This study compared the effect of various immunosuppressive therapies on the development of lupus nephritis using a murine model of SLE, the MRL lpr/lpr mouse. The agents investigated were cyclosporin A (CsA), FK506, rapamycin and mycophenolate mofetil (MM). Female MRL lpr/lpr mice at 12 weeks old were treated with CsA (40mg/kg/day p.o.), FK506 (2.5mg/kg/3 times/week or/day s.c.), rapamycin (1.5mg/kg.day s.c.), MM (50mg/kg/2 times daily p.o.) or vehicle controls. These groups were compared with untreated MRL lpr/lpr and also untreated MRL +/+ mice which do not develop this autoimmune disease. Disease progression was assessed using various markers for SLE and glomerular dysfunction. The results obtained showed CsA and rapamycin to both inhibit glomerular proliferation and reduce glomerular macrophage infiltrate. In addition, rapamycin also reduced chronic inflammatory cell infiltrate, lymphadenopathy and splenomegaly. Rapamycin treated animals did not develop skin lesions and alopecia which became apparent on mice from other groups. In contrast neither low or high dose FK506 treatments prevented the development of the autoimmune pathological features, including renal disease. Likewise, mycophenolate mofetil had no beneficial effects in disease prevention. In conclusion, it appears that both rapamycin and CsA but not FK506 or mycophenolate mofetil reduce macrophage infiltration, glomerular proliferation and, in the case of rapamycin chronic inflammatory cell infiltrate and lymphadenopathy, in the MRL lpr/lpr mouse.