Effects of cyclophosphamide on autoantibody synthesis in the Brown Norway rat

The effects of cyclophosphamide on autoantibody synthesis were studied in an experimental model of glomerulonephritis due to autoantibodies to the glomerular basement membrane (GBM). Brown Norway rats develop anti-GBM antibodies, as part of a polyclonal response, when repeatedly injected with mercuric chloride (HgCl2). Anti-GBM antibody levels peak between days 11 and 14 and thereafter rapidly fall; convalescent animals show a time-dependent resistance to rechallenge with HgCl2 which remains significant for up to 3 months. The administration of cyclophosphamide, as a single intramuscular injection at day 0, has three distinct dose-dependent effects on anti-GBM antibody production. Firstly, lower doses (2.5 mg/kg) increase antibody levels at the time of peak response; secondly, higher doses (greater than or equal to 20 mg/kg) prevent antibody synthesis following HgCl2; and thirdly, the higher doses also reduce the response to rechallenge with HgCl2 3-4 months later. These effects of cyclophosphamide also apply to the polyclonal response to HgCl2, as judged by measurement of total IgG concentrations. Further investigation of the mechanisms of action of cyclophosphamide in this model should provide information relevant to the treatment of human autoimmune disease.