Mycophenolate mofetil (MMF) is the morpholinoethyl
ester of
mycophenolic acid, which is its active metabolite. MMF is effective in prolonging survival of allografts and xenografts. However, little is known about the effects and the main mechanism of action of MMF in
autoimmune diseases. In this study, the effect of MMF on the spontaneous
disease progression in the MRL/lpr mouse model of lupus was examined. Eight-week-old MRL/lpr mice (n=18) were orally treated with MMF dissolved in a vehicle (90 mg/kg) once a day. Control animals received vehicle alone (n=17). The incidence of
albuminuria (>300 microg/18 h) was significantly reduced by MMF treatment compared with vehicle-treated controls (cumulative incidence of
albuminuria at 23 wk in MMF-treated mice; 22% versus 88% in controls; P=0.0001). The
glomerulonephritis was histologically less severe in MMF-treated mice than in control mice (P=0.005). Furthermore, in immunofluorescence studies the amount of
immunoglobulin and C3 deposits in the glomerular capillary wall was significantly less in MMF-treated mice (P < or = 0.002). Surprisingly, in vivo no clear-cut immune-modulating effects were observed because there were no differences between MMF-treated and control animals with regard to
autoantibody formation. Also, spleen enlargement and numbers of CD3+, CD4+, and CD8+ T cells in spleen, lymph nodes, and peripheral blood were not different between both groups. Furthermore, no immunosuppressive properties of 90 mg/kg MMF were found in BALB/c mice on delayed-type
hypersensitivity and primary antibody response to
methylated bovine serum albumin. Interestingly, renal perfusion experiments revealed that binding of
nucleosome/antinucleosome complexes to the glomerular basement membrane is decreased in MMF-treated mice compared with control mice. It is concluded that MMF suppresses the development of
lupus glomerulonephritis and
albuminuria in MRL/ lpr mice. The observed reduction of glomerular
immunoglobulin deposits in MMF-treated mice and the renal perfusion studies indicate that MMF treatment leads to a decreased binding of
immune complexes in the glomerular capillary wall in
lupus nephritis.