The Experts below are selected from a list of 2487 Experts worldwide ranked by ideXlab platform
John V. Forrester - One of the best experts on this subject based on the ideXlab platform.
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involvement of ccr5 in the passage of th1 type cells across the Blood Retina Barrier in experimental autoimmune uveitis
Journal of Leukocyte Biology, 2006Co-Authors: Isabel Joan Crane, Janet Liversidge, Carol Wallace, Ayyakkannu Manivannan, Peter F. Sharp, Matthias Mack, Gabriel Marquez, John V. ForresterAbstract:Although the recruitment of T helper cell type 1 (Th1)/Th2 cells into peripheral tissues is essential for inflammation and the host response to infection, the traffic signals that enable the distinct positioning of Th1/Th2 cells are unclear. We have determined the role of CC chemokine receptor 5 (CCR5) in this using experimental autoimmune uveitis (EAU) as a model system. In EAU, Th1-like cells are preferentially recruited into the Retina across the Blood-Retina Barrier, partly as a result of expression of the adhesion molecules P-selectin glycoprotein ligand 1 and lymphocyte function-associated antigen-1 on these cells. CD3+ T cells, infiltrating the Retina, also expressed the chemokine receptor CCR5, and CCR5 ligands, macrophage-inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated on activation, normal T expressed and secreted (RANTES), were strongly expressed in the Retina at peak EAU. Th1-like cells, polarized in vitro, expressed high levels of CCR5. The trafficking of these CCR5+ cells was examined by tracking them after adoptive transfer in real time in vivo at an early disease stage using scanning laser ophthalmoscopy. Treatment of the cells with antibody against CCR5 prior to transfer resulted in a reduction in their infiltration into the Retina. However, rolling velocity, rolling efficiency, and adherence of the cells to Retinal endothelium were not reduced. CCR5 is clearly important for Th1 cell recruitment, and this study demonstrates for the first time in vivo that CCR5 may act at the level of transendothelial migration rather than at the earlier stage of rolling on the endothelium.
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involvement of ccr5 in the passage of th1 type cells across the Blood Retina Barrier in experimental autoimmune uveitis
Journal of Leukocyte Biology, 2006Co-Authors: Isabel Joan Crane, Janet Liversidge, Carol Wallace, Ayyakkannu Manivannan, Peter F. Sharp, Matthias Mack, Gabriel Marquez, John V. ForresterAbstract:Although the recruitment of T helper cell type 1 (Th1)/Th2 cells into peripheral tissues is essential for inflammation and the host response to infection, the traffic signals that enable the distinct positioning of Th1/Th2 cells are unclear. We have determined the role of CC chemokine receptor 5 (CCR5) in this using experimental autoimmune uveitis (EAU) as a model system. In EAU, Th1-like cells are preferentially recruited into the Retina across the Blood-Retina Barrier, partly as a result of expression of the adhesion molecules P-selectin glycoprotein ligand 1 and lymphocyte function- associated antigen-1 on these cells. CD3 T cells, infiltrating the Retina, also expressed the chemo- kine receptor CCR5, and CCR5 ligands, macroph- age-inflammatory protein-1 (MIP-1), MIP-1, and regulated on activation, normal T expressed and secreted, were strongly expressed in the Retina at peak EAU. Th1-like cells, polarized in vitro, expressed high levels of CCR5. The trafficking of these CCR5 cells was examined by tracking them after adoptive transfer in real time in vivo at an early disease stage using scanning laser ophthal- moscopy. Treatment of the cells with antibody against CCR5 prior to transfer resulted in a reduc- tion in their infiltration into the Retina. However, rolling velocity, rolling efficiency, and adherence of the cells to Retinal endothelium were not re- duced. CCR5 is clearly important for Th1 cell recruitment, and this study demonstrates for the first time in vivo that CCR5 may act at the level of transendothelial migration rather than at the ear- lier stage of rolling on the endothelium. J. Leukoc. Biol. 79: 000-000; 2006.
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Reduction in shear stress, activation of the endothelium, and leukocyte priming are all required for leukocyte passage across the Blood-Retina Barrier
Journal of leukocyte biology, 2003Co-Authors: Ayyakkannu Manivannan, Janet Liversidge, John V. Forrester, Keith A Goatman, Hui-rong Jiang, Peter F. Sharp, Isabel Joan CraneAbstract:The passage of leukocytes across the Blood-Retina Barrier at the early stages of an inflammatory reaction is influenced by a complex series of interactions about which little is known. In particular, the relationship between hydrodynamic factors, such as shear stress and leukocyte velocity, to the adherence and subsequent extravasation of leukocytes into the Retina is unclear. We have used a physiological method, scanning laser ophthalmoscopy, to track labeled leukocytes circulating in the Retina, followed by confocal microscopy of Retinal flatmounts to detect infiltrating cells at the early stage of experimental autoimmune uveitis. This has shown that Retinal vessels are subjected to high shear stress under normal circumstances. During the inflammatory reaction, shear stress in Retinal veins is reduced 24 h before leukocyte infiltration. This reduction is negatively correlated with leukocyte rolling and sticking in veins and postcapillary venules, the sites of leukocyte extravasation. Activation of vascular endothelial cells is also a prerequisite for leukocyte rolling and infiltration. In addition, antigen priming of leukocytes is influential at the early stage of inflammation, and this is seen clearly in the reduction in rolling velocity and adherence of the primed leukocytes in activated Retinal venules, 9 days postimmunization.
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Effect of anti-macrophage inflammatory protein-1α on leukocyte trafficking and disease progression in experimental autoimmune uveoretinitis
European journal of immunology, 2003Co-Authors: Isabel Joan Crane, Janet Liversidge, Carol A. Wallace, S. Mckillop-smith, Ayyakkannu Manivannan, Peter F. Sharp, Graeme R. Lamont, John V. ForresterAbstract:This study has enabled us to identify the influence of the chemokine, macrophage inflammatory protein-1α (MIP-1α), on leukocyte behavior at the Blood-Retina Barrier in vivo and its link with the inflammatory process and disease pathogenesis. MIP-1α has not previously been thought to be effective under conditions of physiological shear flow. However, short-term anti-MIP-1α treatment inhibited leukocyte slowing and accumulation and subsequent extravasation of leukocytes at the Blood-Retina Barrier in animals with experimental autoimmune uveoretinitis. This was effective predominantly in the post-capillary venules which have been shown to be the main site of passage of leukocytes across the Blood-Retina Barrier. Long-term anti-MIP-1α treatment also prevented decreased leukocyte velocity and reduced disease severity as measured clinically, histologically and in terms of Blood-Retina Barrier breakdown.
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control of chemokine production at the Blood Retina Barrier
Immunology, 2000Co-Authors: Isabel Joan Crane, Carol Wallace, S Mckillopsmith, John V. ForresterAbstract:SUMMARY Chemokine production at the Blood‐Retina Barrier probably plays a critical role in determining the influx of tissue-damaging cells from the circulation into the Retina during inflammation. The Blood‐ Retina Barrier comprises the Retinal microvascular endothelium and the Retinal pigment epithelium. Chemokine expression and production by human Retinal microvascular endothelial cells (REC) have never been reported previously, so we examined the in vitro expression and production of monocyte chemoattractant protein-1 (MCP-1), regulated on activation of normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1a, MIP-1b, interleukin (IL)-8, epithelial cell-derived neutrophil activating protein-78 (ENA-78) and growth related oncogene a (GROa) in these cells, both unstimulated and stimulated by cytokines likely to be present during the evolution of an inflammatory response. We compared this to expression and production of these chemokines in vitro in human Retinal pigment epithelial cells (RPE). MCP-1 was expressed and produced constitutively by REC but all the chemokines were produced in greater amounts upon stimulation with the proinflammatory cytokines IL-1b and tumour necrosis factor-a (TNF-a). MCP-1 and IL-8 were produced at much higher levels than the other chemokines tested. MIP-1a and MIP-1b were present only at low levels, even after stimulation with IL-1b and TNF-a. Cytokines with greater anti-inflammatory activity, such as IL-4, IL-10, IL-13, transforming growth factor-b (TGF-b) and IL-6, had little effect on chemokine production either by REC alone or after stimulation with IL-1b and TNF-a. RPE, although a very different cell type, showed a similar pattern of expression and production of chemokines, indicating the site-specific nature of chemokine production. Chemokine production by REC and RPE is probably significant in selective leucocyte recruitment during the development of inflammation in the Retina.
Isabel Joan Crane - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of leukocyte migration across the Blood Retina Barrier
Seminars in Immunopathology, 2008Co-Authors: Isabel Joan Crane, Janet LiversidgeAbstract:Immune-mediated inflammation in the Retina is regulated by a combination of anatomical, physiological and immuno-regulatory mechanisms, referred to as the Blood–Retina Barrier (BRB). The BRB is thought to be part of the specialised ocular microenvironment that confers protection or “immune privilege” by deviating or suppressing destructive inflammation. The Barrier between the Blood circulation and the Retina is maintained at two separate anatomical sites. These are the endothelial cells of the inner Retinal vasculature and the Retinal pigment epithelial cells on Bruch’s membrane between the fenestrated choroidal vessels and the outer Retina. The structure and regulation of the tight junctions forming the physical Barrier are described. For leukocyte migration across the BRB to occur, changes are needed in both the leukocytes themselves and the cells forming the Barrier. We review how the Blood–Retina Barrier is compromised in various inflammatory diseases and discuss the mechanisms controlling leukocyte subset migration into the Retina in uveoretinitis in more detail. In particular, we examine the relative roles of selectins and integrins in leukocyte interactions with the vascular endothelium and the pivotal role of chemokines in selective recruitment of leukocyte subsets, triggering adhesion, diapedesis and migration of inflammatory cells into the Retinal tissue.
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Mechanisms of leukocyte migration across the Blood–Retina Barrier
Seminars in immunopathology, 2008Co-Authors: Isabel Joan Crane, Janet LiversidgeAbstract:Immune-mediated inflammation in the Retina is regulated by a combination of anatomical, physiological and immuno-regulatory mechanisms, referred to as the Blood–Retina Barrier (BRB). The BRB is thought to be part of the specialised ocular microenvironment that confers protection or “immune privilege” by deviating or suppressing destructive inflammation. The Barrier between the Blood circulation and the Retina is maintained at two separate anatomical sites. These are the endothelial cells of the inner Retinal vasculature and the Retinal pigment epithelial cells on Bruch’s membrane between the fenestrated choroidal vessels and the outer Retina. The structure and regulation of the tight junctions forming the physical Barrier are described. For leukocyte migration across the BRB to occur, changes are needed in both the leukocytes themselves and the cells forming the Barrier. We review how the Blood–Retina Barrier is compromised in various inflammatory diseases and discuss the mechanisms controlling leukocyte subset migration into the Retina in uveoretinitis in more detail. In particular, we examine the relative roles of selectins and integrins in leukocyte interactions with the vascular endothelium and the pivotal role of chemokines in selective recruitment of leukocyte subsets, triggering adhesion, diapedesis and migration of inflammatory cells into the Retinal tissue.
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involvement of ccr5 in the passage of th1 type cells across the Blood Retina Barrier in experimental autoimmune uveitis
Journal of Leukocyte Biology, 2006Co-Authors: Isabel Joan Crane, Janet Liversidge, Carol Wallace, Ayyakkannu Manivannan, Peter F. Sharp, Matthias Mack, Gabriel Marquez, John V. ForresterAbstract:Although the recruitment of T helper cell type 1 (Th1)/Th2 cells into peripheral tissues is essential for inflammation and the host response to infection, the traffic signals that enable the distinct positioning of Th1/Th2 cells are unclear. We have determined the role of CC chemokine receptor 5 (CCR5) in this using experimental autoimmune uveitis (EAU) as a model system. In EAU, Th1-like cells are preferentially recruited into the Retina across the Blood-Retina Barrier, partly as a result of expression of the adhesion molecules P-selectin glycoprotein ligand 1 and lymphocyte function-associated antigen-1 on these cells. CD3+ T cells, infiltrating the Retina, also expressed the chemokine receptor CCR5, and CCR5 ligands, macrophage-inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated on activation, normal T expressed and secreted (RANTES), were strongly expressed in the Retina at peak EAU. Th1-like cells, polarized in vitro, expressed high levels of CCR5. The trafficking of these CCR5+ cells was examined by tracking them after adoptive transfer in real time in vivo at an early disease stage using scanning laser ophthalmoscopy. Treatment of the cells with antibody against CCR5 prior to transfer resulted in a reduction in their infiltration into the Retina. However, rolling velocity, rolling efficiency, and adherence of the cells to Retinal endothelium were not reduced. CCR5 is clearly important for Th1 cell recruitment, and this study demonstrates for the first time in vivo that CCR5 may act at the level of transendothelial migration rather than at the earlier stage of rolling on the endothelium.
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involvement of ccr5 in the passage of th1 type cells across the Blood Retina Barrier in experimental autoimmune uveitis
Journal of Leukocyte Biology, 2006Co-Authors: Isabel Joan Crane, Janet Liversidge, Carol Wallace, Ayyakkannu Manivannan, Peter F. Sharp, Matthias Mack, Gabriel Marquez, John V. ForresterAbstract:Although the recruitment of T helper cell type 1 (Th1)/Th2 cells into peripheral tissues is essential for inflammation and the host response to infection, the traffic signals that enable the distinct positioning of Th1/Th2 cells are unclear. We have determined the role of CC chemokine receptor 5 (CCR5) in this using experimental autoimmune uveitis (EAU) as a model system. In EAU, Th1-like cells are preferentially recruited into the Retina across the Blood-Retina Barrier, partly as a result of expression of the adhesion molecules P-selectin glycoprotein ligand 1 and lymphocyte function- associated antigen-1 on these cells. CD3 T cells, infiltrating the Retina, also expressed the chemo- kine receptor CCR5, and CCR5 ligands, macroph- age-inflammatory protein-1 (MIP-1), MIP-1, and regulated on activation, normal T expressed and secreted, were strongly expressed in the Retina at peak EAU. Th1-like cells, polarized in vitro, expressed high levels of CCR5. The trafficking of these CCR5 cells was examined by tracking them after adoptive transfer in real time in vivo at an early disease stage using scanning laser ophthal- moscopy. Treatment of the cells with antibody against CCR5 prior to transfer resulted in a reduc- tion in their infiltration into the Retina. However, rolling velocity, rolling efficiency, and adherence of the cells to Retinal endothelium were not re- duced. CCR5 is clearly important for Th1 cell recruitment, and this study demonstrates for the first time in vivo that CCR5 may act at the level of transendothelial migration rather than at the ear- lier stage of rolling on the endothelium. J. Leukoc. Biol. 79: 000-000; 2006.
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leukocyte diapedesis in vivo induces transient loss of tight junction protein at the Blood Retina Barrier
Investigative Ophthalmology & Visual Science, 2005Co-Authors: Heping Xu, Isabel Joan Crane, R Dawson, Janet LiversidgeAbstract:Purpose Although much is now understood about the molecular structure of tight junctions (TJs), little is known about the regulation of their function during neural inflammatory disease processes in vivo. The mechanisms by which leukocytes transmigrate the Blood-Retina Barrier (BRB) without affecting endothelial permeability are controversial.
Matthew Campbell - One of the best experts on this subject based on the ideXlab platform.
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Tight Junctions of the Outer Blood Retina Barrier
International journal of molecular sciences, 2019Co-Authors: Aisling Naylor, Alan Hopkins, Natalie Hudson, Matthew CampbellAbstract:The outer Blood Retina Barrier (oBRB) formed by the Retinal pigment epithelium (RPE) is critical for maintaining Retinal homeostasis. Critical to this modified neuro-epithelial Barrier is the presence of the tight junction structure that is formed at the apical periphery of contacting cells. This tight junction complex mediates size-selective passive diffusion of solutes to and from the outer segments of the Retina. Unlike other epithelial cells, the apical surface of the RPE is in direct contact with neural tissue and it is centrally involved in the daily phagocytosis of the effete tips of photoreceptor cells. While much is known about the intracellular trafficking of material within the RPE, less is known about the role of the tight junction complexes in health and diseased states. Here, we provide a succinct overview of the molecular composition of the RPE tight junction complex in addition to highlighting some of the most common retinopathies that involve a dysregulation of RPE integrity.
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The Blood-Retina Barrier
Advances in experimental medicine and biology, 2013Co-Authors: Matthew Campbell, Peter HumphriesAbstract:The Blood-Retina Barrier (BRB) is composed of both an inner and an outer Barrier. The outer BRB refers to the Barrier formed at the Retinal pigment epithelial (RPE) cell layer and functions, in part, to regulate the movement of solutes and nutrients from the choroid to the sub-Retinal space. In contrast, the inner BRB, similar to the Blood brain Barrier (BBB) is located in the inner Retinal microvasculature and comprises the microvascular endothelium which line these vessels. The tight junctions located between these cells mediate highly selective diffusion of molecules from the Blood to the Retina and the Barrier is essential in maintaining Retinal homeostasis. In this chapter, we summarize the key differences between the iBRB and oBRB and outline the molecular constituents of the tight junctions associated with the iBRB. We also describe a process for modulation of the iBRB to enhance systemic delivery of therapeutics to the Retina, a technology which may pave the way for safer and more effective therapies for Retinal diseases.
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On Further Development of Barrier Modulation as a Technique for Systemic Ocular Drug Delivery
Advances in experimental medicine and biology, 2011Co-Authors: Finnian Hanrahan, Matthew Campbell, Anh T. H. Nguyen, Anna-sophia Kiang, Sorcha Ní Dhubhghaill, Marian M. Humphries, Mayu Suzuki, Lawrence C. Tam, Oliviero L. Gobbo, Paul F. KennaAbstract:Many systemically deliverable low-molecular-weight drugs with proven efficacy as neuroprotective, anti-inflammatory, anti-neovascular, cytotoxic, or anti-microbial agents are blocked from entering the eye by the inner Blood-Retina Barrier. Recent reports from this laboratory have shown that it is possible to modulate the iBRB reversibly in mice by systemic administration of siRNA targeting transcripts derived from claudin 5, a tight junction protein of the endothelial cells lining the inner Retinal microvasculature, rendering the iBRB transiently permeable to compounds up to approximately 1,000 Da in molecular weight. The system has been validated by demonstrating improved visual function in a model of autosomal recessive retinitis pigmentosa (IMPDH1−/− mice) and by suppression of light-induced damage to the Retina, in each case by systemic drug delivery following Barrier modulation. In this review, we explore how this technique could be improved by the down-regulation of transcripts encoding other tight junction endothelial proteins, particularly ones which would enable outer Blood-Retina Barrier modulation.
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Size-selective and in vitro assessment of inner Blood Retina Barrier permeability.
Methods in molecular biology (Clifton N.J.), 2011Co-Authors: Matthew Campbell, Peter HumphriesAbstract:Assessment of tight junction integrity in vitro is fundamental when studying molecular processes that may be implicated in Barrier dysfunction. At the Blood brain and inner Blood Retina Barrier (BBB and iBRB, respectively) adjacent endothelial cells lining the microvasculature have been shown to have very low rates of fluid phase transcytosis and high electrical resistances, due in part to the expression of tight junction proteins at the apical periphery of these cells. While these high electrical resistances are difficult to achieve in vitro, owing to complex interactions of endothelial cells in vivo with astrocytes and pericytes, it is possible to make an assessment of paracellular permeability when cells are analysed on a number of different fronts. In this regard, we will outline here a method for determining trans-endothelial electrical resistance, tracer molecule diffusion, and tight junction protein localization in primary cultures of bovine Retinal microvascular endothelial cells. This system allows for the screening of a wide range of pro- and anti-angiogenic molecules in an in vitro model of the iBRB and can accurately assess the role individual tight junction proteins play in maintaining tight junction integrity in response to various cell stimuli.
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Reversible and Size-Selective Opening of the Inner Blood-Retina Barrier: A Novel Therapeutic Strategy
Advances in experimental medicine and biology, 2009Co-Authors: Matthew Campbell, Anh T. H. Nguyen, Anna-sophia Kiang, Lawrence Tam, Paul F. Kenna, Sorcha Ní Dhubhghaill, Marian M. Humphries, G. Jane Farrar, Peter HumphriesAbstract:The inner Blood-Retina-Barrier (iBRB) remains a key element in retarding the development of novel therapeutics for the treatment of many ocular disorders. The iBRB contains tight-junctions (TJ’s) which reduce the space between adjacent endothelial cells lining the fine capillaries of the Retinal microvasculature to form a selective and regulatable Barrier. We have recently shown that in mice, the iBRB can be transiently and size-selectively opened to molecules with molecular weights of up to approximately 1 kDa using an siRNA-mediated approach involving suppression of the tight junction protein, claudin-5. We have systemically delivered siRNA targeting claudin-5 to Retinal capillary endothelial cells in mice and through a series of tracer experiments and magnetic-resonance-imaging (MRI), we have shown a transient and size-selective increase in permeability at the iBRB to molecules below 1 kDa. The potential to exploit this specific compromise in iBRB integrity may have far reaching implications for the development of experimental animal models of Retinal degenerative disorders, and for enhanced delivery of therapeutic molecules which would normally not traverse the iBRB. Using RNAi-mediated opening of the iBRB, the systemic delivery of low molecular weight therapeutics could in principle, hold real promise as an alternative to repeated intraocular inoculation of compounds. Results demonstrated here in mouse models, should lead to a ‘humanized’ form of systemic delivery as opposed to the hydrodynamic approach used in our work to date.
Janet Liversidge - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of leukocyte migration across the Blood Retina Barrier
Seminars in Immunopathology, 2008Co-Authors: Isabel Joan Crane, Janet LiversidgeAbstract:Immune-mediated inflammation in the Retina is regulated by a combination of anatomical, physiological and immuno-regulatory mechanisms, referred to as the Blood–Retina Barrier (BRB). The BRB is thought to be part of the specialised ocular microenvironment that confers protection or “immune privilege” by deviating or suppressing destructive inflammation. The Barrier between the Blood circulation and the Retina is maintained at two separate anatomical sites. These are the endothelial cells of the inner Retinal vasculature and the Retinal pigment epithelial cells on Bruch’s membrane between the fenestrated choroidal vessels and the outer Retina. The structure and regulation of the tight junctions forming the physical Barrier are described. For leukocyte migration across the BRB to occur, changes are needed in both the leukocytes themselves and the cells forming the Barrier. We review how the Blood–Retina Barrier is compromised in various inflammatory diseases and discuss the mechanisms controlling leukocyte subset migration into the Retina in uveoretinitis in more detail. In particular, we examine the relative roles of selectins and integrins in leukocyte interactions with the vascular endothelium and the pivotal role of chemokines in selective recruitment of leukocyte subsets, triggering adhesion, diapedesis and migration of inflammatory cells into the Retinal tissue.
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Mechanisms of leukocyte migration across the Blood–Retina Barrier
Seminars in immunopathology, 2008Co-Authors: Isabel Joan Crane, Janet LiversidgeAbstract:Immune-mediated inflammation in the Retina is regulated by a combination of anatomical, physiological and immuno-regulatory mechanisms, referred to as the Blood–Retina Barrier (BRB). The BRB is thought to be part of the specialised ocular microenvironment that confers protection or “immune privilege” by deviating or suppressing destructive inflammation. The Barrier between the Blood circulation and the Retina is maintained at two separate anatomical sites. These are the endothelial cells of the inner Retinal vasculature and the Retinal pigment epithelial cells on Bruch’s membrane between the fenestrated choroidal vessels and the outer Retina. The structure and regulation of the tight junctions forming the physical Barrier are described. For leukocyte migration across the BRB to occur, changes are needed in both the leukocytes themselves and the cells forming the Barrier. We review how the Blood–Retina Barrier is compromised in various inflammatory diseases and discuss the mechanisms controlling leukocyte subset migration into the Retina in uveoretinitis in more detail. In particular, we examine the relative roles of selectins and integrins in leukocyte interactions with the vascular endothelium and the pivotal role of chemokines in selective recruitment of leukocyte subsets, triggering adhesion, diapedesis and migration of inflammatory cells into the Retinal tissue.
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involvement of ccr5 in the passage of th1 type cells across the Blood Retina Barrier in experimental autoimmune uveitis
Journal of Leukocyte Biology, 2006Co-Authors: Isabel Joan Crane, Janet Liversidge, Carol Wallace, Ayyakkannu Manivannan, Peter F. Sharp, Matthias Mack, Gabriel Marquez, John V. ForresterAbstract:Although the recruitment of T helper cell type 1 (Th1)/Th2 cells into peripheral tissues is essential for inflammation and the host response to infection, the traffic signals that enable the distinct positioning of Th1/Th2 cells are unclear. We have determined the role of CC chemokine receptor 5 (CCR5) in this using experimental autoimmune uveitis (EAU) as a model system. In EAU, Th1-like cells are preferentially recruited into the Retina across the Blood-Retina Barrier, partly as a result of expression of the adhesion molecules P-selectin glycoprotein ligand 1 and lymphocyte function-associated antigen-1 on these cells. CD3+ T cells, infiltrating the Retina, also expressed the chemokine receptor CCR5, and CCR5 ligands, macrophage-inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and regulated on activation, normal T expressed and secreted (RANTES), were strongly expressed in the Retina at peak EAU. Th1-like cells, polarized in vitro, expressed high levels of CCR5. The trafficking of these CCR5+ cells was examined by tracking them after adoptive transfer in real time in vivo at an early disease stage using scanning laser ophthalmoscopy. Treatment of the cells with antibody against CCR5 prior to transfer resulted in a reduction in their infiltration into the Retina. However, rolling velocity, rolling efficiency, and adherence of the cells to Retinal endothelium were not reduced. CCR5 is clearly important for Th1 cell recruitment, and this study demonstrates for the first time in vivo that CCR5 may act at the level of transendothelial migration rather than at the earlier stage of rolling on the endothelium.
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involvement of ccr5 in the passage of th1 type cells across the Blood Retina Barrier in experimental autoimmune uveitis
Journal of Leukocyte Biology, 2006Co-Authors: Isabel Joan Crane, Janet Liversidge, Carol Wallace, Ayyakkannu Manivannan, Peter F. Sharp, Matthias Mack, Gabriel Marquez, John V. ForresterAbstract:Although the recruitment of T helper cell type 1 (Th1)/Th2 cells into peripheral tissues is essential for inflammation and the host response to infection, the traffic signals that enable the distinct positioning of Th1/Th2 cells are unclear. We have determined the role of CC chemokine receptor 5 (CCR5) in this using experimental autoimmune uveitis (EAU) as a model system. In EAU, Th1-like cells are preferentially recruited into the Retina across the Blood-Retina Barrier, partly as a result of expression of the adhesion molecules P-selectin glycoprotein ligand 1 and lymphocyte function- associated antigen-1 on these cells. CD3 T cells, infiltrating the Retina, also expressed the chemo- kine receptor CCR5, and CCR5 ligands, macroph- age-inflammatory protein-1 (MIP-1), MIP-1, and regulated on activation, normal T expressed and secreted, were strongly expressed in the Retina at peak EAU. Th1-like cells, polarized in vitro, expressed high levels of CCR5. The trafficking of these CCR5 cells was examined by tracking them after adoptive transfer in real time in vivo at an early disease stage using scanning laser ophthal- moscopy. Treatment of the cells with antibody against CCR5 prior to transfer resulted in a reduc- tion in their infiltration into the Retina. However, rolling velocity, rolling efficiency, and adherence of the cells to Retinal endothelium were not re- duced. CCR5 is clearly important for Th1 cell recruitment, and this study demonstrates for the first time in vivo that CCR5 may act at the level of transendothelial migration rather than at the ear- lier stage of rolling on the endothelium. J. Leukoc. Biol. 79: 000-000; 2006.
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leukocyte diapedesis in vivo induces transient loss of tight junction protein at the Blood Retina Barrier
Investigative Ophthalmology & Visual Science, 2005Co-Authors: Heping Xu, Isabel Joan Crane, R Dawson, Janet LiversidgeAbstract:Purpose Although much is now understood about the molecular structure of tight junctions (TJs), little is known about the regulation of their function during neural inflammatory disease processes in vivo. The mechanisms by which leukocytes transmigrate the Blood-Retina Barrier (BRB) without affecting endothelial permeability are controversial.
Henrik Lund-andersen - One of the best experts on this subject based on the ideXlab platform.
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Fluorescein transport across the human Blood-Retina Barrier in the direction vitreous to Blood. Quantitative assessment in vivo.
Acta ophthalmologica, 2009Co-Authors: Claus B Engler, Peter Dalgaard, Michael Larsen, Birgit Sander, Henrik Lund-andersenAbstract:. Inward and outward movement of fluorescein across the human Blood-Retina Barrier was studied in five healthy volunteers, using a differential spectrofluorometry method that eliminates the contribution of fluorescein glucuronide to the total fluorescence in the vitreous and in plasma. The inward permeability across the Blood-Retina Barrier, which is presumed to be passive, and the diffusion coefficient in the vitreous for fluorescein was calculated from data obtained 1 h after intravenous injection of fluorescein. The rate of elimination of fluorescein from the vitreous across the Blood-Retina Barrier was estimated from data obtained 7 to 12 h after injection of fluorescein. The calculations were based upon the free plasma fluorescein decay curve and the preRetinal fluorescein gradient in the vitreous. The mean inward permeability of fluorescein was 1.39 times 10−7 cm/sec (range: 0.70-2.06 times 10−7 cm/sec), whereas the mean outward permeability was 1.51 times 10−5 cm/sec (range: 1.14-1.73 times 10−5 cm/sec). We have thus found that the movement of fluorescein across the Blood-Retina Barrier is highly asymmetric, the outward transport being more than 100 times faster than the passive inward leakage. This could indicate the presence of an active pumping mechanism in the Blood-Retina Barrier, responsible for fluorescein transport in the direction from the vitreous to the Blood.
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Early changes in diabetic retinopathy: capillary loss and Blood-Retina Barrier permeability in relation to metabolic control.
Acta ophthalmologica, 2009Co-Authors: Birgit Sander, Henrik Lund-andersen, Michael Larsen, Claus B Engler, Hans-henrik ParvingAbstract:In diabetic retinopathy capillary loss and Blood-Retina Barrier leakage are prominent factors. We present a study with quantitative measurements of both capillary loss and leakage and their relation to cumulative metabolic control. Seventeen insulin-dependent diabetic patients with no retinopathy or only mild background retinopathy and 10 years' duration of the disease were included in the study. Status of metabolic regulation had been followed for at least 6 years. Seven healthy subjects were included as controls. In diabetic patients the perifoveal intervascular areas were found to increase significantly with the cumulative HbA1c index (p = 0.02) and in relation to the presence of moderate background retinopathy (p < 0.02). The Blood-Retina Barrier leakage and the area of the foveal avascular zone were not significantly different from healthy subjects and no correlation was found between the HbA1c index and Blood-Retina Barrier permeability. We conclude that perifoveal capillary loss occurs early in the course of diabetic retinopathy and that this loss is related to prior glycemic control and to the ophthalmoscopic retinopathy level.
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Blood‐Retina Barrier permeability in diabetes during acute ACE‐inhibition
Acta ophthalmologica, 2009Co-Authors: Claus B Engler, Michael Larsen, Hans-henrik Parving, Elisabeth R. Mathiesen, Henrik Lund-andersenAbstract:We assessed the acute effect of ACE-inhibition (captopril) on Blood-Retina Barrier (BRB) permeability in 10 hypertensive insulin-dependent diabetic patients with background retinopathy in a double-masked placebo controlled cross-over study. All patients underwent ophthalmological examination, fundus photography, fluorescein angiography, vitreous fluorometry, and continuous Blood pressure recording within 3 h of the drug/placebo administration. The decrease in mean arterial Blood pressure, from placebo treatment 149/92 +/- 17/7 to captopril treatment 132/83 +/- 14/7 mmHg (mean +/- SD), P less than 0.01 was not accompanied by a significant decrease in BRB permeability, which was 2.51 (1.24-9.15) with placebo and 3.02 (1.25-13.93).10(-7) cm/s during captopril treatment (geometric mean and-range), NS. Our study suggests that abnormal leakage through the BRB in hypertensive insulin-dependent diabetic patients with background retinopathy is caused predominantly by structural changes in the Retinal vessels whereas hydrostatic forces play a minor role.
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Probenecid inhibition of the outward transport of fluorescein across the human Blood-Retina Barrier
Acta ophthalmologica, 2009Co-Authors: Claus B Engler, Michael Larsen, Birgit Sander, Hans-henrik Parving, Pernille Koefoed, Henrik Lund-andersenAbstract:. The effect of probenecid on the outward transport of fluorescein from vitreous to Blood was studied in 13 insulin-dependent diabetic patients with background retinopathy in a randomised double-masked placebo controlled cross-over study. Fluorescein and fluorescein glucuronide were separated in the vitreous and in plasma by differential spectrofluorometry. The data for fluorescein were analysed using a simplified mathematical model of the eye. The inward permeability was estimated from data obtained 1 h after injection and the outward transport from data obtained 7 h after injection. During placebo treatment the mean inward permeability was 3.75 times 10−7 cm/sec and the mean outward permeability was 2.25 times 10−5 cm/sec. During probenecid treatment the mean inward permeability was 3.34 times 10−7 cm/sec and the mean outward permeability was 1.44 times 10−5 cm/sec. Thus, we found no significant change in inward permeability (p = 0.5879), whereas a significant decrease of 36% was found in the outward permeability of fluorescein (p = 0.0171). The demonstration that the outward permeability, which is more than 100-fold higher than the inward permeability in the healthy eye, is significantly decreased by probenecid, demonstrates that active transport is involved in movement of fluorescein across the Blood-Retina Barrier from the vitreous to the plasma.
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Passive permeability and outward active transport of fluorescein across the Blood-Retinal Barrier in early ARM
The British journal of ophthalmology, 2001Co-Authors: Birgitte Moldow, Birgit Sander, Michael Larsen, Henrik Lund-andersenAbstract:AIM—To study the passive and active transport of fluorescein across the Blood-Retina Barrier in early age related maculopathy (ARM) (soft drusen > 63 µm, hyperpigmentation and/or hypopigmentation in patients above 50 years of age). METHODS—15 patients and 10 healthy subjects were included. Morphological changes were graded from 30 degrees fundus photographs using a simplified version of the epidemiological ARM study group classification system. Differential vitreous spectrofluorophotometry was used to assess the transport properties of the Blood-Retina Barrier (that is, passive permeability and unidirectional permeability caused by outward active transport from the vitreous to the Blood). RESULTS—The passive permeability of the patient group was not significantly different from that of the control group. Four patients with passive permeability more than 3 SD above the mean of the control group (mean 1.8 (SD 0.7) nm/s, range 1.0-3.0 nm/s, data normally distributed) all had centrally located drusen >500 µm and superjacent pigment clumps of 63-500 µm in diameter. There was no significant difference between the unidirectional permeabilities for the patient group and for the control group (mean 47.4 (29.3) nm/s, range 12.7-91.1 nm/s). CONCLUSION—There was no significant difference in the passive permeability and in the unidirectional permeability of fluorescein. However, the study may indicate that the combination of very large drusen and superjacent pigment clumps in ARM may be associated with a deterioration of the Blood-Retina Barrier.