Inhibition of antigen-specific activation of an L3T4+ T cell line by cyclosporine with maintenance of macrophage-mediated antigen presentation.
Cyclosporine has clearly been shown to directly inhibit T lymphocyte activation by monoclonal antibodies or mitogens where nominal antigen and accessory cells are not present. However, when T lymphocytes are stimulated by antigen, as occurs in allograft rejection, T lymphocytes and accessory cells must interact with one another. Under the latter circumstances, the issue of whether cyclosporine acts on T lymphocyte, accessory cell, or both is not resolved. This issue is addressed in this study. To assess the effect of cyclosporine on T cell activation, macrophages were incubated with heat-killed Listeria and then fixed in paraformaldehyde. These fixed macrophages retained their ability to present antigen to T cells but were not affected by subsequent treatment with cyclosporine. When cyclosporine and a L3T4+ T lymphocyte line were added simultaneously to fixed, antigen-pulsed macrophages, the drug inhibited antigen-specific T cell activation with a half maximal inhibitory concentration of 10 ng/ml. To our knowledge, this is the first evidence that low doses of cyclosporine inhibit antigen-specific T cell activation where the drug's effects on antigen-presenting cells have been excluded. To assess the effects of cyclosporine on macrophage-mediated antigen-presentation, macrophages were exposed simultaneously to cyclosporine and antigen, and then fixed. Antigen-presentation was not inhibited unless extremely large doses (9000 ng/ml) of cyclosporine were used. In our experimental system, any new inhibitory activity acquired by live cyclosporine-treated macrophages could be explained by residual drug. Finally, cyclosporine did not inhibit the induction of macrophage Ia expression nor antigen-presenting function after stimulation in vitro with lymphokine.
Lu
C Y
CY
Brigham and Women's Hospital, Department of Medicine, Boston, Massachusetts 02115.
Lemay
P A
PA
Lombardi
M J
MJ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology; D002460:Cell Line; D003524:Cyclosporins / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000942:Antigens, Bacterial; D003524:Cyclosporins; D000949:Histocompatibility Antigens Class II