Subject(s)
Janus Kinase Inhibitors , Polyendocrinopathies, Autoimmune , Female , Humans , Male , Autoantibodies/blood , Autoantibodies/immunology , Immunotherapy , Janus Kinase Inhibitors/immunology , Janus Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Polyendocrinopathies, Autoimmune/drug therapy , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/physiopathology , Disease Models, Animal , AIRE Protein/deficiency , AIRE Protein/genetics , AIRE Protein/immunologyABSTRACT
Certain inflammatory disorders are characterized by macrophage activation and accumulation in tissue; sometimes leading to the formation of granulomas, as in sarcoidosis. These disorders are often difficult to treat and more effective, molecularly targeted therapies are needed. Recent work has shown that overproduction of inflammatory cytokines, such as interferon gamma (IFN-γ) leading to constitutive activation of the JAK-STAT pathway may be a conserved feature of these disorders. Use of JAK inhibitors, which can block these signals, has resulted in dramatic improvement in several patients with sarcoidosis. JAK inhibitors also appear to have activity in other inflammatory disorders with macrophage activation including hemophagocytic lymphohistiocystosis, Crohn's disease, granuloma annulare, and necrobiosis lipoidica. Here, we review the role of JAK dependent cytokines in macrophage activation and granuloma formation and the clinical evidence supporting the use of JAK inhibition in these disorders. Ongoing efforts to evaluate role of JAK inhibitors in these disorders is also discussed.
Subject(s)
Inflammation/drug therapy , Janus Kinase Inhibitors , Macrophage Activation , Sarcoidosis/drug therapy , Humans , Janus Kinase Inhibitors/immunology , Janus Kinase Inhibitors/pharmacology , Macrophage Activation/drug effects , Macrophage Activation/immunology , Sarcoidosis/immunologyABSTRACT
BACKGROUND AND AIMS: Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473-an oral gut-selective pan-JAK inhibitor-from in vitro characterization through a Phase 1b study in patients with UC. METHODS: TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. RESULTS: TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. CONCLUSION: Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686].
Subject(s)
Colitis, Ulcerative , Intestinal Mucosa , Janus Kinase Inhibitors , Administration, Oral , Adult , Animals , Biomarkers, Pharmacological/analysis , Blood Cell Count/methods , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/immunology , Dose-Response Relationship, Immunologic , Healthy Volunteers , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/immunology , Janus Kinase Inhibitors/immunology , Janus Kinase Inhibitors/pharmacokinetics , Male , Mice , Severity of Illness Index , Tissue Distribution/immunology , Translational Research, Biomedical/methods , Treatment OutcomeABSTRACT
BACKGROUND: Centipedegrass extract (CGE) is rich in several polyphenolic compounds including C-glycosylflavonoids, such as maysin and its derivatives, and exerts antioxidant, anti-adipogenic and anticancer effects. However, the effect of CGE on the immune system is unclear. PURPOSE: CGE might inhibit NO production induced by lipopolysaccharide (LPS). In this study, we propose a molecular mechanism for regulation of aberrant immune responses by CGE in LPS-stimulated RAW264.7 cells. STUDY DESIGN: We will preparation of Centipedegrass extract and purify partially in rich of maysin and its derivatives. And examine the effect of the CGE on immune system using LPS-induced RAW cells and animals. METHODS: LPS-induced nitric oxide (NO) and interleukin-6 levels were measured by enzyme-linked immunosorbent assay. The mRNA and protein levels of immune mediators were analyzed by reverse-transcription polymerase chain reaction and immunoblotting, respectively. RESULTS: CGE inhibited LPS-induced NO production in a concentration-dependent manner by suppressing inducible nitric oxide synthase (iNOS) expression in LPS-stimulated cells; this effect was mediated by inhibition of the JAK/STAT pathway. However, CGE did not regulate the expression of other factors, including phosphorylated p38, c-jun N-terminal kinase, or extracellular signal-regulated kinase 1/2. In addition, CGE increased T cells percentage in peripheral blood after oral administration. CONCLUSION: These results indicate that CGE suppresses LPS-induced production of NO and expression of iNOS by directly inhibiting JAK2 kinase activity and enhancing effects on the immune system in mice.