Differential Glucocorticoid Responsiveness of Hemoclialysis Patients?? Lymphocytes

Abstract

Acute allograft rejection remains a problem after renal transplantation, even in the cyclosporine era. Interindividual differences in the pharmacodynamic responses of the immune system to immunosuppressive agents might contribute to the vulnerability of some patients to rejection. Having previously demonstrated decreased sensitivity of hemodialysis patients' lymphocytes to glucocorticoid suppression of mitogen induced proliferation, the authors undertook a separate study to assess the suppressive effect of glucocorticoids on lymphocyte responsiveness to allogeneic cells and mitogenic stimulation. Lymphocytes were isolated from 32 hemodialysis patients in clinically stable condition for studies in both phytohemagglutinin (PHA) stimulated cultures and in one-way mixed lymphocyte (MLR) cultures. From the concentration-response relationships derived from stimulated cultures with 10 (-6), 10(-7), and 10(-8) M concentrations of prednisolone and methylprednisolone, the concentration of steroid required to achieve 50% inhibition (IC50) of lymphocyte proliferation was determined. A broad range of IC50 values was found in both PHA and MLR cultures, but within individual patients, the IC50 values for both steroids correlated significantly between PHA and MLR cultures. The inhibitory effect of methylprednisolone was significantly greater than that of prednisolone in both PHA and MLR cultures. These results demonstrate a heterogeneity of pharmacodynamic responsiveness to prednisolone and methylprednisolone that is consistent with individuals in two in vitro models of cellular immune response. Pretransplant evaluation by these methods may help identify patients at risk of suboptimal immunosuppression and assist in selecting the steroid component of the immunosuppressive regimen.