roquinimex and Inflammation

Linomide prevents the development of autoimmune insulitis and insulin-deficient diabetes mellitus in female NOD mice. Linomide prevents development of autoimmune manifestations in other experimentally induced and spontaneous autoimmune diseases as well, but the mechanism of action is unknown. The present report summarizes our investigations on the effect of Linomide on different functional T cell subsets in NOD mice analyzed according to their cytokine profile. Supernatants from cultured splenocytes and peritoneal cells taken from Linomide-treated mice contained lower levels of TNFalpha, IL-1 beta, IFN gamma and IL-12 versus higher levels of IL-4, IL-6 and IL-10 in comparison with supernatants from cultures of untreated mice. Our results suggest that regulation of autoimmunity following oral Linomide administration in NOD mice induces a shift from Th(1) to Th(2) phenotype response, thereby preventing the development of diabetes by active cytokine-induced immunoregulation of T cell subsets, including downregulation of Th(1) and upregulation of Th(2).

Topics: Adjuvants, Immunologic; Animals; Autoimmunity; Concanavalin A; Cytokines; Diabetes Mellitus, Type 1; Female; Hydroxyquinolines; Inflammation; Mice; Mice, Inbred NOD; Spleen; Th1 Cells; Th2 Cells

Multiple sclerosis (MS) is characterized by high levels of circulating mononuclear cells (MNC) that respond to myelin proteins like myelin basic protein (MBP) in vitro by expressing mRNA of both pro-inflammatory cytokines, e.g. interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin (LT) that may make MS worse, and anti-inflammatory cytokines like IL-4, IL-10 and transforming growth factor-beta (TGF-beta) that may act beneficially. Substances that down-regulate cytokines such as TNF-alpha or promote IL-10 or TGF-beta can be anticipated to affect MS beneficially.. In situ hybridization to detect and enumerate IFN-gamma, TNF-alpha, LT, IL-4, IL-10 and TGF-beta mRNA expressing blood MNC after stimulation with myelin basic protein (MBP), control antigens and without antigen in presence and absence of Linomide (roquinimex, LS-2616) was employed. In parallel, ELISPOT assay to detect MBP- and PHA-reactive IFN-gamma secreting blood MNC+/-Linomide was used.. Here we report that Linomide, a synthetic immunomodulator, at concentrations effective in vivo reduces the number of MBP-reactive TNF-alpha and increases MBP-reactive IL-10 and TGF-beta mRNA expressing MNC from MS patients' blood when analysed in vitro. Compared to dexamethasone, Linomide up-regulated levels of blood MNC expressing mRNA of TGF-beta after culture in presence of MBP.. Changes of cytokine balance towards a production of anti-inflammatory cytokines could be a desirable effect to be evaluated in future drug studies of Linomide-like substances. At present, Linomide is not evaluable in MS clinical trials due to side-effects.

Topics: Adjuvants, Immunologic; Adult; Aged; Cytokines; Female; Humans; Hydroxyquinolines; Inflammation; Male; Middle Aged; Multiple Sclerosis; RNA, Messenger