ATTENUATION OF MURINE LUPUS NEPHRITIS BY MYCOPHENOLATE MOFETIL

Mycophenolate mofetil (MMF) is the morpholinoethyl ester of mycophenol ic acid, which is its active metabolite. MMF is effective in prolongin g survival of allografts and xenografts. However, little is known abou t the effects and the main mechanism of action of MMF in autoimmune di seases. In this study, the effect of MMF on the spontaneous disease pr ogression 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 mu g/18 h) was significa ntly 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 histol ogically less severe in MMF-treated mice than in control mice (P = 0.0 05). Furthermore, in immunofluorescence studies the amount of immunogl obulin and C3 deposits in the glomerular capillary wall was significan tly less in MMF-treated mice (P less than or equal to 0.002). Surprisi ngly, in vivo no clear-cut immune-modulating effects were observed bec ause there were no differences between MMF-treated and control animals with regard to autoantibody formation. Also, spleen enlargement and n umbers of CD3(+), CD4(+), and CD8(+) T cells in spleen, lymph nodes, a nd peripheral blood were not different between both groups. Furthermor e, 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 exp eriments revealed that binding of nucleosome/antinucleosome complexes to the glomerular basement membrane is decreased in MMF-treated mice c ompared with control mice. It is concluded that MMF suppresses the dev elopment of lupus glomerulonephritis and albuminuria in MRL/lpr mice. The observed reduction of glomerular immunoglobulin deposits in MMF-tr eated mice and the renal perfusion studies indicate that MMF treatment leads to a decreased binding: of immune complexes in the glomerular c apillary wall in lupus nephritis.