Methylfumarates Induce Interleukin-4 and -10 and Improve HSV-1 Keratitis in BALB-c Mice
Heiligenhaus A.1, Li H.1, Wasmuth S.1,2, Bauer D.1
1Ophtha-Lab, Department of Ophthalmology at St. Franziskus Hospital, Muenster
2Department of Ophthalmology, University of Duisburg-Essen
Purpose: Methylfumarates (MF) stimulate T helper-2-cytokines (interleukin (IL)-4, -5, 10) without affecting the T-helper-1-cytokine (IL-2, interferon (IFN)-g)-response. HSV-1 stromal keratitis (HSK) improves with systemic administration of IL-4 or -10. Herein, the influence of systemic MF-treatment on the secretion of T helper-cytokines and the development of keratitis was investigated in the murine HSK model.
Method: The right cornea of BALB/c mice was infected with HSV-1 (KOS). At day 14 post-infection (p.i.), lymphocytes from the regional lymph nodes were co-cultured with monomethylfumarate (MMF) and were stimulated with HSV-1 antigen. The secretion of IL-2, -4, -10 and IFN-g was tested by ELISA. Groups of mice were systemically treated with: 1: vehicle for 28 days pre-infection; or 2: dimethylfumarate (DMF) for 28 days pre-infection; or 3: DMF for 14 days post-infection; or 4: DMF pre- and post-infection. The mice were followed-up clinically for the signs of HSV-1 keratitis. The corneas were studied by histology. Virus replication in the eyes was measured by a standard plaque-assay. The DTH response, the HSV-1 specific proliferation of cells in the regional lymph nodes, and the neutralizing antibodies in serum were investigated.
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