Background. Interleukin- (IL) 15 is a potent non-T cell-derived cytokine with IL-2-like activities. Elevated levels of IL-15 expression were observed in biopsies of acutely rejected human kidney grafts. We tested the role of IL-15 in mixed lymphocyte kidney reaction (MLKR) and the effects of immunosuppressive drugs on this reaction. Methods. Primary cultures of human tubular epithelial cells (TEC) were stimulated by interferon-γ and treated with cyclosporin A (CsA, 10-1000 ng/ml), rapamycin (Rapa, 2.5-10 ng/ml), and dexamethasone (Dex, 10-10-10-7 M). IL-15 levels were measured by ELISA. To induce MLKR, we seeded OKT3-prestimulated allogenic human peripheral blood mononuclear cells (PBMC) on a monolayer of TEC in the presence of CsA (25-250 ng/ml), Rapa (0.25-1 ng/ml), and Dex (10-10-10-7 M). PBMC proliferation was quantified by 3H-thymidine incorporation. Results. CsA, Dex, and Rapa had no effect on IL-15 production by TEC. The presence of TEC induced marked proliferation of PBMC. Pretreatment of TEC with IFN-γ enhanced MLKR in direct correlation with the increased IL-15 levels. MLKR was blocked by anti-IL-15, but not significantly by anti-IL-2 monoclonal antibody. Contrary to Rapa and Dex, CsA failed to inhibit MLKR. Conclusions. IL-15 is a major mediator of lymphocyte proliferation in MLKR. Its production by TEC was unaffected by CsA, Rapa, and Dex. However, IL-15 activity is effectively inhibited by Rapa and Dex but not by CsA. The diversity in the effects of the various drugs is probably related to the different mechanisms. Our results support the possible involvement of renal IL-15 in graft rejection and suggest that resistance to CsA treatment is related to its failure to decrease IL-15 activity.