THE NEW IMMUNOSUPPRESSANTS, THE MALONONITRILAMIDES MNA-279 AND MNA-715, INHIBIT VARIOUS GRAFT-VS.-HOST DISEASES (GVHD) IN RODENTS

The use of inbred mouse strains of defined genetic background has allo wed for the development of systems capable of reproducibly generating either an acute or chronic graft-versus-host disease (GvHD). The malon onitrilamides MNA 279 and MNA 715, analogues of the main metabolite oi leflunomide, have been shown to directly inhibit T-cell proliferation and B-cell functions. Therefore, they have been studied in a local Gv H reaction in the popliteal lymph node (PLN) assay in LBN rats, on the development of an acute and lethal GvHD in B6C3F1 mice and on a chron ic autoimmune GvHD in BDF1 hybrid mice. in the PLN assay an oral admin istration of various concentrations (7,5 to 50 mg/kg) of both MNAs inh ibited the localized GVH reaction dose-dependently and suppressed the lymph node hyperplasia. Both MNAs also acted therapeutically in this a ssay when they were given as late as day 4 or 5 after challenge. in th e model of an acute lethal GvHD the treatment of the GVH-BGC3F1 hybrid mice with the MNAs (2,5 to 20 mg/kg/day) shortly after disease induct ion on days 3 to 12 resulted in a dose-dependently improved survival r ate. With 20 mg/kg of drugs, mortality of this life-threatening GvHD w as completely prevented and also other parameters like splenomegaly, e rythrocyte counts and hematocrit values were strongly suppressed. Trea tment of sensitized GvH-BDF1 hybrid mice in the chronic autoimmune-lik e model with the MNAs (30 mg/kg/day), given on days 3 to 36 by oral ga vage, resulted in an improved survival rate, inhibited lymphadenopathy and splenomegaly, reduced the levels of autoantibodies and other immu noglobulins like IgE and IgG1, prevented proteinuria and the developme nt of glomerulonephritis. Both MNA 279 and MNA 715 can inhibit ongoing aberrant immune responses in animals suffering from GVHD.