg/ml) inhibited both control subject and patient cultures to the same extent. Prostaglandin E 1 in combination with methyl isobutyl xanthine produced, in adherent-cell-depleted control subjects, levels of cyclic AMP that were significantly higher than in cells from uremic patients (p < 0.05). Thus, depressed adherent cell suppressor activity in patients with renal failure may result in part from impaired generation of cyclic AMP by lymphocytes.