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Münster, Germany

Heiligenhaus A.,University of Duisburg - Essen | Heiligenhaus A.,Ophtha Laboratory | Zurek-Imhoff B.,University of Duisburg - Essen | Roesel M.,University of Duisburg - Essen | And 3 more authors.
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2013

Background: This study investigated the efficacy of everolimus, a potent inhibitor of T lymphocyte proliferation, for treating noninfectious uveitis. The study design was an open-label prospective trial. Methods: Twelve patients with severe chronic uveitis (anterior and intermediate n = 9, panuveitis n = 3) refractive to cyclosporine A (CsA) received additional everolimus. Main outcome measure: the primary outcome measure was uveitis inactivity at 3 months. Secondary outcome measures were uveitis recurrence, visual acuity (BCVA), laser flare photometry values, cystoid macular edema, and tapering of concomitant corticosteroids and/or immunosuppressive drugs in 12 months with the addition of everolimus and after withdrawing everolimus. Percentages of peripheral blood CD3+CD4+CD25+Foxp3+ cells were studied. Results: At month 3 with everolimus, uveitis was inactive in all patients. By 12 months, uveitis had recurred in four patients after tapering (n = 2) or withdrawing (n = 2) CsA. BCVA remained stable in all patients, mean foveal thickness (OCT) was slightly reduced from 308 μm at baseline to 255 μm (p = 0.1), and mean flare values were slightly reduced from 27.8 to 19.3 photons/msec (p = 0.1). It was possible to achieve a 50 % dose reduction of systemic prednisone (n = 8) or CsA (n = 8). After withdrawing everolimus, uveitis recurred in 50 % within 1 month; by 6 months, BCVA dropped ≥2 lines in five patients, and prednisone use increased ≥50 % in four patients. The percentage of peripheral blood CD3+CD4+CD25 +FoxP3+ T cells increased during the everolimus treatment, and dropped after withdrawal. Conclusions: Uveitis inactivity was achieved with the addition of everolimus in patients with chronic, CsA-refractive anterior and intermediate uveitis, or panuveitis. © 2012 Springer-Verlag Berlin Heidelberg.

Retinal pigment epithelial detachment (PED) as a specific manifestation in exudative age-related macular degeneration (AMD) may lead to a substantial decrease of central vision. An understanding of important events during the development of PED is necessary for a successful therapeutic intervention. At present the leading pathogenetic theory is that of reduced hydraulic conductivity of Bruch's membrane. The mechanisms underlying this process are caused by increased deposition of lipids, enhanced collagen cross-linking and alteration in the ratio of tissue-dissolving enzymes and their inhibitors. The association of newly formed vessels and an unaltered RPE pump activity can lead to the clinical picture of serous PED during exudative AMD. © 2010 Springer-Verlag.

Lueck K.,Ophtha Laboratory | Wasmuth S.,Ophtha Laboratory | Williams J.,University College London | Hughes T.R.,University of Cardiff | And 5 more authors.
Eye | Year: 2011

Purpose There is evidence for complement dysfunction in age-related macular degeneration (AMD). Complement activation leads to formation of the membrane attack complex (MAC), known to assemble on retinal pigment epithelial (RPE) cells. Therefore, the effect of sub-lytic MAC on RPE cells was examined with regard to pro-inflammatory or pro-angiogenic mediators relevant in AMD. Methods For sub-lytic MAC induction, RPE cells were incubated with an antiserum to complement regulatory protein CD59, followed by normal human serum (NHS) to induce 5% cell death, measured by a viability assay. MAC formation was evaluated by immunofluorescence and FACS analysis. Interleukin (IL)-6, -8, monocytic chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were quantified by enzyme-linked immunosorbent assay (ELISA). Intracellular MCP-1 was analysed by immunofluorescence, vitronectin by western blotting, and gelatinolytic matrix metalloproteinases (MMPs) by zymography. Results Incubation of RPE cells with the CD59 antiserum followed by 5% NHS induced sub-lytic amounts of MAC, verified by FACS and immunofluorescence. This treatment stimulated the cells to release IL-6, -8, MCP-1, and VEGF. MCP-1 staining, production of vitronectin, and gelatinolytic MMPs were also elevated in response to sub-lytic MAC. Conclusions MAC assembly on RPE cells increases the IL-6, -8, and MCP-1 production. Therefore, sub-lytic MAC might have a significant role in generating a pro-inflammatory microenvironment, contributing to the development of AMD. Enhanced vitronectin might be a protective mechanism against MAC deposition. In addition, the increased expression of gelatinolytic MMPs and pro-angiogenic VEGF may be associated with neovascular processes and late AMD. © 2011 Macmillan Publishers Limited All rights reserved.

Hennig M.,Ophtha Laboratory | Hennig M.,University of Duisburg - Essen | Bauer D.,Ophtha Laboratory | Wasmuth S.,Ophtha Laboratory | And 6 more authors.
Experimental Eye Research | Year: 2012

The efficacy and action mechanism of everolimus in the treatment of experimental autoimmune uveoretinitis (EAU) was analyzed. Disease was induced in B10.RIII mice by immunization with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBPp161-180). Everolimus was administered by oral gavage (5 mg/kg/d) beginning either two days before or 14 days after immunization. Everolimus significantly reduced the histopathological uveitis score compared to sham-treated mice. To examine the effect on the antigen-specific immune response, proliferation ([ 3H]-thymidine test) and delayed-type hypersensitivity (DTH) response were measured. Furthermore, content of T-helper-1, -2, and -17 cytokines were analyzed intraocularly (Bead Array) and in cell culture supernatants from splenocytes (sandwich ELISA). To study the effect on the humoral immune response the presence of antigen-specific serum antibodies was tested (indirect ELISA). The DTH, the humoral immune response, the proliferation of splenocytes and the intraocular Th1, Th2, Th17 cytokine content and in vitro production of Th1 and Th17 cytokines were impaired after everolimus treatment. The study of CD4+CD25+FoxP3+ regulatory T cells (T reg) in peripheral blood, draining lymph nodes, and spleen by flow cytometry showed an increased number of splenic T reg in mice of the everolimus therapy group. Furthermore the T reg of these mice had a higher suppressive capacity than cells from sham-treated mice. These results indicate that the immunosuppressive effect of everolimus on EAU was associated with the suppression of pathogenic effector responses and induction of regulatory T cells. © 2012 Elsevier Ltd.

Busch M.,Ophtha Laboratory | Busch M.,University of Duisburg - Essen | Bauer D.,Ophtha Laboratory | Hennig M.,Ophtha Laboratory | And 5 more authors.
Investigative Ophthalmology and Visual Science | Year: 2013

Purpose. To investigate the effect of systemic or local TNF-α inhibition with etanercept on experimental autoimmune uveoretinitis (EAU). Methods. EAU was induced by immunizing B10.RIII mice with IRBPp161-180 or by adoptively transferring uveitogenic splenocytes. Mice received systemic or local treatment with etanercept in the afferent or efferent phase. For systemic treatment, mice were injected intraperitoneally. For local treatment, etanercept was injected intravitreally or subcon-junctivally. Control mice received PBS. EAU scores were determined histologically. Splenic cells were assessed for [3H]thymidine incorporation. ELISA was performed to measure levels of cytokines produced by splenocytes. Vitreous cavity-associated immune deviation (VCAID) was induced by intra-vitreally injecting ovalbumin and evaluated by measuring DTH reaction. Results. After systemic treatment with etanercept in the afferent phase, EAU disease scores, IRBP-specific cell proliferation, and production of Th1, Th2, and Th17 cytokines were reduced. EAU also improved after intravitreal etanercept treatment in the afferent phase, with unaltered IRBP-specific proliferation, reduced IFN-c, but increased IL-6 and IL-10 secretion. VCAID induction was impaired after intravitreal etanercept treatment. No amelioration of EAU or reduction in IRBP-specific cell response was found after systemic or intravitreal treatment in the efferent phase or after subcon-junctival treatment. After adoptive transfer, etanercept- and PBS-treated recipients showed similar disease severity and antigen-specific proliferation of splenocytes. Conclusions. It can be concluded that TNF-α participates mainly in the immunopathology in the induction phase of EAU. The mechanism of action underlying EAU improvement may be different for local and systemic etanercept treatment. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

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