EFFECTS OF THE IMMUNOSUPPRESSIVE MALONONITRILAMIDES ON RHEUMATOID ANDSYSTEMIC LUPUS-ERYTHEMATOSUS (SLE)-LIKE DISEASES

The malononitrilamides MNA 279 and MNA 715 represent derivatives of le flunomide's primary metabolite A771726. They have been shown to block both T-and B-cell proliferation and to suppress IgM and IgG antibody p roduction. Here we investigated their disease modifying activity on th e development of SLE-like diseases in B6D2F1 hybrid mice and MRL/lpr a utoimmune mice. SLE is a rheumatic disease in which remitting relapsin g inflammatory responses can arise in almost any organ of the body. Af ter induction cia chronic GvH reaction, BDF? mice develop an autoimmun e illness strongly resembling the human SLE syndrome, which begins wit h the classic symptoms of proteinuria followed by a glomerulonephritis 5 to 6 weeks after induction. This disease includes lymphoid hyperpla sia, formation of multiple antibodies and immune-complex glomeruloneph ritis, with the animals dying within 12 weeks. When these sensitized B DF1 hybrid mice were treated by oral gavage on days 6 to 33, both MNAs prevented the development of proteinuria and glomerulonephritis and t hey strongly inhibited autoantibody formation and other immunoglobulin s like IgE and IgG1. The massive lymphadenopathy and splenomegaly were also prevented and the survival rate was significantly increased. MRL /pr autoimmune mice spontaneously develop a SLE-like disease with clin ical and serological characteristics that mimic not only human SLE but other autoimmune disorders, such as rheumatoid arthritis. They form a utoantibodies against dsDNA, hypergamma-globulinemia and glomeruloneph ritis; they have circulating rheumatoid factors, and develop histologi cal changes in their joints, characterized by pannus formation, cartil age and bone erosions. Treating these MRL/pr mice with MNAs resulted i n an improved survival rate reduced splenomegaly and swollen lymph nod es, inhibited autoantibody formation and prevented proteinuria and glo merulonephritis, even in the established disease. These results indica te that both MNA 279 and MNA 715 can prevent the development, as well as treat ongoing murine rheumatoid SLE-like disorders.