title: Treatment of experimental autoimmune uveoretinitis with atorvastatin and lovastatin.
abstract: Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are approved for cholesterol reduction and are commonly used to treat atherosclerosis and coronary artery disease. Statins may also be potent immunomodulatory agents and may be beneficial in the treatment of autoimmune diseases. In this study, we investigated therapeutic effects of atorvastatin and lovastatin on experimental autoimmune uveoretinitis (EAU). EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide. Atorvastatin was suspended in 0.5% aqueous methylcellulose and was administered orally at a dose of 10 mg/kg and at a low-dose of 1 mg/kg. Lovastatin was dissolved in DMSO:PBS (1:1) and was administered by intraperitoneal (i.p.) injection at a dose of 2 mg/kg. Both statin treatments were initiated after the clinical onset once daily for 14 days. The rats were examined every other day for clinical signs of EAU. The histological scores and delayed-type hypersensitivity (DTH) were evaluated on day 28 post-immunization. Morphologic and immunohistochemical examinations were performed with light and confocal microscopy, respectively. Lymphocyte proliferation was measured by [(3)H]thymidine incorporation into antigen-stimulated T cells from inguinal lymph nodes. After 72 h, supernatants were collected and assayed for IFN-gamma by ELISA. Clinical and histological scores of EAU were decreased in both the atorvastatin (10 mg/kg)- and lovastatin (2 mg/kg)-treated groups. The invasion of T cells and macrophages, and Müller cell proliferation, were inhibited in both atorvastatin- and lovastatin-treated groups. DTH was significantly inhibited in both groups, compared with vehicle-treated groups (controls). Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 microg/ml S-Ag peptide in both groups, compared with controls. In the supernatants of lymph node cells stimulated with S-Ag peptide (5 microg/ml), 77 or 87% inhibition of IFN-gamma production was observed in rats treated with atorvastatin or lovastatin, respectively, compared with controls. The current results indicate that atorvastatin administrated orally following the clinical onset has therapeutic effect in EAU as well as lovastatin administrated intraperitoneally. Statins may be useful for treating intraocular inflammation.
authors.affiliation: Department of Ophthalmology, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. kohnohideo@jikei.ac.jp
authors.forename: Hideo
authors.initials: H
authors.lastname: Kohno
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sakai
authors.forename: Saburo
authors.initials: S
authors.lastname: Saito
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Okano
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitahara
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019393:Arrestin / Q000276:immunology / Q000494:pharmacology; D000069059:Atorvastatin; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002417:Cattle; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006968:Hypersensitivity, Delayed; D007150:Immunohistochemistry / Q000379:methods; D007274:Injections, Intraperitoneal; D008148:Lovastatin / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D023421:Models, Animal; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000276:immunology; D012173:Retinitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D014602:Uvea / Q000276:immunology; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D019393:Arrestin; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D008148:Lovastatin; D000069059:Atorvastatin