Leukocyte Trafficking in Experimental Autoimmune Uveitis: Breakdown of Blood–Retinal Barrier and Upregulation of Cellular Adhesion Molecules

Xu, Heping; Forrester, John V.; Liversidge, Janet; Crane, Isabel J.

doi:10.1167/iovs.01-1202

Cited by 134 publications

(133 citation statements)

References 25 publications

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“…The Evans Blue albumin method was used as previously described with some modifications [14][15][16][17] (see ESM Methods). Digital images from different random fields of all retinas were acquired using a confocal laser scanning microscope (FV1000; Olympus) at ×20 using the 561 nm laser line, and each image was recorded with identical beam intensity at a size of 1024 pixels × 1024 pixels.…”

Section: Animal Studiesmentioning

confidence: 99%

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

et al. 2017

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Aims/hypothesis The main aims of the present study were: (1) to assess the expression and content of dipeptidyl peptidase IV (DPP-IV) in human and db/db mouse retinas, and in human vitreous fluid; and (2) to determine whether the topical administration of the DPP-IV inhibitors (DPP-IVi) would prevent retinal neurodegeneration and vascular leakage in db/db mice by reducing endogenous glucagon-like peptide 1 (GLP-1) degradation. Methods To assess the expression and content of DPP-IV, human samples of vitreous fluid and retinas were obtained from participants with type 2 diabetes (n = 8) and agematched non-diabetic individuals (n = 8), as well as from db/db (n = 72) and db/+ (n = 28) mice. The interventional study, which included 72 db/db mice, consisted of the topical administration (eye drops) of saxagliptin, sitagliptin or vehicle for 14 days. DPP-IV mRNA levels were assessed by RT-PCR, and protein content was measured by ELISA or western blotting. GLP-1 was assessed by immunofluorescence, and its downstream effector exchange protein activated by cAMP-1 (EPAC-1) was used as a measure of GLP-1 receptor activation. Retinal analyses were performed in vivo by electroretinography and ex vivo by RT-PCR (Epac-1, Iba-1 [also known as Aif1]), western blotting (EPAC-1, glial fibrillar acidic protein [GFAP], glutamate−aspartate transporter [GLAST]) and immunofluorescence measurements (GLP-1, GFAP, ionised calcium binding adaptor molecule 1 [IBA-1], TUNEL, GLAST, albumin and collagen IV). Glutamate was quantified by HPLC. In addition, vascular leakage was examined by the Evans Blue method. Results DPP-IV was present in human vitreous fluid but in a range 100-fold less than in plasma. Both mRNA levels and protein content were much lower in the retina than in the liver or bowel, but were significantly higher in retinal pigment epithelium (RPE) from diabetic donors in comparison to non-diabetic donors (p < 0.05). Topical treatment with DPP-IVi prevented glial activation, apoptosis and vascular leakage induced by diabetes in db/db mice (p < 0.05). Moreover, it also significantly prevented diabetes-induced functional abnormalities in the electroretinogram. A significant increase of both GLP-1 and EPAC-1 was found after treatment with DPP-IVi (p < 0.05). Furthermore, GLAST downregulation induced by diabetes was prevented, resulting in a significant reduction of extracellular glutamate concentrations. All these effects were observed without any changes in blood glucose levels. Conclusions/interpretation The topical administration of DPP-IVi is effective in preventing neurodegeneration and vascular leakage in the diabetic retina. These effects can be attributed to an enhancement of GLP-1, but other mechanisms unrelated to the prevention of GLP-1 degradation cannot be ruled out.

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Section: Animal Studiesmentioning

confidence: 99%

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

et al. 2017

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“…Inflammation has been shown to play a key role in damaging both the inner and outer components of the blood retinal barrier (Cunha-Vaz, 1997. Ocular inflammation stimulates upregulation of cell adhesion molecules, permitting inflammatory cell and macromolecule extravasation into the vitreous and subretinal spaces (Huber, et al, 2006;Xu, et al, 2003). Inflammatory mediator production in this area likely exacerbates and maintains the inflammatory response, which can result in loss of vision (Koizumi, et al, 2003).…”

Section: Blood Retinal Barrier Permeabilitymentioning

confidence: 99%

Bacterial endophthalmitis: Therapeutic challenges and host–pathogen interactions

Callegan

Gilmore

Gregory

et al. 2007

Progress in Retinal and Eye Research

156

153

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Endophthalmitis is an infection of the posterior segment of the eye that frequently results in loss of vision. This devastating result occurs despite prompt and often aggressive therapeutic and surgical intervention. Over the past decade, research has centered on determining the bacterial and host factors involved in this potentially blinding disease. The initial focus on the bacterial factors responsible for intraocular virulence has recently expanded into analysis the inflammatory response to infection, including the molecular and cellular interactions between the pathogen and host. This review discusses the epidemiology and therapeutic challenges posed by endophthalmitis, as well as recent findings from the analysis of interactions between the host and pathogen. Based on these findings, a model for the pathogenesis of endophthalmitis is presented. A more comprehensive understanding of the molecular and cellular interactions taking place between pathogen and host during endophthalmitis will expose possible therapeutic targets designed to arrest the infection and prevent vision loss.

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“…Severity of EAU for each eye was graded on a scale of 0 (no disease) to 4 (maximum disease) in half-point increments, according to a semiquantitative system previously described (1, 37,38). Identification of retinal microvascular changes using retinal whole mounts were prepared as previously described (39).…”

Section: Histology and Retinal Mountingmentioning

confidence: 99%

Limited Peripheral T Cell Anergy Predisposes to Retinal Autoimmunity

Lambe¹,

Leung²,

Ferry³

et al. 2007

The Journal of Immunology

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Autoimmune uveoretinitis accounts for at least 10% of worldwide blindness, yet it is unclear why tolerance to retinal Ags is so fragile and, particularly, to what extent this might be due to defects in peripheral tolerance. To address this issue, we generated double-transgenic mice expressing hen egg lysozyme, under the retinal interphotoreceptor retinoid-binding promoter, and a hen egg lysozyme-specific CD4+ TCR transgene. In this manner, we have tracked autoreactive CD4+ T cells from their development in the thymus to their involvement in uveoretinitis and compared tolerogenic mechanisms induced in a variety of organs to the same self-Ag. Our findings show that central tolerance to retinal and pancreatic Ags is qualitatively similar and equally dependent on the transcriptional regulator protein AIRE. However, the lack of Ag presentation in the eye-draining lymph nodes results in a failure to induce high levels of T cell anergy. Under these circumstances, despite considerable central deletion, low levels of retinal-specific autoreactive CD4+ T cells can induce severe autoimmune disease. The relative lack of anergy induction by retinal Ags, in contrast to the same Ag in other organs, helps to explain the unique susceptibility of the eye to spontaneous and experimentally induced autoimmune disease.

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Leukocyte Trafficking in Experimental Autoimmune Uveitis: Breakdown of Blood–Retinal Barrier and Upregulation of Cellular Adhesion Molecules

Cited by 134 publications

References 25 publications

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

Bacterial endophthalmitis: Therapeutic challenges and host–pathogen interactions

Limited Peripheral T Cell Anergy Predisposes to Retinal Autoimmunity

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