title: Effects of cyclosporine on systemic MHC expression. Evidence that non-T cells produce interferon-gamma in vivo and are inhibitable by cyclosporine.
abstract: The ability of lipopolysaccharide to induce major histocompatibility complex hyperexpression in vivo in a variety of mouse tissues--particularly kidney--and the effect of cyclosporine on this process were studied. MHC expression was measured by a radiolabeled antibody-binding assay using tissue homogenates, as well as by assessment of tissue sections by indirect immunoperoxidase staining. LPS administered to mice in two doses, 4 days apart, induced an increase in class I expression in several tissues but also induced an increase in class II expression in kidney. A similar increase in class II expression in kidney was not elicited with polyinosinic acid/polycytidylic acid, an agent that induces release of IFN-alpha/beta and increases class I MHC product expression. Thus we reasoned that LPS in vivo may release IFN-gamma, which then induces increased expression of MHC products. We validated this hypothesis by demonstrating that monoclonal antibody against IFN-gamma inhibited the induction of renal MHC products by LPS. However, the LPS effects did not require the participation of T cells, being demonstrable in nude mice and in mice with severe combined immunodeficiency. Moreover, the effect of LPS on MHC expression in normal and nude mice was inhibited by in vivo administration of monoclonal antibody against IFN-gamma just as it was in normal mice. Thus the class II hyperexpression that follows LPS is apparently mediated by non T cells and is due to the systemic release of IFN-gamma. This mechanism was inhibited by high doses of CsA in vivo, both in normal and in nude mice. The results indicate that there is a non T cell pathway for IFN-gamma release (and MHC induction) in vivo that is sensitive to CsA. This observation raises the possibility that some of the immunosuppressive effects of CsA may be due to inhibition of mediator release from non T cells.
mesh_terms: D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D006183:H-2 Antigens / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D003524:Cyclosporins; D006183:H-2 Antigens; D006649:Histocompatibility Antigens; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D007371:Interferon-gamma; D011070:Poly I-C