Mechanism of action of Cyclosporin A: inhibition of lymphokine secretion studied with antigen-stimulated T cell hybridomas.
We have employed bifunctional T cell hybridomas, which can be stimulated to secrete lymphokine(s) and lyse specific target cells, to analyze the effect of Cyclosporin A (CsA) on T cell helper and effector functions. We report here the effects of CsA on antigen- and lectin-induced lymphokine secretion. We have found that a pharmacologic level of CsA (10 ng/ml) blocks antigen- and lectin-driven interleukin 2 (IL 2) secretion without affecting cell proliferation. In addition, one monoclonal hybridoma that is induced by concanavalin A to secrete colony stimulating factors (CSF) as well as IL 2 is concomitantly blocked by CsA for production of IL 2 and CSF. Because the hybridomas grow constitutively and are devoid of functional IL 2 receptors, they permit analysis of the kinetics of the inhibitory response. We have shown that CsA blocks not only stimulation of lymphokine secretion but also ongoing IL 2 production, probably by interfering with the effective interaction of receptor and antigen. Thus, blocking of IL 2 secretion from preactivated cells by CsA occurs by 1 to 2 hr, the time required to stop IL 2 production by removal of Ag/Lectin stimulator. The results are consistent with a mechanism of action of CsA on T cells that involves a direct interference of CsA with binding of Ag to Ag-receptor and results in blocking of induction and active secretion of multiple lymphokines.
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001667:Binding, Competitive; D003115:Colony-Stimulating Factors / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D006825:Hybridomas / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D011971:Receptors, Immunologic / Q000187:drug effects; D015375:Receptors, Interleukin-2; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013945:Thymoma / Q000276:immunology
D000951:Antigens, Neoplasm; D003115:Colony-Stimulating Factors; D003524:Cyclosporins; D007376:Interleukin-2; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D003208:Concanavalin A