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Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro

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Summary

In phase-I clinical trials of adoptive immunotherapy using lymphokine-activated killer (LAK) cells plus recombinant interleukin-2 (rIL-2) (Cetus) for the treatment of malignant glioma, we observed that blood mononuclear cells (MNC) from patients dependent on dexamethasone for management of cerebral edema produced substantially less LAK activity as compared to MNC of normal blood donors or glioma patients not receiving steroid therapy. Therefore, we examined the in vitro effects, brought about by therapeutically attainable concentrations of various corticosteroids, on the proliferative response, production of γ interferon (IFN-γ), and induction of LAK activity from blood MNC of normal donors. Incubation in media containing rIL-2 (1000 U/ml) with either dexamethasone, hydrocortisone, methylprednisolone, or prednisolone profoundly affected all of these parameters. First, while 0.01 μg/ml of either dexamethasone or hydrocortisone caused a slight enhancement of the mitogenic response of lymphocytes to phytohemagglutinin, a dose-dependent decline occurred as concentrations increased to 10 μg/ml. The addition of prednisolone and methylprednisolone elicited a dose-dependent inhibition of lymphocyte proliferation over the entire concentration range tested. At 0.1 μg/ml or higher, dexamethasone, hydrocortisone, methylprednisolone and prednisolone significantly (P<0.02) inhibited the production of IFN-γ: respectively 18.9%, 4.4%, 2.2%, and 12.3% of the IFN-γ produced by MNC in the absence of steroids. All four corticosteroids inhibited the induction of LAK activity. Compared to MNC that had been incubated with 1000 U/ml rIL-2 alone, MNC cultured with rIL-2 and 10 μg/ml either dexamethasone or prednisolone demonstrated significantly lower cytotoxicity (P<0.05) for the natural-killer-cell-resistant cell line, Daudi. Culturing MNC with hydrocortisone had a more dramatic result, causing a significant decline (P<0.01) in lytic activity at both 1.0 μg/ml and 10 μg/ml, while incubation with methylprednisolone produced a significant drop (P<0.02) in LAK-mediated cytotoxicity at 0.1 μg/ml as well as 1.0 μg/ml and 10 μg/ml. When cytotoxicity was expressed as lytic units per million effectors, a dose-response decline in lytic activity was once again apparent, with hydrocortisone, methylprednisolone and prednisolone showing significant inhibition (P<0.05) at both 1.0 μg/ml and 10 μg/ml and dexamethasone at 10 μg/ml (P<0.01). These results indicate that corticosteroids commonly used in the management of cerebral tumors and other malignancies inhibit induction of LAK activity in vitro, and this may explain why it is often difficult to generate LAK activity from blood MNC of patients who are receiving chronic steroid therapy.

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Authors and Affiliations

  1. Department of Anatomy MCV Station, Virginia Commonwealth University, Medical College of Virginia, Box 709, 23298-0709, Richmond, VA

    Daniel W. McVicar & Randall E. Merchant

  2. Division of Neurosurgery, Department of Surgery, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia, USA

    Lynn H. Merchant & Harold F. Young

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  1. Daniel W. McVicar
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  2. Randall E. Merchant
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  3. Lynn H. Merchant
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  4. Harold F. Young
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McVicar, D.W., Merchant, R.E., Merchant, L.H. et al. Corticosteroids inhibit the generation of lymphokine-activated killer activity in vitro. Cancer Immunol Immunother 29, 211–218 (1989). https://doi.org/10.1007/BF00199998

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