title: Improvement of herpetic stromal keratitis with fumaric acid derivate is associated with systemic induction of T helper 2 cytokines.
abstract: Fumaric acid derivates have been shown to stimulate T helper-2-cytokines (interleukin (IL)-4, -5) without affecting the T-helper-1-cytokine (IL-2, interferon (IFN)-gamma)-response. Herein, the influence of systemic treatment with the fumaric acid derivate dimethylfumarate (DMF) on the secretion of T helper-cytokines and the development of HSV-1 stromal keratitis (HSK) was studied in mice. The corneas from BALB/c mice were infected with 10(5) PFU of HSV-1 (KOS strain). While one group of mice was treated intraperitoneally with PBS, another group of mice received DMF at 15 mg/kg of body weight. Expression of IL-2, -4, -10 and IFN-gamma was analysed in HSV-1 activated lymphocytes by ELISA. The severity of epithelial and stromal herpetic keratitis was investigated clinically. Corneas were studied for the inflammatory cell infiltration, and the CD3-, CD4- and CD8-positive cells were analysed by immunohistochemistry. The IL-2, -4, 10 and IFN-gamma content was measured in the corneas. Virus replication in the eyes was analysed by a plaque-assay. The DTH-response, the HSV-specific T cell proliferation and the serum neutralizing antibody-titres were investigated. DMF increased IL-4 and IL-10, but not IL-2 and IFN-gamma, secretion in activated lymphocytes from the spleen. Incidence and severity of stromal HSV-1 keratitis was reduced in the DMF group (P < 0.01). In the corneas from DMF-treated mice, the numbers of CD3+ and CD4+ cells were decreased and IL-4 was increased. Severity of epithelial disease and the virus-clearance from the eyes did not differ between the PBS and DMF group of mice. DTH, HSV-specific T cell proliferation and the neutralizing antibody-titres were not impaired. DMF increased the T helper-2-cytokine secretion in activated lymphocytes. After corneal HSV-1 infection, corneas from DMF treated mice had increased IL-4 content. This is associated with an improvement of herpetic stromal keratitis and reduced corneal T cell infiltration. DMF did not impair the systemic antiviral response.
authors.affiliation: Ophtha-Lab, Department of Ophthalmology at St. Franziskus Hospital, Muenster, Germany. arnd.heiligenhaus@uveitis-zentrum.de
authors.forename: A
authors.initials: A
authors.lastname: Heiligenhaus
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Schmitz
authors.forename: S
authors.initials: S
authors.lastname: Wasmuth
authors.forename: D
authors.initials: D
authors.lastname: Bauer
mesh_terms: D000818:Animals; D003208:Concanavalin A / Q000276:immunology; D003315:Cornea / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D000069462:Dimethyl Fumarate; D005260:Female; D005650:Fumarates / Q000276:immunology / Q000627:therapeutic use*; D018259:Herpesvirus 1, Human / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000276:immunology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D016849:Keratitis, Herpetic / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D005650:Fumarates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D003208:Concanavalin A; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D000069462:Dimethyl Fumarate