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J V Forrester

Publications and source records attributed to J V Forrester.

At least 127 records · Page 7Linked to original sources
PubMed1994

Therapeutic advances in immunosuppression.

Immunosuppressive therapy is appropriate for the prevention or reversal of allograft rejection, and for the treatment of autoimmune disorders and allergic disease. Recent advances in our understanding of the cellular and molecular mechanisms that regulate immune responses have paralleled elucidation of the modes of action of a variety of therapeutic immunosuppressive agents, both 'old' and new. These developments have identified potential targets for more refined and specific intervention strategies that are now being tested in the clinic.

Animals↗
PubMed1994

Clinical investigation of an infrared digital scanning laser ophthalmoscope.

An infrared scanning laser ophthalmoscope (SLO) has been custom built in order to investigate the application of confocal and indirect mode SLO imaging to patients with fundus disease. Infrared light is reflected from the fundus to a greater extent than visible light permitting lower illumination power and, as it penetrates the retinal pigment epithelium, choroidal structures can be readily imaged. Furthermore, as conventional infrared illumination and detection systems are not well suited to ophthalmoscopy, this area is underdeveloped as a potential source of useful clinical data. Confocal, direct and indirect imaging modes have been used to image fundi of normal volunteers and patients with fundus disease. In comparison with conventional fundus photography confocal infrared SLO imaging improves visualisation of choroidal vasculature, retinal pigment epithelial abnormalities, laser photocoagulation scars, and optic disc pores in the lamina cribrosa. Direct infrared SLO imaging enables fundus visualisation through nuclear lens opacities. Furthermore, indirect mode imaging enhances significantly the appearance of macular drusen. The potential clinical benefit of these observations is discussed.

Adult↗
PubMed1994

Rat retinal pigment epithelial cells express an inducible form of nitric oxide synthase and produce nitric oxide in response to inflammatory cytokines and activated T cells.

In this report we show that rat retinal pigment epithelial (RPE) cells express an inducible form of nitric oxide synthase (iNOS) and secrete high levels of nitric oxide (NO.) when co-cultured with activated lymphocytes. We have previously shown that cultured rat RPE cells suppress syngeneic lymphocyte proliferation, an effect attributed to prostaglandin E2 (PGE2) secretion by the RPE cells. However supernatants from such co-cultures were also found to contain high levels of nitrite (NO2-), the stable end-product of NO. synthesis. RPE cell secretion of NO. was stimulated by the cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), an effect enhanced by endotoxin [lipopolysaccharide (LPS)], reduced by the competitive inhibitor of L-arginine metabolism, NG-monomethyl-L-arginine (L-NMMA) and inhibited by cycloheximide. These effects were dose dependent. Using reverse transcription (RT)/PCR a product of 1398 bp was amplified which showed sequence identity with iNOS cloned from rat vascular smooth muscle. Northern blot analysis of total RNA extracted from rat RPE before and after cytokine stimulation showed induction of a 4.5 kb (kilobase) transcript which hybridized with a 1398 bp (base pair) polymerase chain reaction (PCR)-generated cDNA probe derived from the sequence of rat RPE cell iNOS. These results indicate RPE cells express an inducible form of nitric oxide synthase (NOS) and that high levels of NO. may be produced locally in the eye by the RPE in the presence of activated lymphocytes. Given the cytostatic and cytotoxic properties of this molecule, NO. may play an important role as an inducible mediator of immunosuppressive mechanisms within the microenvironment of the eye at the site of lymphocyte activation.

Amino Acid Oxidoreductases↗
PubMed1994

ICAM-1/LFA-1 interactions in T-lymphocyte activation and adhesion to cells of the blood-retina barrier in the rat.

To identify the signals involved in the adhesion and subsequent migration of lymphocytes across the endothelium (REC) and pigment epithelium (RPE) of the blood-retina barrier we have studied the effects of monoclonal antibodies (mAb) to rat adhesion/accessory molecules on the binding of normal and concanavalin A (Con A)-activated rat spleen lymphocytes to cultured unstimulated and interferon-gamma (IFN-gamma)-stimulated RPE and REC. Forty to 48% of unactivated T cells were found to bind to normal REC or RPE by leucocyte function-associated antigen-1/intercellular adhesion molecule-1 (LFA-1/ICAM-1)-independent mechanisms, despite constitutive expression of ICAM-1 by the RPE cells and LFA-1 by the T cells. Con A-activated lymphocytes showed an enhanced adhesion to both RPE and REC. However, IFN-gamma-stimulated RPE and REC did not demonstrate a significant increase in adhesiveness for normal lymphocytes highlighting the importance of lymphocyte integrin activation from low-affinity to high-affinity state. Activated lymphocyte adhesion to unstimulated RPE and REC was significantly blocked by LFA-1 mAb (35%, P < 0.0001) and ICAM-1 mAb (20%, P < 0.001). Inhibition of adhesion by antibody to CD2 was not significant. Both ICAM-1 and LFA-1 mAb also significantly (P < 0.05) blocked antigen presentation following retinal extract stimulation of lymphocytes from immunized rats in proliferation assay. These data suggest that the ICAM-1/LFA-1 system is important in lymphocyte trafficking into the eye only after lymphocyte activation.

Animals↗
PubMed1994

Intranasal administration of retinal antigens suppresses retinal antigen-induced experimental autoimmune uveoretinitis.

Bovine retinal extract (RE) is a heterologous mixture of highly uveitogenic proteins including S-Antigen (S-Ag), interphotoreceptor retinol binding protein (IRBP) and rhodopsin, and is a potent inducer of experimental autoimmune uveoretinitis (EAU). Intranasal inoculation of Lewis rats with RE performed daily for 10 days prior to immunization with RE suppresses both the severity and the incidence of the clinical response and histopathological changes in EAU. Significant suppression of the disease in treated animals could be achieved with a total (cumulative) intranasal inoculum of 42 micrograms of antigen. Animals which were treated with extract exhibited a normal total antibody response to S-Ag, IRBP and retinal extract when compared with controls [phosphate-buffered saline (PBS) treated] animals. The antibody response in tolerized animals was predominantly anti-S-Ag IgG2a with suppression of anti-S-Ag IgM response. Treated animals had a significantly suppressed delayed-type hypersensitivity (DTH) response to retinal extract but normal response to purified protein derivative (PPD) compared to control animals. Adoptive transfer of splenocytes from treated animals also demonstrated some protection against RE-induced EAU. These results demonstrate that tolerance induction impairs the onset and severity of EAU by inhibiting the DTH response to heterologous mixture of retinal antigens.

Administration, Intranasal↗
PubMed1994

Localization and characterization of major histocompatibility complex class II-positive cells in the posterior segment of the eye: implications for induction of autoimmune uveoretinitis.

PURPOSE: To identify potential antigen-presenting cells in the choroid and retina of the normal rat eye, with a view to proposing a role for such cells in the induction and perpetuation of experimental autoimmune uveoretinitis, a model of human uveoretinal inflammation. METHODS: Immunohistochemical and electron microscopic studies using a panel of monoclonal antibodies were performed on frozen sections of the perfused-fixed normal Lewis rat eye, choroid whole mounts, and cytospin preparations of cells harvested from choroid/ciliary body explant cultures. In addition, time-lapse video recordings of migratory uveal tract cells in culture were taken. RESULTS: No major histocompatibility complex class II-positive cells were found in the normal Lewis rat retina. However, at least three populations of potential antigen-presenting cells were found in the uveal tissues of the eye: classical dendritic cells expressing high levels of major histocompatibility complex class II antigen; resident dendritiform macrophages, which were negative for major histocompatibility complex class II antigen, but expressed specific macrophage markers (ED2); and blood-borne macrophages (ED1) that had emigrated from the vasculature into the tissue compartment. In addition there were small numbers of cells expressing novel markers such as markers usually found only on macrophage subsets in splenic tissue (ED3) and a recently described marker for veiled dendritic cells (OX62). Dendritic cells and resident dendritiform macrophages closely interacted with each other and with tissue cells, particularly retinal pigment epithelial cells. CONCLUSIONS: The posterior uveal tract is richly populated with classical dendritic cells expressing constitutive high levels of major histocompatibility complex class II antigen. There are also several types of macrophages with the potential to modulate immune responses in the posterior segment. Interactions among these cells and with resident tissue cells such as retinal pigment epithelial cells are probably central to the initiation of (auto)immune responses in the posterior segment of the eye.

Animals↗
PubMed1993

Retinal pigment epithelial cells modulate lymphocyte function at the blood-retina barrier by autocrine PGE2 and membrane-bound mechanisms.

Retinal pigment epithelial cells (RPE) in vitro display many characteristics typical of antigen-presenting cells (APC) yet are poor inducers of lymphocyte proliferation and in vivo appear to remain MHC class II negative within the acute inflammatory chorioretinal lesions associated with experimental autoimmune uveoretinitis. In an in vitro assay system designed to mimic the in vivo situation as closely as possible, RPE cells profoundly suppressed lymphocyte proliferation to antigen, mitogen, and IL-2 even in the presence of exogenous APC. RPE immunosuppression was found to comprise both soluble and membrane-bound components and to be reversible as lymphocytes could be restimulated by thymocytes after coculture on RPE cells. Indomethacin restored proliferative responses of cocultured lymphocytes to specific antigen and mitogen indicating that the soluble component of suppression was mediated in part by PGE2 production by the RPE cells. Constitutive production of PGE2 by RPE cells was found to be low (approximately 10(-9) M), but increased to high levels (approximately 10(-6) M) in coculture with activated lymphocytes. In addition, antigen-specific primed lymphocyte responses during coculture with RPE were enhanced in the presence of indomethacin compared to similar splenocyte responses in the absence of RPE cells. However, indomethacin did not reverse RPE inhibition of IL-2-driven lymphocyte proliferation, and the failure of lymphocyte proliferation could not be attributed to TGF beta production by RPE cells, indicating that other RPE cell-immunosuppressive mechanisms were involved. Trypsin pretreatment of RPE cell monolayers removed an as yet unidentified inhibitory factor present on the RPE cell membrane and in combination with indomethacin enabled RPE cells to function as antigen-presenting cells.

Animals↗
PubMed1993

Regulation of glucose transporter (GLUT 3) and aldose reductase mRNA inbovine retinal endothelial cells and retinal pericytes in high glucose and high galactose culture.

The regulation of GLUT-3 and aldose reductase mRNA in retinal endothelial cells and retinal pericytes was studied in response to variations in the extracellular concentration of hexoses. In physiological concentrations of glucose (5 mmol/l), an increase in the level of GLUT-3 mRNA was observed in cultured cells compared to the level of mRNA found in the absence of glucose. In contrast, there was little change in the level of GLUT-3 mRNA when the cells were cultured in the presence of 5 mmol/l galactose. In high concentrations of glucose, there was a decline in GLUT-3 mRNA indicating that the GLUT-3 mRNA is regulated by the extracellular concentration of glucose. In contrast, at both 5 mmol/l and 25 mmol/l glucose, the level of aldose reductase mRNA was increased. Furthermore, there were differences in the magnitude of the increase of aldose reductase mRNA between bovine retinal pericytes and bovine retinal endothelial cells with a greater increase being observed in the pericytes. We propose that this demonstration of a facilitative glucose transporter system within retinal cells, and in particular the specific response to different hexoses and the known distinct kinetic parameters of the transporter system in specific cell types, highlights the heterogeneity of hexose transport mechanisms in retinal cells. Thus, hypergalactosaemia as a model system for the study of diabetic retinopathy should be used with caution.

Aldehyde Reductase↗
PubMed1993

Corneal epithelial cell migration in humans: 'hurricane and blizzard keratopathy'.

Replicative turnover of the corneal epithelium is believed to occur from a population of stem cells located at the corneo-scleral limbus. During the healing of corneal epithelial wounds, sheets of epithelial cells move centripetally from the limbus and circumferentially along the limbus to cover the defect. A whorled or vortex pattern, similar to that seen in cornea verticillata, has been reported to occur on the corneal surface as an effect of topical steroid medication, during the healing of grafted corneas. This condition has been termed 'hurricane keratopathy'. We have noted this appearance in 6 patients who did not have corneal grafts. In all our patients the whorled pattern was best visible on fluorescein staining. This feature differentiates 'hurricane keratopathy' from cornea verticillata secondary to deposition of substances in corneal epithelial cells. Further, in all our patients the vortex was clockwise. Examination of illustrations of 'hurricane keratopathy' and cornea verticillata reported in the literature reveals that the whorled pattern is almost always clockwise. We believe that this specific pattern is likely to be due to the effect of the electromagnetic fields of the eye on the migrating epithelial cells and present a theory to explain this phenomenon. In 3 eyes of 2 other patients with chronic epitheliopathies we observed a random distribution of cells that did not conform to any specific pattern. We have termed this condition 'blizzard keratopathy'.

Adult↗
PubMed1993

A spectrum of clinical signs in anterior uveitis.

The range of clinical changes that occur in posterior uveitis have been well documented. We describe two clinical features of anterior uveitis which we have termed 'iris pigment epithelitis' and 'iris vasculitis'. Other clinical forms of iritis also exist and together with our described findings parallel the spectrum of clinical presentations in posterior uveitis.

Adult↗
PubMed1993

Digital fundus imaging using a scanning laser ophthalmoscope.

While many systemic diseases have ophthalmic manifestations with visible pathological features affecting the fundus, diabetic eye disease is of particular interest. There are many advantages in using digital image analysis to quantify the extent of retinal pathology in diabetes particularly to monitor its progression. However, the usual method of imaging involves photographing the retina using a fundus camera. Not only does this require that the photographs be digitized prior to analysis, but the resulting illumination across the image is non-uniform and this creates problems in digital image analysis. This paper describes the construction of a scanning laser ophthalmoscope interfaced to a computer, which has a number of significant advantages for digital retinal imaging. Firstly, it has better uniformity of illumination than the fundus camera and operates at much lower light levels. Secondly, it permits imaging at various wavelengths with no consequent degradation in image quality; in particular, the value of imaging at infrared wavelengths to give greater tissue penetration is demonstrated. Finally, by introducing the capability for confocal imaging, tomographic images can be taken, improving the perceptibility of features situated deep in the retina. Typical images are shown to demonstrate the potential of this instrument.

Diabetic Retinopathy↗
PubMed1993

Clinical experience with interferon alfa-2a for exudative age-related macular degeneration.

There has been recent interest in the use of systemic interferon alfa-2a treatment for choroidal neovascular membranes (CNV). Here a pilot study is reported in which 10 patients with exudative age-related macular degeneration (ARMD) have been treated with a course of interferon injections. Of nine eyes with CNV there has been clinical and angiographic improvement in one eye and maintenance of visual acuity at pretreatment levels in three eyes (mean follow up period 7.6 months). Clinical appearance in five eyes was unchanged but these eyes still had active CNV. Two eyes with pigment epithelial detachment showed no clinical or angiographic change after interferon therapy although visual acuity in one eye had improved. Interferon alfa-2a may have a role to play in the treatment of ARMD as an adjunct to laser photocoagulation.

Aged↗
PubMed1993

Nasal administration of retinal antigens suppresses the inflammatory response in experimental allergic uveoretinitis. A preliminary report of intranasal induction of tolerance with retinal antigens.

Current immunotherapy of posterior uveitis is non-specific and limited by drug toxicity and unpredictable relapses on therapy. Alternative modes of therapy being investigated using the rat model of experimental autoimmune uveoretinitis (EAU) have included the induction of tolerance with oral administration of milligram quantities of retinal antigens. In this preliminary report we demonstrate that tolerance to retinal antigens can be induced via the upper respiratory tract with microgram doses of antigen, preventing subsequent induction of EAU.

Animals↗
PubMed1993

Adhesion molecule expression in acute and fibrotic sympathetic ophthalmia.

Samples of iris ciliary body, choroid and retina from normal eyes and from 2 cases of sympathetic ophthalmitis (one acute and one late stage fibrosis) were examined for the expression of the VLA integrins beta 1 and alpha 1-6, and the integrin beta 3, in addition to ICAM-1, VCAM-1, ELAM-1 and CD44 using an APAAP staining technique. The expression of VLA-4, VLA-5, VCAM-1, ICAM-1, and CD44 was significantly increased and ELAM-1 was slightly increased in acute sympathetic ophthalmitis in comparison to fibrotic and normal eyes. VLA-6 was moderately increased in acute and fibrotic cases and VLA-2 VLA-3 and beta 3 were moderately expressed on all tissues examined. The differential expression of molecules known to be involved in lymphocyte activation and adhesion in acute sympathetic ophthalmitis suggests that certain adhesion molecules play a role in the pathogenesis of intraocular inflammation and may be suitable targets for immunotherapy.

Acute Disease↗
PubMed1993

Ultrastructural pathology of experimental autoimmune uveitis in the rat.

Experimental autoimmune uveoretinitis (EAU) has been extensively studied as a model for human posterior uveitis, however, few ultrastructural studies of EAU in the rat have been reported. In the present report we document a systematic time-course study of the posterior segment changes in the Lewis rat. The disease varied somewhat in severity in animals sacrificed at identical times after immunisation. In the prodromal stage of the disease, usually around day 14, early pathological changes included mild peripapillary vasculitis and low grade mononuclear and neutrophilic infiltration of the subretinal space with phagocytosis of the rod outer segments. The features of the severe or active diseases were most evident on day 21 and included mixed cellular infiltrate of the vitreous, subretinal serohaemorrhagic exudate, focal retinal detachment and necrosis. Outer retinal destruction was often most severe adjacent areas of retinal vasculitis. Focal monocytic subpigment epithelial microgranulomas, reminiscent of Dalen-Fuch's nodules in humans, were also identified. By day 28 and 49 active inflammation had subsided and large segments of the outer retina were completely destroyed. The retinal pigment epithelium (RPE) also showed signs of activation in the vicinity of focal retinochoroidal mononuclear infiltrates including multilayering, proliferation and increased phagocytosis. Finally, neovascularisation of the RPE by non-fenestrated capillaries derived from the retinal vasculature was evident in the late stages of the disease.

Acute Disease↗
PubMed1993

Retinal antigen specific lymphocytes, TCR-gamma delta T cells and CD5+ B cells cultured from the vitreous in acute sympathetic ophthalmitis.

CD5+ B lymphocytes and TCR gamma-delta T lymphocytes, phenotypes implicated in the pathogenesis of autoimmune disease, were isolated from the vitreous in a case of acute sympathetic ophthalmitis. These cells were obtained using a method which allows the selective maintainance in vitro of in vivo activated T lymphocytes. Dual colour flow cytometry showed that after 3 days culture in IL-2 containing medium 61% of cells were CD5/CD19 + ve and 41% CD3/TCR gamma delta + ve. Of the total CD3 + ve population, 15% were gamma/delta negative. These cells formed a population which also responded in a proliferation assay to retinal antigens. Histologically the eye showed a marked mononuclear cell infiltration of the retina, ciliary body and choroid. Granulomatous lesions within the choroid contained lymphocytes, plasma cells and multinucleate giant cells. Immunocytochemistry showed lymphocyte populations to be predominantly CD2 + ve CD3 + ve T lymphocytes of the CD4 sub-set. Distribution of monocytes/macrophages throughout the lesions and restriction of B-lymphocytes to granulomata were all consistent with a DTH type reaction. Despite immunosuppressive therapy, the expression of activation antigens HLA-DR and ICAM-1 on infiltrating and resident ocular tissue cells was high, although IL-2 receptor (CD25) expression was virtually absent. Flow cytometric analysis of peripheral blood cells prior to treatment with Cyclosporin-A showed systemic activation of lymphocytes, with high levels of HLA-DR and CD25 expression and a raised CD4/CD8 ratio.

Antigens↗