title: Suppression of autoimmune retinal inflammation by an antiangiogenic drug.
abstract: Chronic and recurrent uveitis account for approximately 10% of legal blindness in the western world. Autoimmune uveitis is driven by activated CD4(+) T cells that differentiate into effector T helper cells (Th1, Th2, and Th17) which release proinflammatory cytokines that damage the retina. In this study we investigated the effect of the methionine aminopeptidase 2 (MetAP2) inhibitor, Lodamin, on T cell activation and differentiation. MetAp2 is an enzyme which regulates cellular protein synthesis and is highly expressed in T cells. Lodamin was found to suppress T cell receptor (TCR) mediated T cell proliferation and reduced the production of Th1 and Th17 cells. Further, Lodamin suppressed overall inflammation in the mouse model of experimental autoimmune uveitis (EAU) by a six fold. This effect was attributed in part to a reduction in retinal proinflammatory cytokines, down regulation of MetAP2 expression in purified lymph node CD4(+) T cells, and a general normalization of the systemic immune reaction.
authors.affiliation: Department of Surgery, Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Takeru
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Ofra
authors.initials: O
authors.lastname: Benny
authors.forename: Lauren
authors.initials: L
authors.lastname: Bazinet
authors.forename: Robert J
authors.initials: RJ
authors.lastname: D'Amato
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D011091:Polyesters / Q000008:administration & dosage / Q000494:pharmacology*; D012173:Retinitis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D014605:Uveitis / Q000188:drug therapy / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D017252:CD3 Complex; D016207:Cytokines; D018836:Inflammation Mediators; D011091:Polyesters; D012717:Sesquiterpenes; C585731:lodamin