Bone spicule pigment formation in retinitis pigmentosa: insights from a mouse model

Jaissle, Gesine B.; May, Christian Albrecht; Pavert, Serge A. van de; Wenzel, Andreas; Claes-May, Ellen; Gießl, Andreas; Szurman, Peter; Wolfrum, Uwe; Wijnholds, Jan; Fisher, Mark D.; Humphries, Pete; Seeliger, M. W.

doi:10.1007/s00417-009-1253-9

Cited by 45 publications

(30 citation statements)

References 20 publications

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“…This feature in EAU was identified from day 36 onwards showing vascular remodelling to occur earlier in disease course than indicated by similar vascular membranes recently observed only from day 60 post-induction [22]. The vascular lesions share some similarities with those described in degenerative models with a chronic low grade inflammatory component, such as rhodopsin kinase knockout mice [23] or those carrying the rd8 mutation [18]. The mice used in our study carry neither defect and thus the lesion may represent a more widespread feature of tissue remodelling in response to degenerative or inflammatory processes in the retina.…”

Section: Discussionsupporting

confidence: 71%

Assessment and In Vivo Scoring of Murine Experimental Autoimmune Uveoretinitis Using Optical Coherence Tomography

Chu¹,

Herrmann²,

Carvalho³

et al. 2013

PLoS ONE

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Despite advances in clinical imaging and grading our understanding of retinal immune responses and their morphological correlates in experimental autoimmune uveoretinitis (EAU), has been hindered by the requirement for post-mortem histology. To date, monitoring changes occurring during EAU disease progression and evaluating the effect of therapeutic intervention in real time has not been possible. We wanted to establish whether optical coherence tomography (OCT) could detect intraretinal changes during inflammation and to determine its utility as a tool for accurate scoring of EAU. EAU was induced in C57BL/6J mice and animals evaluated after 15, 26, 36 and 60 days. At each time-point, contemporaneous Spectralis-OCT scanning, topical endoscopic fundal imaging (TEFI), fundus fluorescein angiography (FFA) and CD45-immunolabelled histology were performed. OCT features were further characterised on retinal flat-mounts using immunohistochemistry and 3D reconstruction. Optic disc swelling and vitreous opacities detected by OCT corresponded to CD45+ cell infiltration on histology. Vasculitis identified by FFA and OCT matched perivascular myeloid and T-cell infiltrates and could be differentiated from unaffected vessels. Evolution of these changes could be followed over time in the same eye. Retinal folds were visible and found to encapsulate mixed populations of activated myeloid cells, T-cells and microglia. Using these features, an OCT-based EAU scoring system was developed, with significant correlation to validated histological (Pearson r2 = 0.6392, P<0.0001, n = 31 eyes) and TEFI based scoring systems (r2 = 0.6784, P<0.0001). OCT distinguishes the fundamental features of murine EAU in vivo, permits dynamic assessment of intraretinal changes and can be used to score disease severity. As a result, it allows tissue synchronisation with subsequent cellular and functional assessment and greater efficiency of animal usage. By relating OCT signals with immunohistochemistry in EAU, our findings offer the opportunity to inform the interpretation of OCT changes in human uveitis.

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Section: Discussionsupporting

confidence: 71%

Assessment and In Vivo Scoring of Murine Experimental Autoimmune Uveoretinitis Using Optical Coherence Tomography

Chu¹,

Herrmann²,

Carvalho³

et al. 2013

PLoS ONE

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“…Retinal pigment epithelial (RPE) cells closely interacted with the MicroBeads, and collagen fibers were apparent in the extracellular matrix of the confluent connective tissue adjacent to the alginate capsule. The interaction between RPE and MicroBeads displayed similarities to previously described observations on the active role of RPE cells in bone spicule formation in Retinitis pigmentosa [35]. In one instance, we observed surface invaginations into the alginate sphere (Fig.…”

Section: Resultssupporting

confidence: 87%

Successful Subretinal Delivery and Monitoring of MicroBeads in Mice

Fischer

Goldmann

Wallrapp³

et al. 2013

PLoS ONE

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BackgroundTo monitor viability of implanted genetically engineered and microencapsulated human stem cells (MicroBeads) in the mouse eye, and to study the impact of the beads and/or xenogenic cells on retinal integrity.Methodology/Principal FindingsMicroBeads were implanted into the subretinal space of SV126 wild type mice using an ab externo approach. Viability of microencapsulated cells was monitored by noninvasive retinal imaging (Spectralis™ HRA+OCT). Retinal integrity was also assessed with retinal imaging and upon the end of the study by light and electron microscopy. The implanted GFP-marked cells encapsulated in subretinal MicroBeads remained viable over a period of up to 4 months. Retinal integrity and viability appeared unaltered apart from the focal damage due to the surgical implantation, GFAP upregulation, and opsin mistargeting in the immediate surrounding tissue.Conclusions/SignificanceThe accessibility for routine surgery and its immune privileged state make the eye an ideal target for release system implants for therapeutic substances, including neurotrophic and anti-angiogenic compounds or protein based biosimilars. Microencapsulated human stem cells (MicroBeads) promise to overcome limitations inherent with single factor release systems, as they are able to produce physiologic combinations of bioactive compounds.

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“…Atrophic changes in the photoreceptor layer seem to precede and thus promote pigment-hyperplasia, which is in line with the observation that retinal pigment plaques are always associated with an absolute scotoma (see Chapter 7). Therefore, the pathophysiology may be similar to bone spicule-like pigmentation in retinitis pigmentosa: an accordant mouse model where photoreceptor atrophy with resulting direct contact between retinal vessels and the retinal pigment epithelium is associated with intraretinal pigment migration around retinal vessels (Jaissle et al, 2010). Sometimes, retinal pigment plaques may be surrounded by RPE atrophy (Fig.…”

Section: Clinical Findingsmentioning

confidence: 99%

Macular telangiectasia type 2

Issa

Gillies

Chew

et al. 2013

Progress in Retinal and Eye Research

314

244

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Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment–outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the nonneovascular disease stages. Recent progress in structure–function correlation may help to develop surrogate outcome measures for future clinical trials. In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.

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Bone spicule pigment formation in retinitis pigmentosa: insights from a mouse model

Cited by 45 publications

References 20 publications

Assessment and In Vivo Scoring of Murine Experimental Autoimmune Uveoretinitis Using Optical Coherence Tomography

Assessment and In Vivo Scoring of Murine Experimental Autoimmune Uveoretinitis Using Optical Coherence Tomography

Successful Subretinal Delivery and Monitoring of MicroBeads in Mice

Macular telangiectasia type 2

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