mna-279 and Disease-Models--Animal

Topics: Acrylamide; Acrylamides; Alkynes; Animals; Antibodies, Antinuclear; Arthritis, Experimental; Arthritis, Rheumatoid; Caproates; Disease Models, Animal; Female; Immunoglobulin G; Immunosuppressive Agents; Isoxazoles; Mice; Mice, Mutant Strains; Nitriles; Rats; Rats, Inbred Lew

The use of inbred mouse strains of defined genetic background has allowed for the development of systems capable of reproducibly generating either an acute or chronic graft-versus-host disease (GvHD). The malononitrilamides MNA 279 and MNA 715, analogues of the main metabolite of leflunomide, have been shown to directly inhibit T-cell proliferation and B-cell functions. Therefore, they have been studied in a local GvH 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 chronic autoimmune GvHD in BDF1 hybrid mice. In the PLN assay an oral administration of various concentrations (7.5 to 50 mg/kg) of both MNAs inhibited the localized GvH reaction dose-dependently and suppressed the lymph node hyperplasia. Both MNAs also acted therapeutically in this assay when they were given as late as day 4 or 5 after challenge. In the model of an acute lethal GvHD the treatment of the GvH-B6C3F1 hybrid mice with the MNAs (2.5 to 20 mg/kg/day) shortly after disease induction on days 3 to 12 resulted in a dose-dependently improved survival rate. With 20 mg/kg of drugs, mortality of this life-threatening GvHD was completely prevented and also other parameters like splenomegaly, erythrocyte counts and hematocrit values were strongly suppressed. Treatment of sensitized GvH-BDF1 hybrid mice in the chronic autoimmune-like model with the MNAs (30 mg/kg/day), given on days 3 to 36 by oral gavage, resulted in an improved survival rate, inhibited lymphadenopathy and splenomegaly, reduced the levels of autoantibodies and other immunoglobulins like IgE and IgG1, prevented proteinuria and the development of glomerulonephritis. Both MNA 279 and MNA 715 can inhibit ongoing aberrant immune responses in animals suffering from GvHD.

Topics: Alkynes; Animals; Disease Models, Animal; Graft vs Host Disease; Graft vs Host Reaction; Immunosuppressive Agents; Isoxazoles; Lupus Erythematosus, Systemic; Lymph Nodes; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Nitriles; Rats; Rats, Inbred BN; Rats, Inbred Lew

Due to their immunosuppressive mode of action, we examined the therapeutic effects of the malononitrilamides MNA 279 and MNA 715 in acute EAE, and two models of chronic relapsing EAE in Lewis rats and Biozzi mice. In the first model, sensitization of adult Lewis rats with guinea pig spinal cords results in an acute clinical episode of severe EAE, and by day 15 all animals had died. Treatment of these sensitized rats with the MNAs was most effective in delaying and reducing the onset of clinical symptoms, and mortality of acute EAE was prevented in a dose-dependent manner. The protection afforded by the two MNAs was long-lasting and no subsequent relapse was observed. Similarly, in the chronic relapsing disease, aged Lewis rats were immunized with rabbit myelin basic protein, and all untreated animals developed a disease with up to three relapses. The second and third episodes were both milder and shorter in duration than the first. All animals treated with the MNAs survived the first attack, which also was delayed. Pathological signs were reduced and relapses did not occur. Inhibition of chronic relapsing EAE in aged Lewis rats was observed, even when the MNA-treatment was started after the first appearance of clinical symptoms. All treated animals recovered completely and mortality was prevented. Also in the second model of chronic relapsing EAE in Biozzi AB/H mice, MNA treated animals showed only one acute and delayed episode and no further relapses. All these results qualify both MNA 279 and MNA 715 as powerful immunosuppressants with therapeutic potential in human multiple sclerosis (MS).

Topics: Acute Disease; Alkynes; Animals; Chronic Disease; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Guinea Pigs; Immunosuppressive Agents; Isoxazoles; Mice; Mice, Inbred Strains; Nitriles; Rabbits; Rats; Rats, Inbred Lew

Topics: Aging; Alkynes; Animals; Antibody Formation; Crosses, Genetic; Disease Models, Animal; Female; Graft vs Host Disease; Immunoglobulin E; Immunoglobulin G; Immunosuppressive Agents; Isoxazoles; Lupus Erythematosus, Systemic; Mice; Mice, Inbred DBA; Mice, Mutant Strains; Nitriles