mna-279 and Graft-vs-Host-Disease

Topics: Alkynes; Aniline Compounds; Animals; Autoimmune Diseases; Biological Availability; Crotonates; Drug Design; Graft Rejection; Graft Survival; Graft vs Host Disease; Graft vs Host Reaction; Heart Transplantation; Humans; Hydroxybutyrates; Immunosuppressive Agents; Isoxazoles; Nitriles; Skin Transplantation; Toluidines; Transplantation, Homologous

Malononitrilamides (MNAs) represent a new class of low molecular weight immunosuppressants and have been shown to prevent and reverse ongoing acute allograft rejection and effectively prolong xenograft survival in rodents. MNAs were also found to be potent inhibitors of B and T cell-mediated autoimmune processes and mediate their effects by binding specifically to dihydro-orotate dehydrogenase (DHODH), inhibiting de novo pyrimidine biosynthesis, thereby blocking T and B cell proliferation and strongly suppressing the IgM and IgG antibody production. Here we evaluated the effects of the MNAs (HMR 1279 and HMR 1715) on the in vivo lymphoproliferation that occurs after challenge with allogeneic cells in a local graft-versus-host reaction in Lewis x Brown Norway F1 hybrid rats by measuring the enlargement of the popliteal lymph nodes (PLN) draining the site of allogeneic cell injection. Oral administration of the MNAs dose-dependently prevented the localized lymphoproliferative response in the PLN assay and suppressed the lymph node hyperplasia. The MNAs even acted therapeutically when they were given during an ongoing alloreactivity as late as days 4 or 5 after challenge. Consistent with the mode of action, a complete reversal of the immunosuppression on the lymphoproliferation in vivo was attempted in this protocol by the addition of exogenous uridine during days 0-5. These data suggest the HMR 1279 and HMR 1715 mediate their antiproliferative and immunosuppressive effects in the PLN assay in vivo by decreasing the activity of DHODH in the lymph node cells and thereby inhibiting pyrimidine biosynthesis.

Topics: Alkynes; Animals; Graft vs Host Disease; Immunosuppression Therapy; Immunosuppressive Agents; Isoxazoles; Lymph Nodes; Nitriles; Rats; Rats, Inbred BN; Rats, Inbred Lew

Topics: Acrylamide; Acrylamides; Alkynes; Animals; Antibody Formation; Autoantibodies; Autoimmune Diseases; Caproates; Crosses, Genetic; Female; Glomerulonephritis; Graft vs Host Disease; Immunoglobulin E; Immunoglobulin G; Immunosuppressive Agents; Isoxazoles; Lupus Erythematosus, Systemic; Lymphocyte Transfusion; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Mutant Strains; Nitriles; Spleen; Transplantation, Homologous

Topics: Alkynes; Animals; Graft vs Host Disease; Immunosuppressive Agents; Isoxazoles; Lymph Nodes; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Nitriles; Rats; Rats, Inbred BN; 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

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

Topics: Alkynes; Animals; Graft vs Host Disease; Graft vs Host Reaction; Immunosuppressive Agents; Isoxazoles; Lupus Erythematosus, Systemic; Lymphocyte Transfusion; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Nitriles; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Spleen; Splenomegaly; Time Factors; Transplantation, Homologous