ABSTRACT
The anti-depressive drug trifluoperazine (TFP) was studied on in vitro immune responses. TFP proved to be an inhibitor of lymphokine-activated killer (LAK) cells in its generative step, as well as in its effector phase. Natural killer (NK) activity and interleukin-2 (IL-2) or mitogen-induced lymphocyte proliferation were just as sensitive to the drug effects, whereas the division of tumor cells was more resistant. The mechanism through which TFP suppresses these lymphocytic systems remains unclear. It does not, however, affect an early stage of cellular activation as the addition of the drug as late as 24 h after the start of the culture was still inhibitory for lymphocyte mitogenesis. Neither the expression of CD25, nor that of CD56 was affected by TFP, and exogenous IL-2 was unable to overcome the suppression of proliferation. In relation to cell-mediated cytotoxicity, TFP partially interfered with the effector/target binding. However, addition of lectin to the assay did not overcome the inhibition of lysis produced by the drug. Although further work remains to be done, the effect of TFP on immune responses must be taken into consideration when treating immunosuppressed patients.
Subject(s)
Killer Cells, Lymphokine-Activated/drug effects , Trifluoperazine/toxicity , Antigens, Differentiation, T-Lymphocyte/drug effects , Antigens, Differentiation, T-Lymphocyte/genetics , Binding, Competitive , Cell Division/drug effects , Dipeptidyl Peptidase 4/biosynthesis , Flow Cytometry , Humans , Immunosuppression Therapy , Interleukin-2/pharmacology , Killer Cells, Natural/drug effects , Leukemia, Erythroblastic, Acute/pathology , Leukemia, T-Cell/pathology , Lymphocyte Activation/drug effects , Lymphocyte Activation/genetics , Mitogens/pharmacology , Receptors, Interleukin-2/biosynthesis , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Tumor Cells, CulturedABSTRACT
A large amount of evidence points towards the potential role of lymphokine activated killer (LAK) cells as tools in the treatment of chronically stressed conditions, such as cancer. The modulation of this activity by biologically active endogenous compounds of the HPA (hypothalamic-pituitary-adrenal) axis, however, is not completely understood. Ouabain, a specific inhibitor of Na(+)-K(+)-ATPase, and now recognized as an endogenous component present in human plasma, was tested on IL-2 and TPA-activated killer cells. Ouabain was able to inhibit the generation of LAK activity, as well as to suppress either PHA or TPA-induced lymphocyte proliferation. Once the cells were triggered for cytotoxicity, however, ouabain was not able to interfere with their effector phase, as it did not show any effect when present only during the assay. TPA-induced "LAK-simile" cells displayed the same sensitivity towards ouabain as LAK cells did. Although the physiological relevance of endogenous ouabain secretion remains elusive, these effects of ouabain on LAK cytotoxicity should be considered in patients undergoing this kind of immunotherapy.
