title: Immunosuppressive activity of a new pteridine derivative (4AZA1378) alleviates severity of TNBS-induced colitis in mice.
abstract: Besides TNF, activated T cells play a central role in the pathogenesis of inflammatory bowel diseases such as Crohn's disease. New therapies are still awaited to cure these often debilitating diseases. Natural occurring pteridines such as tetrahydrobiopterin (BH4) and neopterin have been reported to have immune modulating activities. Starting from a pteridine scaffold library, we intended to select compounds with potent in vitro inhibitory effects on T cells and to evaluate in vivo efficacy of selected compounds on trinitrobenzenesulphonate (TNBS) colitis in mice. Compound 4AZA1378 was selected because it potently inhibits human T cell proliferation at low nM concentrations (IC50 4 nM) while an almost 50-fold higher concentration was needed to inhibit LPS-induced TNF production. Mice treated with 4AZA1378 had less severe signs of colitis after TNBS rectal administration, with a more rapid weight recovery. Myeloperoxidase (MPO) activity and intralesional cytokine production were lower in mice of the treated groups. Furthermore anti-TNBS antibody responses were completely inhibited by treatment with 4AZA1378. In conclusion, we identified a pteridine analogue 4AZA1378 with immunosuppressive activity and a strong remission-inducing effect in TNBS colitis, supporting further pre-clinical and clinical development of this novel molecule for treatment of inflammatory diseases.
authors.affiliation: Laboratory of Experimental Immunology, Faculty of Medicine, Katholieke Universiteit Leuven, Belgium.
authors.forename: Chong
authors.initials: C
authors.lastname: Shen
authors.forename: Ellen
authors.initials: E
authors.lastname: Dillissen
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kasran
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.forename: Jean
authors.initials: J
authors.lastname: Herman
authors.forename: Ilse
authors.initials: I
authors.lastname: Sienaert
authors.forename: Steven
authors.initials: S
authors.lastname: De Jonghe
authors.forename: Luk
authors.initials: L
authors.lastname: Kerremans
authors.forename: Karel
authors.initials: K
authors.lastname: Geboes
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Jan L
authors.initials: JL
authors.lastname: Ceuppens
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000187:drug effects; D011621:Pteridines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects; D014302:Trinitrobenzenesulfonic Acid / Q000276:immunology* / Q000633:toxicity
chemical_list: C516914:4AZA1378; D016207:Cytokines; D007166:Immunosuppressive Agents; D011621:Pteridines; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase