We have recently shown that combining CTLA4Ig with cyclophosphamide (CTX) results in a marked reversal of active lupus nephritis in NZB/NZW mice. To determine whether similar benefit might be obtained with less CTX, we have compared the effect of a single dose of CTX combined with CTLA4Ig with that of continuous CTX and CTLA4Ig administration. Female mice were treated with either continuous CTX (50 mg/kg every 10 days × 7 weeks), continuous CTLA4Ig (50 mg ip 3×/week × 8 weeks), a single ip injection of CTX (50 mg/kg) plus brief CTLA4Ig (50 mg/kg ip 3×/week x 2 weeks), a single dose of cyclophosphamide (50 mg/kg ip) plus continuous CTLA4Ig, continuous CTX + CTLA4Ig, or saline. After 8 weeks, none of the treated mice had died, while 36% of the saline group had significant proteinuria and 18% had died. Mice that had received either continuous CTX, or a combination of prolonged CTLA4Ig with either prolonged or brief CTX had preserved kidney function (>50% vs <10%). However, survival in the CTX alone group was reduced compared with either the continuous CTX+CTLA4Ig or the single dose CTX+continuous CTLA4Ig groups (73% vs 100%). In a subsequent experiment, NZB/NZW mice with either mild of advanced renal disease were treated with low dose CTX (5 mg/kg) or high dose CTX (50 mg/kg) in combination with CTLA4Ig. Although mice with advanced renal disease that received either low dose or high dose CTX plus CTLA4Ig had a reduction in proteinuria compared to controls, the improvement was significantly greater among mice receiving the higher dose of CTX. However, among mice with mild disease, the delay in progression of proteinuria was equivalent in mice that received either low dose or high dose CTX in combination with CTLA4Ig. These results indicate that the benefits of CTX in murine lupus nephritis are amplified or sustained by CTLA4Ig, and that the clinical benefits of combining these agents might be realised while at the same time reducing exposure to CTX.
Supported by the Veterans Administration and NIAID
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