The in vivo effect of cyclosporine A on macrophages.

Abstract

The macrophage disappearance reaction (MDR) was induced when muramyl dipeptide (MDP) was injected intraperitoneally into guinea pigs bearing macrophage-rich peritoneal exudate cells. Heparin could inhibit the MDR induced by MDP. In the present study, we tested the effect of the immunosuppressive agent cyclosporine A (CsA) on MDR. The MDR was significantly suppressed in guinea pigs given 20 or 100 mg/kg of CsA, although 5 mg/kg of CsA had no effect. The number of macrophages elicited by liquid paraffin was significantly reduced in guinea pigs given with 20 or 100 mg/kg of CsA, but not in those given 5 mg/kg of CsA. These results indicate that CsA could directly affect macrophages in vivo, through a relatively high dose was required. Cyclosporine A (CsA), a cyclic peptide of 11 amino acids, is a fungal metabolite with potent immunosuppressive properties. Numerous experimental and clinical trials have demonstrated its effectiveness in organ transplantation. It has been suggested that primary target cells of CsA were T-lymphocytes, and macrophages were not directly affected. However, recent studies in an in vitro system have shown that some functions of macrophage are affected by CsA. These include chemotaxis (Drath & Kahan, 1983), interleukin-1 generation (Bunjes et al., 1981), prostaglandin E production (Whisler et al., 1984) and procoagulant activity (Carlsen et al., 1985). However, the effect of CsA on macrophages has not been elucidated in vivo. The macrophage disappearance reaction (MDR) is an in vivo manifestation of cell-mediated immunity and/or delayed type hypersensitivity (Sonozaki et al., 1975). Furthermore, our previous study demonstrated a possibility that MDR was an in vivo manifestation of macrophage activation (Ochiya et al., 1982). Muramyl dipeptide (MDP; N-acetyl-muramyl-L-alanyl-D-isoglutamine), a synthetic analogue of water soluble components of bacterial cell wall peptidoglycans, is known to have the ability to activate macrophages (Nagao et al., 1979). In the present study, attempts were made to induce MDR by MDP and the effect of CsA on the MDR was studied.