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NZB/NZW mice were treated with various immunosuppressive drugs used in human SLE. Cyclophosphamide (5 mg/kg 6 days out of 7), alone or with prednisolone, was better than azathioprine, prednisolone, or azathioprineplus-prednisolone, in prolonging survival and/or reducing proteinuria, Coomb's antibodies, antinuclear antibodies, and glomerular deposits of y-globulin. Intermittent bolus therapy with cyclophosphamide (50 mg/kg/lO days) was as effective as daily therapy. However, 61 % of the mice receiving any cyclophosphamide regimen developed malignant tumors compared to none in the other groups. immune complex glomerulonephritis and numerous circulating autoantibodies, many of which are directed against nuclear constituents. Their illness resembles systemic lupus erythematosus (SLE) in man. Therefore, they provide a useful model for studies of therapeutic agents used in SLE.Numerous reports demonstrate the efficacy of various immunosuppressive agents in New Zealand mice. These include single-drug therapy with corticosteroids ( 1 3 , azathioprine (2-4), and cyclophosphamide (2,5-9), as well as studies of various combinations of these drugs (3,lO). In this investigation, we have compared the effects and toxicities of a) single-drug, high-dose, long-term therapy with azathioprine, prednisolone, and cyclophosphamide, b) double-drug therapy with azathioprine-plus-prednisolone and cyclophosphamide-plus-prednisolone, and c) intermittent and daily cyclophosphamide therapy. Cyclophosphamide proved to be the best agent for suppressing the immune disorder, whether used on a daily basis, intermittently, or in combination with corticosteroid. Unfortunately all cyclophosphamide regimens, in contrast to the other therapies, were associated with a high incidence of malignancy. MATERIALS AND METHODSAnimals. NZB/NZW F, hybrids were bred from NZB/B, and NZW stock colonies maintained a t Washington University. Each therapeutic group contained 20 mice, approximately half of which were female a n d half male.

Administration of thymosin fraction V to NZB/NZW F1 mice, an animal model for human SLE, accelerated the appearance of proteinuria and anti‐nDNA antibodies, increased deposition of immunoglobulins in kidneys, and significantly shortened survivals. Although the addition of thymosin to in vitro cultures of spleen and lymph node cells from thymosin‐treated mice increased DNA synthesis in response to stimulation with Con A, in vivo treatment with thymosin did not affect the Con A response. There was no effect on in vitro responses to PHA or LPS, or on IgM antibody formation to SRBC (T cell dependent) or SSS III (T cell independent) immunizations. Antibodies to thymosin or contamination of our thymosin preparations with nucleic acids could not be demonstrated. The acceleration of autoimmune disease produced by thymosin treatment could not be explained by alteration of the T and B cell functions studied.

NZB/NZW F1 female mice received levamisole in an attempt to increase suppressor T cell function. Responses varied with dosage of drug and age of mice. When treatment with 25 μg/gm doses (intermittent or daily) was begun at 12 weeks of age, nephritis was accelerated in spite of transient reduction of anti‐DNA antibodies. When treatment was begun at 4 weeks, or when doses of 250 μg/gm were given, no clinical effects were observed. In the mice with accelerated disease, delayed hypersensitivity and antibody responses to sheep erythrocytes increased; antibody responses to pneumococcal poiysaccharide were unaffected. It is possible that some increased immune responses associated with levamisole are undesirable in murine lupus.

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