Deficient natural killer function in patients receiving immunosuppressive drugs: analysis at the cellular level.

Renal transplant recipients receiving low maintenance immunosuppression (azathioprine, 2 mg/kg/day, and prednisolone, 10 mg/day), tolerating their transplants well, and without viral infection disclose a profound depression of NK activity as assessed by 51Cr-release assay. By combining the analysis of the different steps of cytolysis with the agarose single-effector assays and the estimation of circulating large granular lymphocytes (LGL), the defect is shown to be due to a significant decrease of the number of NK cells capable of binding (% target-binding cells 2.0 +/- 0.3 versus 5.7 +/- 0.7 in normals, P less than 0.001) and killing (% cytotoxic target-binding cells 12.4 +/- 1.9 versus 22.0 +/- 0.5 in normals, P less than 0.001) of targets. There is also a significant reduction (P less than 0.001) of both percentages (1.0 +/- 0.2 versus 3.3 +/- 0.4 in normals) and absolute values (9.8 +/- 2.4 versus 62.3 +/- 8.0/microliters in normals) of LGL. These observations indicate that depressed NK activity is due mostly to depletion of NK cells. Functional impairment of NK cells can also be involved. Lack of direct in vitro effects of drugs (6-mercaptopurine, hydrocortisone, and methylprednisolone) at concentrations likely to be reached in vivo during treatments and relative resistance of NK activity after in vivo steroid administration suggest that immunosuppressive drugs act at the precursor cell level or on regulatory mechanisms. Despite functional integrity of two suppressor cell systems of allogeneic NK activity (suppression induced by preculture of lymphocytes with Con A and suppressor granulocytes) in immunosuppressed patients, tested on normal NK cells, NK cells of immunosuppressed patients did not disclose greater susceptibility to Con A-induced suppression. This analysis indicates that the depletion phenomenon is probably a major mechanism in NK depression of patients receiving immunosuppressive drugs.