Abstract:
:In the ophthalmological clinic, intravitreally applied antibodies or Fc-containing fusion proteins are frequently used, but the biology and pharmacokinetics of these therapeutics in the retina are not well understood. We have previously shown intracellular uptake of Fc-containing molecules in RPE cells. In this study, we investigated the involvement of Fc-receptors, both Fcγ-receptors and the neonatal Fc-receptor (FcRn) in the uptake and intracellular trafficking of the VEGF-antagonists bevacizumab, aflibercept and the anti-CD20 antibody rituximab in three different model systems, primary porcine RPE cells, ARPE-19 cells and porcine RPE/choroid explants. The expression of Fcγ-receptors was tested in primary porcine RPE cells, and the expression of Fcγ-receptors I and II could be shown in RT-PCR and qRT-PCR, while the expression of FcRn was additionally confirmed in Western blot and immunocytochemistry. All three compounds, bevacizumab, rituximab and aflibercept, were taken up into the cells and displayed a characteristic time-dependent pattern, as shown in Western blot and immunohistochemistry. The uptake was not altered by the inhibition of Fcγ-receptors using different inhibitors (TruStain FcX, genistein, R406). However, the inhibition of FcRn with an antagonistic antibody reduced intracellular IgG in porcine RPE cells (rituximab) and ARPE-19 cells (bevacizumab, rituximab). Colocalisations between the tested compounds and myosin7a could be found. In addition, limited colocalization with FcRn and the tested compounds, as well as triple localization between compound, FcRn and myosin7a could be detected, indicating a role of myosin7a in FcRn mediated transport. However, the colocalizations are restricted to small fractions of the Fc-containing compounds. Furthermore, the FcRn is mainly found in the membrane section, where only minute amounts of the Fc-containing compounds are seen, suggesting a limited interaction. An apical to choroidal transport of IgG through the RPE/choroid can be found in RPE/choroid explants. Inhibition of FcRn increases the amount of bevacizumab found on the choroidal side, suggesting a role of FcRn in the recycling of bevacizumab. In conclusion, our data indicate a role for FcRn, but not Fcγ-receptors, in the uptake and transport of Fc-containing molecules in the RPE and indicate a recycling function of FcRn in the retina.
journal_name
Exp Eye Resjournal_title
Experimental eye researchauthors
Dithmer M,Hattermann K,Pomarius P,Aboul Naga SH,Meyer T,Mentlein R,Roider J,Klettner Adoi
10.1016/j.exer.2015.12.013subject
Has Abstractpub_date
2016-04-01 00:00:00pages
187-205eissn
0014-4835issn
1096-0007pii
S0014-4835(15)30098-1journal_volume
145pub_type
杂志文章abstract::Accumulation of specific deposits and extracellular molecules under the retinal pigment epithelium (RPE) has been previously observed in eyes with age-related macular degeneration (AMD) and may play a role in the pathogenesis of AMD. Even though age is the major determinant for developing AMD, clinical studies have re...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2009.02.020
更新日期:2009-06-15 00:00:00
abstract::This study was undertaken to develop a feline model of corticosteroid-induced ocular hypertension. In the first experiment, eight cats were selected whose intraocular pressure (17 +/- 0.4 mmHg) was consistently below the mean baseline intraocular pressure of our colony (24 +/- 0.5) during the preceding 2 months. Unila...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/s0014-4835(05)80210-6
更新日期:1992-02-01 00:00:00
abstract::Harmonic analysis was used to characterize the rabbit flicker ERG elicited by sinusoidally modulated full-field stimuli under light-adapted conditions. The frequency-response function for fundamental amplitude, derived from Fourier analysis of the ERG waveforms, exhibited two limbs, with an amplitude minimum at approx...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2010.10.005
更新日期:2010-12-01 00:00:00
abstract::In this study, we examined calcium-mediated degradation of a neurofilament protein (NFP), and autolytic activation of calpain in Lewis rat optic nerve in vitro. After incubation with calcium, homogenized optic nerve samples were analysed by SDS-PAGE in association with ECL immunoblot techniques. 68 kD NFP, calpain, an...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1006/exer.1997.0286
更新日期:1997-07-01 00:00:00
abstract::cDNA clones encoding S-antigen (arrestin) were isolated from the expression library constructed from porcine retina and sequenced. The 1490 base pair fragment contained a 1215 base pair open reading frame. From the nucleotide sequence, an amino acid sequence consisting of 405 residues was deduced and a molecular mass ...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1006/exer.1996.0036
更新日期:1996-03-01 00:00:00
abstract::The Raman microspectroscopic method was used to determine the local water and protein content in human lenses. In 18 lenses of varying age position-defined water/protein content measurements were carried out along the visual and the equatorial axis. A main characteristic of the human lens is its constant and relativel...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/0014-4835(91)90079-t
更新日期:1991-08-01 00:00:00
abstract::Myofibroblast development and haze generation in the corneal stroma is mediated by cytokines, including transforming growth factor-beta (TGF-beta), and possibly other cytokines. This study examined the effects of stromal PDGF-beta blockade on the development of myofibroblasts in response to -9.0 diopter photorefractiv...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2008.12.006
更新日期:2009-05-01 00:00:00
abstract::The zebrafish retina regenerates in response to acute retinal lesions, replacing damaged neurons with new neurons. In this study we test the hypothesis that chronic stress to inner retinal neurons also triggers a retinal regeneration response in the bugeye zebrafish. Mutations in the lrp2 gene in zebrafish are associa...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2011.06.001
更新日期:2011-10-01 00:00:00
abstract::Elevated permeability of retinal endothelial cells (REC), as observed in diabetic retinopathy (DR), is induced by extended exposure to ≥25 ng/ml vascular endothelial growth factor A165 (VEGF165) for up to 3 d and this effect is more pronounced when equimolar amounts of basic fibroblast growth factor (bFGF) and insulin...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2013.07.018
更新日期:2013-10-01 00:00:00
abstract::Ischemic preconditioning (IPC) protects the rat retina against the injury that ordinarily follows severe ischemia. We showed previously that release of adenosine and de novo protein synthesis were required for IPC protection. The mechanisms of IPC were studied in the rat retina by examining the signal transduction med...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1006/exer.2000.0843
更新日期:2000-06-01 00:00:00
abstract::Myopia is one of the leading ocular disorders causing visual impairment worldwide, with the prevalence increasing rapidly. It's a significant global public health concern in 21st century. Myopia, particularly high myopia, often exhibits apparent familial aggregation, and multiple evidences have shown that genetic fact...
journal_title:Experimental eye research
pub_type: 杂志文章,评审
doi:10.1016/j.exer.2019.107778
更新日期:2019-11-01 00:00:00
abstract::The association between the use of statins and age-related macular degeneration (AMD), a leading cause of blindness, has been evaluated in many clinical studies; however, the results have been contradictory. We evaluated the effect of pitavastatin administration on laser-induced experimental choroidal neovascularizati...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2007.02.005
更新日期:2007-06-01 00:00:00
abstract::RPE65-related Leber's congenital amaurosis (LCA) is a rod-cone dystrophy whose clinical outcome is mainly attributed to the loss of rod photoreceptors followed by cone degeneration. Pathogenesis in Rpe65(-/-) mice is characterized by a slow and progressive degeneration of rods dependent on the constitutive activation ...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2011.12.019
更新日期:2012-03-01 00:00:00
abstract::Retinal pigment epithelial cell dysfunction mediated by reactive oxygen intermediates has been suggested as a possible cause of age-related macular degeneration. To test the hypothesis that retinal pigment cells are susceptible to genetic damage mediated by reactive oxygen intermediates, retinal pigment epithelial cel...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1006/exer.1998.0661
更新日期:1999-06-01 00:00:00
abstract::Congenic hereditary cataract mice, BALB/c-nct/nct, were established by introducing the nct gene from Nakano into BALB/c mice. These mice developed a milder cortical form of cataract which developed sporadically and later in life than in Nakano mice. Combined use of BALB/c and BALB/c-nct/nct mice enables biochemical co...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/0014-4835(91)90049-k
更新日期:1991-05-01 00:00:00
abstract::We have examined the mercapturic acid pathway of the cataractous rabbit lens following induction by naphthalene as an oxidative foreign substance. 1,2-Naphthoquinone, which is formed in the eye from naphthalene diol and other naphthalene derivatives by a combination of enzymic and non-enzymic reactions, readily oxidiz...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/0014-4835(88)90058-9
更新日期:1988-09-01 00:00:00
abstract::Anti-Vascular Endothelial Growth Factors (Anti-VEGF) agents have received recent interest as potential anti-fibrotic agents for their concurrent use with trabeculectomy. Preliminary cohort studies have revealed improved bleb morphology following trabeculectomy augmented with ranibizumab. The effects of this humanized ...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2014.08.005
更新日期:2014-10-01 00:00:00
abstract::Human limbal epithelial cells (LECs) intended for treatment of limbal stem cell deficiency are commonly cultivated on a 3T3 feeder layer with complex culture medium supplemented with fetal bovine serum (FBS). However, FBS is a xenogeneic component containing poorly characterised constituents and exhibits quantitative ...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2018.06.019
更新日期:2018-11-01 00:00:00
abstract::Retinal degeneration (RD) results from photoreceptor apoptosis. Cell transplantation, one potential therapeutic approach, requires expandable stem cells that can form mature photoreceptors when differentiated. Freshly dissociated primary retinal cells from postnatal day 2-6 (PN2-6) mouse retina can give rise, post-tra...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2010.07.003
更新日期:2010-10-01 00:00:00
abstract::Crystallin-bound non-tryptophan fluorescence and protein cross-linking were studied in chronic galactosemia. Fluorescence (excitation/emission--370/440 nm) was significantly higher in galactosemic rats compared to controls (P less than 0.001). Accumulation of fluorescence was significantly reduced both in water solubl...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/0014-4835(90)90153-l
更新日期:1990-10-01 00:00:00
abstract::Following the identification of potent, orally active inhibitors of aldose reductase, the next challenge comes in demonstrating clinical utility in the treatment of diabetic complications. It is not feasible to conduct pivotal studies in all indications within the same trial and neuropathy evolved as the lead indicati...
journal_title:Experimental eye research
pub_type: 临床试验,杂志文章,评审
doi:10.1016/0014-4835(90)90103-2
更新日期:1990-06-01 00:00:00
abstract::Rabbit immunoglobulin G (IgG) binds specifically to the human corneal epithelium. We investigated this phenomenon to identify the binding material in the tissue. Sections of human cornea were immunostained with negative-control grade rabbit IgG, F(ab')(2) (the antigen recognition fragment of IgG yielded by pepsin dige...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2004.01.006
更新日期:2004-06-01 00:00:00
abstract::The purpose of this study was to evaluate the inhibitory activity of the heparan sulfate suleparoide on vascular cell growth in vitro and angiogenesis in vivo. Human HUV-EC-C endothelial cell proliferation and microvessel sprouting from cultured rat aortic rings were assayed by the bioreduction of 3-[4,5-dimethylthiaz...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1006/exer.1998.0512
更新日期:1998-08-01 00:00:00
abstract::Multidrug resistance associated protein (MRP) is a major family of efflux transporters involved in drug efflux leading to drug resistance. The objective of this study was to explore physical barriers for ocular drug absorption and to verify if the role of efflux transporters. MRP-2 is a major homologue of MRP family a...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2006.08.015
更新日期:2007-01-01 00:00:00
abstract::Bombina variegata 8 (Bv8), also known as prokineticin-2 (PK-2), is a potent pro-angiogenic factor. However, its role in retinal neovascularization (RNV) remains unknown. In this study, we explored the role of Bv8 in the pathogenesis of RNV. We found that the expression of Bv8 was significantly increased in two differe...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2020.107993
更新日期:2020-04-01 00:00:00
abstract::Nitric oxide (NO) production by vascular endothelium is important in regulation of blood flow. Reduced production of NO can adversely affect blood flow and other vascular functions. We investigated the expression of three nitric oxide synthase (NOS) isoforms in retina and choroid of aged human eyes and eyes with AMD. ...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2009.10.004
更新日期:2010-01-01 00:00:00
abstract::γ-secretase inhibitor has been shown to promote intestinal goblet cell differentiation. We now demonstrated that the in vitro addition of γ-secretase inhibitor in the culture of human conjunctival epithelial cells significantly promoted the differentiation of conjunctival goblet cells with typical droplet-like phenoty...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1016/j.exer.2014.04.001
更新日期:2014-06-01 00:00:00
abstract::Eosinophil infiltration is one of the aspects of the inflammatory response to an allergen. The aim of this study was to establish T-helper type-2 (Th2)-induced conjunctival eosinophilia in mice to evaluate the effect of anti-allergic drugs. Th2 clone, D10.G4.1. (D10) with its specific antigen, conalbumin was co-inject...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1006/exer.1999.0677
更新日期:1999-07-01 00:00:00
abstract::Post-translational modifications and/or structural changes induced by modifications are likely causes of the decrease in crystallin solubility associated with aging and the development of cataract. Characterization of human lens crystallins by mass spectrometry has demonstrated that betaB2-crystallin undergoes less mo...
journal_title:Experimental eye research
pub_type: 杂志文章
doi:10.1006/exer.2001.1023
更新日期:2001-08-01 00:00:00
abstract::Glaucoma is defined as a progressive optic neuropathy and is characterized by an irreversible loss of retinal ganglion cells. The main risk factor to develop glaucoma is an increased intraocular pressure (IOP). During the course of glaucoma structural changes in the optic nerve head (ONH) take place which lead to the ...
journal_title:Experimental eye research
pub_type: 杂志文章,评审
doi:10.1016/j.exer.2015.08.014
更新日期:2016-01-01 00:00:00