GLUCOCORTICOID-RESISTANT LEUKEMIC LYMPHOCYTES

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The long-term objectives are to elucidate the actions and interactions of glucocorticoids and cytokines such as gamma interferon (IFN-gamma) and interleukin 2 (IL-2) on tumor proliferation and on inactivation of the immune system. We will study these phenomena both in vitro in cell culture systems and in vivo in mice. Proposed experiments are based on numerous recent observations with these substances. They include those made on this project, which demonstrated that glucocorticoids inhibit production of lymphokines, but may inhibit or enhance their actions; and that the lymphokines, in turn, may counteract certain immunosuppressive actions of glucocorticoids, suggesting the possibility of using lymphokines to selectively counteract unwanted side effects of glucocorticoid therapy. The fact that glucocorticoids are already widely used in treatment of leukemias and lymphomas, and that lymphokines, which are now becoming generally available, are being tested experimentally in cancer therapy, emphasizes the importance of understanding interactions and mechanisms of these agents. With respect to tumoricidal activity, the specific aims are directed at two fundamental questions: (i) Do glucocorticoids in vitro or in mice alter tumoricidal activation, and in particular antibody-dependent cellular cytotoxicity (ADCC), of macrophages and other phagocytes by IFN-glamma and lymphotoxin? (ii) Do glucocorticoids alter the tumoricidal activity of interferons and lymphotoxin on glucocorticoid-sensitive and -resistant lymphoid cell lines in culture or in mice? With respect to stimulation of the immune system for bactericidal activity, the questions to be answered are: (i) Do glucocorticoids alter bactericidal activation of cultured human and mouse leukocytes by IFN-gamma plus IL-2? (ii) Can IFN-gamma and/or IL-2 reverse the increased susceptibility to infection in mice caused by glucocorticoids? Finally, using cDNA probes to measure cellular levels of mRNA for IFN-gamma and IL-2, the goals are to answer the following questions: (i) Is reduction by glucocorticoids of lymphokine mRNA levels in human T lymphocytes mediated by induced protein(s)? (ii) Are those levels under negative feedback control by the lymphokines themselves?