Macrophages as targets for inhibition by cyclosporine.
In order to understand the mechanism of immunosuppression by cyclosporine, its effects on macrophage-mediated antigen-specific T cell activation (IL-2 production) were studied in vitro. While cyclosporine (CsA) present during the macrophage-T cell coculture inhibited antigen presentation effectively, pretreatment (2 hr) of macrophages with the drug also caused marked inhibition regardless of the antigen concentration and order of drug/antigen addition. Pretreatment of T cells caused only modest inhibition. With macrophage pretreatment, the structural analog cyclosporine-G had the same inhibitory activity as cyclosporine (cyclosporine-A), whereas dihydro-cyclosporine-D and cyclosporine-H were inactive. Cyclosporine demonstrated saturable binding to macrophages suggesting the existence of CsA-binding sites. A 50% inhibition of IL-2 production was achieved with 10(-6) M CsA and 60-70% of the binding sites were occupied at this concentration. CsA-treated macrophages did not release inhibitory material and the drug did not appear to be transferred from the macrophages to the T cells during the coculture. Although antigen-specific T cells could bind to drug-treated macrophages, they did not produce IL-2. Collectively, these results suggest that CsA has a direct effect on macrophages that subsequently interferes with IL-2 production at a stage following T cell antigen recognition.
Benson
A
A
Department of Microbiology, and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322.
Ziegler
H K
HK
D000818:Animals; D003524:Cyclosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D003524:Cyclosporins; D007376:Interleukin-2