Comparison of therapeutic and immunosuppressive effects of azathioprine, prednisolone and combined therapy in nzp/nzw mice

Abstract

Since NZB/NZW mice develop an immune nephritis similar t o that of systemic lupus erythematosus in man, a study was designed in these mice to compare the clinical and immunologic effects of three immunosuppressive drug regimens. For 72 weeks, groups of 20 mice received daily oral therapy with a) no drugs, b) azathioprine, c) prednisolone or d) combined azathioprine-prednisolone. The combined regimen was superior t o either drug used alone in preventing deaths from renal disease. Prednisolone alone also prolonged life significantly, but not as effectively as combination therapy. Azathioprine alone was not effective. All drugs suppressed the antibody response to an exogenous antigen (Vi polysaccharide) equally well. None of the drug regimens prevented the appearance of proteinuria, antinuclear antibodies, Coombs' antibody, or 7-globulin deposits in glomeruli. However, the ability of a therapeutic regimen t o suppress antibodies to native DNA correlated well with its ability t o suppress renal disease. No malignancies were found among 73 animals autopsied, but significant hepatic damage occurred in the groups receiving prednisolone. Thus, combined therapy was superior t o either drug used alone, and the immunosuppressive effect of greatest clinical importance seemed to be the ability to prevent formation of anti-DNA antibodies.New Zealand black and New Zealand white hybrid mice (NZB/NZW F,) spontaneously develop a disease quite similar to systemic lupus erythematosus (SLE) in man. Virtually all mice of this strain develop lethal, immune complex

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

“…Azathioprine, 5 mglkg, prednisolone, 5 mg/kg, and the combination of azathioprine plus prednisolone were given 6 days a week for 24 to 36 weeks starting at 2 months of age. All regimens were found to increase survival rates at 9 '/2 months; however, the combination regimen was not observed to be superior (14). We are not aware of any experimental trials in NZB/W mice using more than two drugs.…”

Prostaglandin E1 treatment of NZB/NZW mice

“…That PGE, suppresses adjuvant arthritis in adrenalectomized rats (16) indicates that its effect in that model of chronic inflammation is not mediated solely through stimulation of the pituitary and/or adrenal glands. I n addition, although treatment of NZB/NZW mice with prednisolone has been shown to prolong survival, approximately 50% of treated animals were dead at the end of 1 year of therapy (17).…”

Successful treatment of autoimmune disease in (NZB/NZW)F1 female mice by using fractionated total lymphoid irradiation.

“…As they age, they develop, spontaneously and uniformly, autoantibodies with specificity to nucleic acid antigens (1), erythrocytes with a positive Coombs test (1,2), lymphocytes (3), and lethal immune-complex glomerulonephritis (4,5). The course of disease in NZB/NZW mice and in SLE can be modified with prolonged high-dose cyclophosphamide therapy which results in some suppression of anti-DNA antibodies and renal disease and prolongation of life (6)(7)(8)(9). Thoracic duct drainage, another mode of immunosuppression resulting in isolated lymphocyte depletion (cell-free lymph is reinfused after lymphocyte separation), has also been shown to be effective in decreasing the disease activity in SLE as well as in rheumatoid arthritis (10).…”