roquinimex and Proteinuria

Roquinimex is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models, but the mechanism is still unknown. In this study, we investigated the effect of roquinimex on chronic graft-versus-host disease (GVHD) in mice, a well-established model for human systemic lupus erythematosus (SLE). Oral administration of roquinimex significantly suppressed the development of proteinuria and ameliorated nephritis symptoms in chronic GVHD mice. In addition, renal histopathology and immunohistochemistry studies revealed reduced glomerulonephritis and decreased IgG deposition in chronic GVHD mice treated with roquinimex. Chronic GVHD is characterized by a predominance of Th2 cytokines, and proinflammatory cytokines that also play an important role in the pathology of tissue damage. Therefore, we focused on the effect of roquinimex on cytokine production. Chronic GVHD mouse splenocytes exhibited severely reduced interferon (IFN)-gamma production in response to Concanavalin (Con A) stimulation and an overt Th2 skewness. Roquinimex treatment, however, induced IFN-gamma production and restored the Th1/Th2 cytokine balance, although only a minimal effect of roquinimex on interleukin (IL)-4 secretion was observed. The production of the proinflammatory cytokines TNF-alpha and IL-1 beta by peritoneal macrophages from lipopolysaccharide (LPS)-treated GVHD mice was significantly inhibited by roquinimex treatment. These data suggested that the beneficial effect of roquinimex on lupus might, at least in part, result from a restoration of Th1/Th2 cytokine balance and inhibition of inflammatory cytokine production.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Antinuclear; Blood Urea Nitrogen; Cells, Cultured; Cholesterol; Chronic Disease; Creatinine; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Graft vs Host Disease; Hydroxyquinolines; Immunoglobulin G; Inflammation Mediators; Kidney; Macrophages; Male; Mice; Mice, Inbred DBA; Proteinuria; Spleen; Th1 Cells; Th2 Cells; Triglycerides

A series of linomide-related quinoline-3-carboxamides and their analogues was prepared and evaluated for antinephritic activities. The 6-MeS derivative 7a was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Topics: Amides; Animals; Antibodies, Antinuclear; Autoimmune Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Graft vs Host Disease; Mice; Mice, Inbred MRL lpr; Nephritis; Proteinuria; Quinolines; Structure-Activity Relationship

A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Antibody Formation; Autoimmune Diseases; Disease Models, Animal; Dogs; Graft vs Host Disease; Half-Life; Immunization; Mice; Nephritis; Proteinuria; Quinolines; Structure-Activity Relationship; Thioamides