Effect of cyclophosphamide on lymphokine production in MRL/lpr.Yaa mice

The Y chromosome (Yaa gene) from autoimmune BXSB mice has been shown to be responsible for the acceleration of autoimmune symptoms when transferred to MRL/lpr mice. We examined the pathological, serological and immunological characteristics of MRL/lpr. Yaa mice and the suppressive effect of cyclophosphamide (CP) on the mice. MRL/lpr. Yaa mice spontaneously developed a massive lymphadenopathy characterized by hypergammaglobulinemia, the presence of several autoantibodies, and autoimmune disease. In MRL/lpr. Yaa mice, IL-2, IL-4 and IL-5 production in concanavalin A (Con A)-stimulated splenocytes were about 10-fold lower than in BALB/c mice at 5 weeks of age. The concentrations of these lymphokines remained low until the mice were 16 weeks of age. The production of IFN-gamma and IL-6 in 16 week old MRL/lpr. Yaa mice was about 4- and 2-fold lower, respectively, though these levels were similar in both strains at 8 weeks of age. It was found that this dysregulation of T cell function was almost identical to that in MRL/lpr mice. Administration of CP to MRL/lpr. Yaa mice ameliorated nephritis, and suppressed production of autoantibodies and the accumulation of abnormal T cells. CP also significantly elevated the production of lymphokines. These findings suggest that an abnormality of T cell function may contribute to the autoimmune pathogenesis of MRL/lpr. Yaa mice and that CP probably ameliorates auto-immune disease by improving the T cell functions.