Therapeutic studies in NZB/W mice. I. Synergy of azathioprine, cyclophosphamide and methylprednisolone in combination

Abstract

This study compares different immunosuppressive regimens in the treatment of the lupus-like nephritis of NZB/W mice. Groups of 5-month-old female NZB/W mice were given azathioprine, cyclophosphamide and methylprednisolone in all one-, two-and three-drug regimens, each drug in the relatively low dose of 1.5 mg/kg/day. Treatment for 3 months with one or two drugs resulted in modest suppression of NZB/W disease. Mice receiving all three drugs had significantly less proteinuria, lower titers of anti-DNA antibody and less severe, histologically evident renal involvement than mice treated with one or two drugs. Survival at 1 year was 10% for untreated controls, 44% for one-drug-treated, 37% for two-drugtreated and 86% for the three-drug-treated mice. The survival for the three-drug regimen was significantly longer than any other group ( P < 0.01). The three-drug regimen was synergistic, since mice treated with each drug at three times the dose had significantly more proteinuria after 3 months of treatment and lowered 1 year survival (33%). The beneficial effects of triple-drug therapy were attained without increased toxicity. This study represents the first controlled evaluation of single versus combination therapy in a model of autoimmune disease. Based on these results, a controlled evaluation of triple-drug therapy in human systemic lupus erythematosus appears warranted.Combined immunosuppressive regimens are being used widely to treat malignancies, allograft rejection and immunologically mediated diseases. Encouraging results have been reported in the treatment of some leukemias with combinations of as many as four agents (l), and it is now standard therapy to administer prednisone in combination with azathioprine or cy-

Therapeutic studies in NZB/W mice. II. Relative efficacy of azathioprine, cyclophosphamide and methylprednisolone

“…T h e first report in this series compared the combined results of low dose single, double and triple agent therapy, and concluded that triple agent therapy was superior (6). T h e present report details the individual effects of cyclophosphamide, azathioprine and methylprednisolone at different doses upon the autoimmune nephritis of NZB/W mice.…”

“…Fifty glomeruli in each kidney specimen were graded on a 0 to 3 scale, as previously described (6). Grade 0 glomeruli contained no identifiable lesion.…”

Complement and the Kidney

“…The latter arises due to deficiency of Fas protein on the autoimmune-prone MRL/Mp background (21). Although observational and therapeutic studies have long been possible (22)(23)(24), a more comprehensive understanding for the role of C in lupus nephritis has come recently through the use of specific transgenic and gene-targeted strains (25), and recombinant forms of natural protein and Ab inhibitors of C activation.…”

Differing Effects of Azathioprine and Cyclophosphamide on Immune Responses to Flagellin in Man

“…On the other hand transformation of lymphocytes by phytohemagglutinin, believed to be a T cell response, was not depressed in azathioprine-treated patients (17). T h e foregoing observations might be said to provide some endorsement for the combined use of t h e t w o drugs, azathioprine a n d cyclophosphamide, in certain immunopathic disorders (26,27 in press), studying mouse lymphocytes in culture and using a cytotoxicity assay, found that T cells were 300-fold more sensitive to azathioprine than B cells.…”