Effects of mizoribine on MHC-restricted exogenous antigen presentation in dendritic cells

Abstract

Mizoribine (MZR) has been shown to possess immunosuppressive activity that selectively inhibits the proliferation of lymphocytes by interfering with inosine monophosphate dehydrogenase. The efficacy of MZR is not only in patients who have had renal transplantation, but also in patients with rheumatoid arthritis (RA), lupus nephritis, and primary nephritic syndrome. Because the exact mechanism of its immunosuppressive action is not clear, the object of this study was to examine the ability of MZR to regulate the antigen presenting cells (APCs), dendritic cells (DCs). In this work, we tested whether MZR (1-10 microg/mL) could inhibit the cross-presentation of DCs. DC2.4 cells (H-2K(b)) or bone marrow-derived DCs (BM-DCs) generated from BM cells of C57BL/6 mouse (H-2K(b)) were cultured in the presence of MZR with OVA-microspheres, and the amount of OVA peptide-class I MHC complexes was measured by a T cell hybridoma, B3Z, that recognizes OVA (257-264 : SIINFEKL)-H-2Kb complex and expresses-galactosidase. MZR profoundly inhibited the expression of SIINFEKL-H-2K(b) complexes. This inhibitory activity of MZR appeared to affect the phagocytic activity of DCs. MZR also decreased IL-2 production when we examined the effects of MZR on CD4+ T cells. These results provide an understanding of the mechanism of immunosuppressive activity of MZR on the inhibition of MHC-restricted antigen presentation and phagocytic activity in relation to their actions on APCs.