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J V Forrester

Publications and source records attributed to J V Forrester.

At least 73 records · Page 4Linked to original sources
PubMed1999

Fas-Fas ligand-mediated apoptosis within aqueous during idiopathic acute anterior uveitis.

PURPOSE: Despite ocular immune privilege, (auto)immune-mediated acute anterior uveitis (AAU) is relatively common. However, although relapses of AAU are usually self-limiting, possible regulatory mechanisms remain undefined in humans. Experimentally, Fas-Ligand (FasL)-mediated apoptosis of Fas+ inflammatory cells contributes to the immune privilege within the anterior chamber and provides an explanation for the success of corneal allograft transplantation. Therefore, whether such mechanisms regulate the immune response in AAU was investigated. METHODS: Aqueous and peripheral blood samples from consecutive patients presenting with idiopathic AAU were obtained with consent. Leukocytic phenotype was analyzed by flow cytometry, and apoptosis was determined by both flow cytometry and TdT-dUTP terminal nick-end labeling analysis. Presence of soluble Fas and FasL was determined by western blot analysis and enzyme-linked immunosorbent assay and compared with control aqueous from patients undergoing cataract surgery. The ability of the aqueous to induce apoptosis in a Fas+ Jurkat cell line was also determined. RESULTS: During AAU aqueous-infiltrating Fas+ cells included CD3+ T cells and granulocytes, whereas FasL+ cells comprised predominantly of non-CD3+ T cells. Higher levels of functional soluble FasL were found in aqueous of AAU patients than in normal aqueous, capable of inducing apoptosis in 68.9% +/- 7.6% of Fas+ lymphoid cells. Compared with peripheral blood, the CD4+ T cells infiltrate within aqueous showed significantly increased CD69 and CD25(IL-2r) expression. Flow cytometric analysis of aqueous showed that 9.32% +/- 1.2% of infiltrating non-granulocyte CD45+ cells were apoptotic, confirmed as T cells on subsequent three-color flow cytometric analysis. CONCLUSIONS: Taken together with published experimental data, the present study provides evidence for FasL-mediated apoptotic cell death contributing to the local immune regulation of ocular inflammatory disease and provides a mechanism to account for the self-limiting clinical course of AAU.

Acute Disease↗
PubMed1999

Macrophages and dendritic cells in IRBP-induced experimental autoimmune uveoretinitis in B10RIII mice.

PURPOSE: To investigate the characteristics of the mononuclear cell infiltrate in murine experimental autoimmune uveoretinitis (EAU). METHODS: EAU was induced by immunization with bovine interphotoreceptor retinal binding protein (IRBP) in Freund's complete adjuvant (subcutaneous injection) and pertussis toxin (intraperitoneal injection) in B10RIII mouse. Then animals were killed on days 7, 9, 12, 15, 20, 26, and 39 after immunization. Eyes were processed for hematoxylin and eosin staining to characterize the disease and to assess the severity and extent of the EAU. Single and dual immunohistochemical staining in various combinations with monoclonal antibodies against CD45, CD4, CD8, major histocompatibility complex (MHC) class II, CD11c, NLDC-145, and a variety of macrophage markers was performed. RESULTS: The authors' results showed that vitritis, vasculitis and perivasculitis, retinal detachment, and granuloma formation in retina and choroid were the predominant features of IRBP-induced B10RIII mice EAU. Immunohistologic results showed that CD4+ T cells and macrophages were the main infiltrating cells in retina and choroid throughout the entire course of the disease. MHC class II negative macrophages expressing antigens reacting with MOMA-2, F4/80, sialoadhesin, and CD11b were prominent during the peak phase of tissue damage in the retina and choroid. Dendritic cells (DCs) characterized by dual positivity for MHC class II and CD11c and negative for sialoadhesin appeared at time of disease onset and continued to be recruited during the inflammatory process. DCs at the site of inflammation were NLDC-145 weak and CD8 negative, indicating that they were of the myeloid rather than the lymphoid lineage. CONCLUSIONS: The results suggest that EAU in B10RIII mice is initiated by local-infiltrating, dendritic antigen-presenting cells, whereas tissue damage is associated with sialoadhesin-positive, phagocytic nonantigen-presenting macrophages during the effector stage.

Animals↗
PubMed1999

Modelling corneal epithelial wound closure in the presence of physiological electric fields via a moving boundary formalism.

A new framework for the modelling of corneal epithelial wound healing is presented, which can include the presence of a physiological electric field. The difficulty inherent in the inclusion of this biological phenomenon motivates our use of a moving boundary formalism. A key conclusion is that the model predicts a linear relation between the wound healing speed and the physiological electric field strengths over a physiologically large range of electric field strength. Another key point is that this linear relationship between electric field strength and wound healing speed is robust to variations in critical parameters that are difficult to estimate. The linearity is also robust to different realizations of the modelling framework presented.

Animals↗
PubMed1998

Cytokine regulation of RANTES production by human retinal pigment epithelial cells.

The mechanism whereby inflammatory cells gain access to the retina in posterior intraocular inflammatory disease remains unclear. The chemokine RANTES has the potential to influence the migration of memory T cells and monocytes across the blood-retinal barrier during inflammatory eye disease. We have therefore examined the production of RANTES by cultured human retinal pigment epithelial cells (RPE), which form a part of the blood-retinal barrier, in response to cytokines likely to be present in the microenvironment. IL-1 beta and TNF alpha stimulated RANTES production by these cells. IFN-gamma acted synergistically with TNF alpha to increase RANTES production. In contrast, IL-4 downregulated RANTES production stimulated by TNF alpha. RT-PCR studies showed that RANTES mRNA from RPE followed the same pattern of expression in response to cytokines as did RANTES production indicating that RANTES production was controlled at, or prior to, transcription. RANTES is produced in vitro by RPE in response to the proinflammatory cytokines IL-1 beta, TNF alpha, and IFN-gamma and is therefore likely to play a role in the development of the inflammatory eye disease endogenous posterior uveitis.

Cell Movement↗
PubMed1998

Immunosuppressive treatment of choroidal neovascularization associated with endogenous posterior uveitis.

OBJECTIVE: To determine whether resolution of choroidal neovascularization (CNV), a recognized sight-threatening complication of endogenous posterior uveitis, and maintenance of vision could be achieved with immunosuppression. PATIENTS AND METHODS: Fourteen patients (17 eyes) with CNV associated with endogenous posterior uveitis were enrolled in an open study. Ages ranged from 5 to 51 years. Three eyes had extrafoveal CNV, 6 juxtafoveal, and 8 subfoveal. Three patients were treated with a single course of oral corticosteroids, 2 had additional cyclosporine for up to 2 years, and 9 continued to receive a low-dose regimen of a combination of immunosuppressive drugs. RESULTS: After a median follow-up of 15 months (range, 7 months to 6 1/2 years), 9 of 17 eyes had an improvement in visual acuity; 6 remained within 1 Snellen line of initial visual acuity, and 2 had lost 2 Snellen lines. Angiographically, CNV resolved in 13 eyes, resolved then recurred in 3, and improved but persisted in 4. CONCLUSION: These results support a role for immunosuppressive therapy in the treatment of CNV associated with endogenous posterior uveitis.

Adolescent↗
PubMed1998

A comparison of computer based classification methods applied to the detection of microaneurysms in ophthalmic fluorescein angiograms.

We compared the performance of three computer based classification methods when applied to the problem of detecting microaneurysms on digitised angiographic images of the retina. An automated image processing system segmented 'candidate' objects (microaneurysms or spurious objects), and produced a list of features on each candidate for use by the classifiers. We compared an empirically derived rule based system with two automated methods, linear discriminant analysis and a learning vector quantiser artificial neural network, to classify the objects as microaneurysms or otherwise. ROC analysis shows that the rule based system gave a higher performance than the other methods (p = 0.92) although a much greater development time is required.

Aneurysm↗
PubMed1998

Uveitogenic epitopes of retinal S-antigen are generated in vivo via an alternative antigen-presentation pathway.

We have found that different antigen-processing pathways are involved in the induction of experimental autoimmune uveoretinitis (EAU) by the retinal autoantigens S-antigen and interphotoreceptor retinoid-binding protein (IRBP). Although in vitro T-cell proliferative responses to IRBP were completely inhibited in the presence of irreversible cysteine protease inhibitors, no significant reduction of S-antigen proliferative responses was found. Furthermore, acidic proteolysis of S-antigen by the cysteine protease cathepsin B prior to immunization radically reduced pathogenicity (disease severity). In addition, in vitro processing of S-antigen, but not IRBP, was also found to be resistant to the action of cycloheximide and lysosomotropic agents, inhibition of proliferation only occurring after extended exposure of antigen-presenting cells to methyl amine or high concentrations of chloroquine. These data indicate that an alternative pathway of antigen processing exists for S-antigen, which is independent of processing within the normal endolysosomal pathway and that uveitogenic peptides of naturally processed S-antigen bind to major histocompatibility complex class II antigens either at the cell surface or within very early endosomes where cathepsin B is inactive.

Animals↗
PubMed1998

Glucose-dependent regulation of DNA synthesis in bovine retinal endothelial cells.

PURPOSE: Clinical trials have demonstrated that the onset and progression of diabetic retinopathy is influenced by the glucose control of the patient. The disease is characterised by the coexistence of impaired cell growth and excessive cell proliferation, and we wished to determine the effect that glucose has upon these parameters. METHODS: Bovine retinal endothelial cells were exposed to a range of glucose concentrations from 0-25 mmol/l. The level of DNA synthesis and cell number was then determined using pulse labelling with tritiated thymidine and a Coomassie blue dye-based assay, respectively. RESULTS: The level of DNA synthesis declined significantly as the concentration of glucose increased. DNA synthesis was further decreased by the presence of an inhibitor of PI3 kinase (Wortmannin). The decline in DNA synthesis was abrogated by the presence of a protein kinase C (PKC) inhibitor or by incubating the cells with antibodies specific for the GLUT-1 and GLUT-3 specific isoforms of glucose transporter proteins. TGF-beta antibody significantly increased the level of DNA synthesis in cells exposed to high concentrations of glucose. The changes that are observed in the level of DNA synthesis was not coincident with any significant changes in cell number as measured by the Coomassie blue assay. CONCLUSIONS: This demonstrated that the decline in DNA synthesis is dependent upon the entry of glucose into the cells and that this is mediated via a PKC dependent pathway.

Androstadienes↗
PubMed1998

Tacrolimus (FK506) in failed cyclosporin A therapy in endogenous posterior uveitis.

Tacrolimus (FK506) is effective in Japanese endogenous posterior uveitis (EPU), but there is limited data on its role in refractory EPU where cyclosporin A (CsA) toxicity/resistance develops. This open prospective clinical study aimed to assess the efficacy and adverse effects of low-dose FK506 therapy in western patients with refractory EPU where CsA resistance or toxicity has developed. Patients with CsA resistant/toxic EPU were started on low-dose (< 0.10 mg/kg/day) FK506 therapy. Immunosuppressive efficacy was assessed by visual acuity, binocular indirect ophthalmoscopy (BIO) scores, and change in clinical features. Adverse effects were assessed by routine biochemical tests (including serum creatinine) and symptoms. Seven patients (13 eyes), aged (mean +/- SD) 37.5 +/- 14.8 years, were recruited with previous CsA nephrotoxicity as the main indication and prior duration of EPU of (mean +/- SD) 13.1 +/- 7.3 years. Behçet's disease was the commonest diagnosis. FK506 therapy was maintained at 0.06 +/- 0.02 mg/kg/day, trough level of 8.7 +/- 1.8 ng/ml, in combination with low-dose prednisolone (0.11 +/- 0.04 mg/kg/day) in all patients for a mean duration of 8.7 months (range 1.0-17.7). From baseline (for 11 eyes with meaningful follow-up), visual acuity was maintained in nine eyes and BIO score improved in nine eyes. No major adverse effects developed, with only a 7.5 +/- 6.5% maximum increase in serum creatinine in patients with previous CsA-induced nephrotoxicity. Minor adverse effects (especially mild hyperglycaemia and neurological symptoms) were common and usually well tolerated, except for two patients in whom drug withdrawal was necessary, thus producing therapeutic failure. Low-dose FK506 is effective in refractory EPU as CsA-rescue therapy, and should be considered earlier in the evolution of refractory EPU.

Adult↗
PubMed1998

Marrow-derived activated macrophages are required during the effector phase of experimental autoimmune uveoretinitis in rats.

PURPOSE: Experimental autoimmune uveoretinitis (EAU), an established model for human endogenous (autoimmune) posterior uveitis, is a CD4+ T cell-mediated disease inducible in Lewis rats by intradermal inoculation with retinal antigens. Immunohistochemical studies have previously documented the lymphocyte profiles during various stages of the disease process. The purpose of the present study was to investigate the role of macrophages in EAU. METHODS: EAU was induced in Lewis rats, and the effect of macrophage depletion, using the drug dichlorodimethylene diphosphonate (Cl2MDP) encapsulated in liposomes and administered intravenously, was assessed based on the clinical and histological profile of the disease. RESULTS: The results have shown that in control animals macrophages occur early, feature prominently throughout the course of the disease and display considerable heterogeneity: marrow-derived ED1+ cells and ED3+ cells are the major infiltrating cells, with many cells also expressing ED7 and ED8. In contrast, few cells expressed the ED2 antigen during EAU, even though ED2+ "resident" macrophages occur in the normal choroid. Macrophage depletion, using intravenously injected dichloromethylene diphosphonate (Cl2MDP) enclosed in liposomes, caused a delay in the onset and a reduction in the severity of EAU when administered during the "effector" stage of the disease, i.e. 9-11 days after inoculation with retinal antigen. The delay in disease onset was greater when liposomes were mannosylated and was accompanied by a reduction in the overall inflammatory cell infiltrate into the eye and reduced tissue damage. In addition, there was a reduction in the level of expression of MHC Class II antigen and CR3 (ED7) antigen, a marker of macrophage activation, in Cl2MDP-treated animals compared to controls. CONCLUSION: These results suggest that blood-borne, activated macrophages are major effectors of tissue damage during EAU.

Animals↗
PubMed1998

Quantifying changes in retinal circulation: the generation of parametric images from fluorescein angiograms.

Fluorescein angiography is an established technique for examining the functional integrity of the retinal circulation. The ability to quantify this function offers the possibility of early detection of changes due to retinopathy. We have developed a technique to generate functional, parametric images of the retinal circulation. A given angiogram is first registered to align consecutive frames. At each point in the retina, a graph of fluorescein intensity versus time is then constructed and fitted with a gamma variate curve. Parameters are extracted from these curves and formed into parametric images showing the variation in fluorescein passage across the entire area of the angiogram. Parameters examined to date include time to maximum intensity, time of arrival and rise time. The technique has been demonstrated using photographic and scanning laser ophthalmoscopic angiograms of both normal subjects and patients with a variety of retinopathies. The time to maximum images of the normal subjects reveals a similar fillings pattern in each case, whilst the pathologies present in the abnormal angiograms are clearly identified. The generation of functional time to maximum images enables the health of the retinal circulation to be quantified with respect to the rate at which the vasculature fills with fluorescein. This offers a potential tool for detecting the onset of retinopathy and monitoring its progression.

Fluorescein Angiography↗
PubMed1998

Novel approach towards colour imaging using a scanning laser ophthalmoscope.

AIMS: Conventional fundus imaging using a fundus camera produces colour fundus pictures. The scanning laser ophthalmoscope (SLO) has the advantages of lower levels of light exposure, improved contrast, and direct digital imaging but until now has produced monochromatic images as a laser of single wavelength is used. True representation of the fundus is possible by combining images taken using blue, green, and red lasers. METHODS: A custom built SLO was used to capture blue, green, and red fundus images from suitable volunteers and patients with fundus disease. Images were corrected for eye movement and combined to form a colour image. Colour fundus photographs were taken using a fundus camera for comparison with the SLO image. RESULTS: The background fundus and retinal vasculature had similar appearances with the two imaging modalities. Internal limiting membrane reflections were prominent with the SLO. Identification of new vessels in the diabetic fundus was easier with the SLO than the colour fundus photographs. CONCLUSION: A colour SLO offers all the advantages of the present monochromatic imaging system with the added advantage of true colour representation of the fundus.

Adult↗
PubMed1998

Cyclosporin A therapy in refractory non-infectious childhood uveitis.

AIMS: To assess the immunosuppressive efficacy, steroid sparing effect and adverse effects of cyclosporin A (CsA) therapy in refractory non-infectious childhood uveitis. METHODS: A retrospective case series review of the medical records of children on CsA therapy attending a tertiary referral centre for refractory endogenous uveitis was performed. Low dose (< or = 5.0 mg/kg/day) CsA therapy was started either as monotherapy or in combination with other agents. The CsA immunosuppressive efficacy was assessed by visual acuity and binocular indirect ophthalmoscopy (BIO) score outcomes and steroid sparing effect by growth charts and ability to withdraw or maintain a low steroid dose. Possible CsA adverse effects were monitored by routine biochemistry (including serum creatinine) and haematological tests, blood pressure recordings, and symptoms. RESULTS: 14 patients (25 eyes, 10 males, four females) were recruited with steroid failure as the most common CsA indication. Age (mean (SD)) at start of CsA therapy was 8.7 (4.1) years with a duration of CsA therapy of 20.9 (range 3.5-88.3) months at a maintenance CsA dose of 4.0 (1.0) mg/kg/day. From baseline, visual acuity improved or was maintained in 23 (92%) eyes and BIO score improved in 19 (76%) eyes. Height centiles were preserved and the maintenance prednisolone dose was 6.3 (3.3) mg/day, where required, in 10 (71%) patients. Nephrotoxicity was not observed, with transient systemic hypertension developing in one patient. Minor adverse effects were more common but were well tolerated. CONCLUSIONS: Cyclosporin A therapy is effective and safe in the medium term, if closely monitored, in refractory non-infectious childhood uveitis.

Adolescent↗
PubMed1998

Effects of mycophenolate mofetil on nasal mucosal tolerance induction.

PURPOSE: The authors investigated mucosal tolerance therapy as a treatment for autoimmune conditions, including uveitis. Although nasal antigen administration was unable to suppress the disease when given to primed animals, previous studies of experimental autoimmune uveoretinitis (EAU) have shown that nasal antigen administration can maintain disease suppression when combined with oral cyclosporin A. This study aimed to determine whether mucosal tolerance can be induced when EAU is suppressed with mycophenolate Mofetil (MM) and whether tolerance can be maintained when immunosuppression with MM is stopped. METHODS: Lewis rats were immunized with retinal extract, and then they received either oral MM 7 to 20 days after immunization or retinal extract intranasally in combination with oral MM on days 7 to 20. Thereafter, weekly nasal administration of the antigen was given until the termination of the experiment at day 38. One group of control animals received the drug vehicle orally and phosphate-buffered saline intranasally. Clinical and histologic changes were assessed along with changes in immune status including delayed-type hypersensitivity, antibody responses to retinal antigens, and flow cytometric phenotyping of infiltrating ocular leukocytes. RESULTS: EAU was delayed, but not prevented, by a short-term course of MM (7-20 days after immunization). Tolerance to the retinal extract could not be induced during MM treatment by nasal retinal extract administration. Despite the delay in onset of EAU in MM and in MM- and nasal antigen-treated animals, profound target organ damage occurred as seen in untreated controls with EAU. However, fluoroscein-activated cell sorter analysis of retinal leukocytic infiltrate indicated that there was a reduced macrophage recruitment at all time points, whereas lymphocyte infiltration was reduced in proportion to the overall reduction in leukocyte infiltration during therapy. CONCLUSIONS: Nasal retinal antigen administration does not induce tolerance or maintain disease suppression when combined with MM therapy during the effector stage of the (auto)immune response. MM therapy delays disease onset, but target organ damage occurs when therapy is stopped, despite a marked inhibition of macrophagemonocyte infiltration into the chorioretina.

Animals↗