J V Forrester

University of Aberdeen, Aberdeen, Scotland, United Kingdom

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Publications (365)1349.25 Total impact

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    Lucia Kuffova · John V Forrester · Andrew Dick
    BMJ (online) 08/2015; 351. DOI:10.1136/bmj.h3216 · 16.38 Impact Factor
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    ABSTRACT: Mycobacteria in complete Freund's adjuvant (CFA) are an essential component of immunization protocols in a number of autoimmune disease animal models including experimental autoimmune encephalomyelitis and uveoretinitis (EAE and EAU, respectively). We determined the role in EAU of two C-type lectin receptors on myeloid cells that recognize and respond to mycobacteria. Using receptor-specific antibodies and knockout mice, we demonstrated for the first time that the macrophage mannose receptor delays disease development but does not affect severity. In contrast, dectin-1 is critically involved in the development of CFA-mediated EAU. Disease severity is reduced in dectin-1 knockout mice and antibody blockade of dectin-1 during the induction, but not the effector phase, prevents EAU development. Significantly, similar blockade of dectin-1 in vivo has no effect in non-CFA-mediated, spontaneously induced or adoptive transfer models of EAU. Thus dectin-1 plays a critical role in the ability of complete Freund's adjuvant to induce EAU in mice. Copyright © 2015. Published by Elsevier Ltd.
    Molecular Immunology 07/2015; DOI:10.1016/j.molimm.2015.07.002 · 3.00 Impact Factor
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    Dataset: mjv032supp
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    ABSTRACT: Dendritic cells (DC) are the major antigen-presenting cells bridging innate and adaptive immunity, a function they perform by converting quiescent DC to active, mature DC with the capacity to activate naïve T cells. They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues. Here, we demonstrate that myeloid cell-specific genetic deletion of PTP1B (LysM PTP1B) leads to defects in lipopolysaccharide-driven bone marrow-derived DC (BMDC) activation associated with increased levels of phosphorylated Stat3. We show that myeloid cell-specific PTP1B deletion also causes decreased migratory capacity of epidermal DC, as well as reduced CCR7 expression and chemotaxis to CCL19 by BMDC. PTP1B deficiency in BMDC also impairs their migration in vivo. Further, immature LysM PTP1B BMDC display fewer podosomes, increased levels of phosphorylated Src at tyrosine 527, and loss of Src localisation to podosome puncta. In co-culture with T cells, LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC. Finally, LysM PTP1B BMDC fail to present antigen to T cells as efficiently as control BMDC. These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.
    Journal of Molecular Cell Biology 06/2015; DOI:10.1093/jmcb/mjv032 · 8.43 Impact Factor
  • Izabela P Klaska · John V Forrester
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    ABSTRACT: Uveitis is a sight threatening intraocular inflammation accounting for approximately 10% of blindness worldwide. On the basis of aetiology, disease can be classified as infectious or non-infectious; and by anatomical localization of inflammation as anterior, posterior and panuveitis. Non-infectious uveitis is believed to be autoimmune in nature with Th1 and Th17 cells being identified as the prominent effector cell types. Numerous animal models of autoimmune uveitis were developed contributing to our understanding of this inflammatory condition. The classical peptide-induced experimental autoimmune uveoretinitis (EAU) model resembles human posterior uveitis due to the recurrent/relapsing nature of the disease; while the intraocular inflammation triggered by administration of bacterial lipopolisaccharide (endotoxin-induced uveitis, EIU) mimics closely anterior uveitis. The clinical need for novel, more targeted forms of anti-inflammatory therapy has emerged as currently available therapeutic strategies are associated with a number of adverse effects and intolerance in patients. This review summarises knowledge about existing mouse models of uveitis, discusses mechanisms driving intraocular inflammation and describes possible customised translational treatment strategies that can be potentially used in the clinic to prevent blindness in patients.
    Post Communist Economies 03/2015; 21(18). DOI:10.2174/1381612821666150316122928 · 0.46 Impact Factor
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    ABSTRACT: Background Experimental autoimmune uveoretinitis (EAU) is a widely used experimental animal model of human endogenous posterior uveoretinitis. In the present study, we performed in vivo imaging of the retina in transgenic reporter mice to investigate dynamic changes in exogenous inflammatory cells and endogenous immune cells during the disease process.Methods Transgenic mice (C57Bl/6 J Cx 3 cr1 GFP/+ , C57Bl/6 N CD11c-eYFP, and C57Bl/6 J LysM-eGFP) were used to visualize the dynamic changes of myeloid-derived cells, putative dendritic cells and neutrophils during EAU. Transgenic mice were monitored with multi-modal fundus imaging camera over five time points following disease induction with the retinal auto-antigen, interphotoreceptor retinoid binding protein (IRBP1¿20). Disease severity was quantified with both clinical and histopathological grading.ResultsIn the normal C57Bl/6 J Cx 3 cr1 GFP/+ mouse Cx3cr1-expressing microglia were evenly distributed in the retina. In C57Bl/6 N CD11c-eYFP mice clusters of CD11c-expressing cells were noted in the retina and in C57Bl/6 J LysM-eGFP mice very low numbers of LysM-expressing neutrophils were observed in the fundus. Following immunization with IRBP1¿20, fundus examination revealed accumulations of Cx3cr1-GFP+ myeloid cells, CD11c-eYFP+ cells and LysM-eGFP+ myelomonocytic cells around the optic nerve head and along retinal vessels as early as day 14 post-immunization. CD11c-eYFP+ cells appear to resolve marginally earlier (day 21 post-immunization) than Cx3cr1-GFP+ and LysM-eGFP+ cells. The clinical grading of EAU in transgenic mice correlated closely with histopathological grading.Conclusions These results illustrate that in vivo fundus imaging of transgenic reporter mice allows direct visualization of various exogenously and endogenously derived leukocyte types during EAU progression. This approach acts as a valuable adjunct to other methods of studying the clinical course of EAU.
    Journal of Neuroinflammation 01/2015; 12(1):17. DOI:10.1186/s12974-015-0235-6 · 4.90 Impact Factor
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    ABSTRACT: Macrophage adherence to the inner corneal surface and formation of MGCs in the stroma are common signs of chronic inflammation following corneal infection. To determine whether macrophage adherence (known clinically as KPs) and giant cell formation were specific to innate immune activation via particular TLR ligands, macrophage activation was examined in a murine model of TLR-mediated corneal inflammation. The corneal epithelium was debrided and highly purified TLR ligands were topically applied once to the cornea of TLR7(-/-), TLR9(-/-), Cx3cr1(gfp/+), CD11c(eYFP), and IL-4(-/-) mice. At 1 week post-treatment macrophage activation and phenotype was evaluated in the cornea. Treatment with TLR2, TLR3, TLR4, and TLR5 ligands caused an increase in the number of activated stromal macrophages in the central cornea at 1 week post-treatment. However, treatment with TLR9 ligand CpG-ODN and the TLR7/8 ligand R848/Resiquimod led to an accumulation of macrophages on the corneal endothelium and formation of multinucleated giant macrophages in the corneal stroma. We suggest that giant cell formation, which is a characteristic feature of granuloma formation in many tissues, may be a unique feature of TLR9- and TLR7/8-mediated macrophage activation. © Society for Leukocyte Biology.
    Journal of Leukocyte Biology 11/2014; 97(1). DOI:10.1189/jlb.3AB0414-216R · 4.30 Impact Factor
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    ABSTRACT: Corneal graft rejection is primarily a CD4(+) T cell-mediated mechanism in which macrophages may play an important inflammatory role. CD200Fc fusion protein is an artificial agonist of CD200R1, a receptor expressed predominantly on myeloid cells, engagement of which is known to down-regulate macrophage function. We therefore wished to test whether CD200Fc could be used as a therapeutic agent to prolong corneal graft survival. The distribution of CD200R1 and CD200, its natural ligand, was examined by immunohistology in the cornea and conjunctiva of unoperated rats and rats that had received corneal allografts. Mouse CD200Fc was injected subconjunctivally into transplanted rats on six occasions from the day of surgery until day 10 after transplantation. Control groups received injections of mouse IgG or diluent PBS. Allo-transplants were also performed in CD200(-/-) and control mice. The ability of CD200Fc to bind rat macrophages in vitro and to inhibit nitric oxide production was tested. Mean day of rejection in CD200Fc, IgG and PBS-treated rats was 12, 10 and 9 respectively (p=0.24). Mean day of rejection in CD200(-/-) and wild type mice was 17.5 and 16.0 respectively (p=0.07). Mouse CD200Fc bound to rat macrophages in a dose-dependent manner, but was unable to inhibit nitric oxide production. The fact that treatment with CD200Fc did not inhibit graft rejection and the failure of CD200 deficiency to affect graft survival suggests that local targeting of the CD200-CD200R axis to suppress macrophage activation is not a useful therapeutic strategy in corneal graft rejection. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Experimental Eye Research 11/2014; 130C:1-8. DOI:10.1016/j.exer.2014.11.006 · 3.02 Impact Factor
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    ABSTRACT: Interleukin (IL)-33 is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ+ and IL-17+ CD4+ T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5+ and IL-4+ CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization towards an alternatively-activated macrophage (M2) phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis.This article is protected by copyright. All rights reserved
    European Journal of Immunology 11/2014; 44(11). DOI:10.1002/eji.201444671 · 4.52 Impact Factor
  • Kurt Spiteri Cornish · Lucia Kuffova · John V Forrester
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    ABSTRACT: Diffuse subretinal fibrosis uveitis (DUS) syndrome is a rare form of granulomatous multifocal choroiditis (MFC) characterised by enlarging areas of subretinal fibrosis (SRF) which coalesce with subsequent macular involvement and visual loss. First described by Palestine, DUS carries a poor visual prognosis despite use of high-dose corticosteroids and systemic immunosuppression. We report two cases of bilateral DUS successfully treated with rituximab. We believe given the B-cell predominance in the underlying pathogenesis of the disease, rituximab should be considered first line in the management of this potentially devastating disease.
    British Journal of Ophthalmology 05/2014; 99(2). DOI:10.1136/bjophthalmol-2013-304686 · 2.81 Impact Factor
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    ABSTRACT: To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37.
    05/2014; 3(3):4. DOI:10.1167/tvst.3.3.4
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  • Zexu Dang · Lucia Kuffová · Lei Liu · John V Forrester
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    ABSTRACT: The transport of antigen to the secondary lymphoid tissue is a central component in the initiation of the adaptive immune response. The mechanism of antigen delivery to the DLN from the avascular cornea has not been fully explored. Previous studies in the mouse have shown that cell-associated corneal antigen is delivered within 6 h to the eye draining SM DLN via DCs and macrophages. In this study, we used a system in which antigen and the processed p-MHCII complexes derived from the antigen could be tracked in vivo. We report that soluble antigen applied to an abraded cornea in the mouse is transported rapidly (within 30 min) to the SM DLN, where a proportion is taken up by resident DCs and presented as p-MHCII complexes, while the larger part is cleared by 8 h. At a later time, a second wave of antigen transport in migratory DCs enters the DLN and participates in further continued antigen presentation. With the use of an antigen-specific TCR transgenic mouse system, we demonstrate that T cell activation does not occur during the early stages of soluble antigen delivery to LN, even though p-MHCII complexes are generated. Antigen-specific T cell activation occurs in the later, presumed cell-associated phase but requires codelivery of a "danger" signal, such as the TLR ligand CpG. We suggest that the early delivery of soluble antigen is more likely to induce T cell nonresponsiveness (anergy) unless presented in the context of an innate-immune cell activation (danger) signal.
    Journal of leukocyte biology 12/2013; 95(3). DOI:10.1189/jlb.0612294 · 4.99 Impact Factor
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    ABSTRACT: Protein-tyrosine phosphatase-1B (PTP1B) negatively regulates insulin and leptin signalling, rendering it an attractive drug target for treatment of obesity-induced insulin resistance. However, some studies suggest caution when targeting macrophage-PTP1B, due to its potential anti-inflammatory role. We assessed the role of macrophage-PTP1B in inflammation and whole body metabolism using myeloid-cell (LysM)-PTP1B-knockout mice (LysM-PTP1B). LysM-PTP1B mice were protected against LPS-induced endotoxemia and hepatic damage, associated with decreased pro-inflammatory cytokine secretion in vivo. In vitro, LPS-treated LysM-PTP1B bone-marrow-derived-macrophages (BMDMs) displayed increased IL10 mRNA expression, with a concomitant decrease in TNFα mRNA levels. These anti-inflammatory effects were associated with increased LPS- and IL10-induced STAT3 phosphorylation in LysM-PTP1B BMDMs. Chronic inflammation induced by high-fat (HF)-feeding led to equally beneficial effects of macrophage-PTP1B deficiency; LysM-PTP1B mice exhibited improved glucose- and insulin tolerance, protection against LPS-induced hyperinsulinemia, decreased macrophage infiltration into adipose tissue and decreased liver damage. HF-fed LysM-PTP1B mice had increased basal and LPS-induced IL10 levels, associated with elevated splenic STAT3 phosphorylation, IL10 mRNA expression, and expansion of cells expressing myeloid markers. These increased IL10 levels negatively correlated with circulating insulin and ALT levels. Our studies implicate myeloid-PTP1B in negative regulation of STAT3/IL10-mediated signalling, highlighting its inhibition as a potential anti-inflammatory and anti-diabetic target in obesity.
    Diabetes 11/2013; 63(2). DOI:10.2337/db13-0885 · 8.47 Impact Factor
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    ABSTRACT: We have previously shown that recombinant human collagen can be cross-linked with N-(3 - Dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) to fabricate transparent hydrogels possessing the shape and dimensions of the human cornea. These corneal implants have been tested in a Phase I human clinical study. Although these hydrogels successfully promoted corneal tissue and nerve regeneration, during manufacture of the implants, the gelling kinetics were difficult to control. An alternative carbodiimide capable of producing hydrogels of similar characteristics as EDC in terms of strength and biocompatibility, but with a longer gelation time would be a desirable alternative. Here, we compared the cross-linking kinetics and properties of hydrogels cross-linked with a sterically bulky carbodiimide, N-cyclohexyl-N'-(2-morpholinethyl) carbodiimide metho-p-toluenesulfonate (CMC), with that of EDC. CMC cross-linking was possible at ambient temperature while the EDC reaction was too rapid to control and had to be carried out at low temperatures. The highest tensile strength obtained using optimized formulations were equivalent, although CMC cross-linked hydrogels were found to be stiffer. The collagenase resistance of CMC cross-linked hydrogels was superior to that of EDC crosslinked hydrogels while biocompatibility was similar. We are also able to substitute porcine collagen with recombinant human collagen and show that the in vivo performance of both resulting hydrogels as full thickness corneal implants is comparable in a mouse model of anorthotopic corneal graft. In conclusion, CMC is a viable alternative to EDC as a cross-linker for collagen-based biomaterials for use as corneal implants, and potentially for use in other tissue engineering applications.
    Acta biomaterialia 04/2013; 9(8). DOI:10.1016/j.actbio.2013.04.014 · 5.68 Impact Factor
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    Chen M · Hombrebueno JR · Luo C · Penalva R · Zhao J · Colhoun L · Pandi SP · Forrester JV · Xu H
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    ABSTRACT: Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation) have an early onset (6 weeks) of spontaneous retinal degeneration. In this study, we generated CCL2-/-CX3CR1GFP/GFP mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2-/-CX3CR1GFP/GFP mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17,60% of 12-month, and 30,100% of 18-month CCL2-/-2CX3CR1GFP/GFP mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE) and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL22/ 2CX3CR1GFP/GFP mice respectively, but not in wild-type mice. All CCL22/2CX3CR1GFP/GFP mice exposed to extra-light (~800lux, 6 h/day, 6 months) developed patches of retinal atrophy, and only 20–25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL) of area related to photoreceptor loss in CCL22-/-CX3CR1GFP/GFP mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL22/2CX3CR1GFP/GFP mice. GABA expression was reduced in the inner retina of aged CCL2-/-CX3CR1GFP/GFP mice. Significantly increased Mu¨ ller glial and microglial activation was observed in CCL22/2CX3CR1GFP/GFP mice compared to age-matched WT mice. Macrophages from CCL2-/-CX3CR1GFP/GFP mice were less phagocytic, but expressed higher levels of iNOS, IL-1b, IL-12 and TNF-a under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2-/-CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy.
    PLoS ONE 04/2013; 8(4):e61381. · 3.23 Impact Factor
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    ABSTRACT: Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation) have an early onset (6 weeks) of spontaneous retinal degeneration. In this study, we generated CCL2(-/-)CX3CR1(GFP/GFP) mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2(-/-)CX3CR1(GFP/GFP) mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17∼60% of 12-month, and 30∼100% of 18-month CCL2(-/-)CX3CR1(GFP/GFP) mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE) and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL2(-/-)CX3CR1(GFP/GFP) mice respectively, but not in wild-type mice. All CCL2(-/-)CX3CR1(GFP/GFP) mice exposed to extra-light (∼800lux, 6 h/day, 6 months) developed patches of retinal atrophy, and only 20-25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL) of area related to photoreceptor loss in CCL2(-/-)CX3CR1(GFP/GFP) mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL2(-/-)CX3CR1(GFP/GFP) mice. GABA expression was reduced in the inner retina of aged CCL2(-/-)CX3CR1(GFP/GFP) mice. Significantly increased Müller glial and microglial activation was observed in CCL2(-/-)CX3CR1(GFP/GFP) mice compared to age-matched WT mice. Macrophages from CCL2(-/-)CX3CR1(GFP/GFP) mice were less phagocytic, but expressed higher levels of iNOS, IL-1β, IL-12 and TNF-α under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2/CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy.
    PLoS ONE 04/2013; 8(4):e61381. DOI:10.1371/journal.pone.0061381 · 3.23 Impact Factor
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    ABSTRACT: Since the plasticity and the potential for re-programming cells has become widely accepted, there has been great interest in cell-based therapies. These are being applied to a range of diseases, not least ocular diseases, where it is assumed that there is a reduced risk of immune rejection although this may be more perceived than real. There are two broad classes of cell- based therapies: those aimed at restoring structure and function of specific tissues and cells; and those directed towards restoring immunological homeostasis by controlling the damaging effects of inflammatory disease. Stem cells of all types represent the first group and prototypically have been used with the aim of regenerating failing cells. In contrast, immune cells have been suggested as potential modulators of inflammation. However, there is functional overlap in these two applications, with some types of stem cells, such as mesenchymal stem cells, demonstrating a potent immunomodulatory effect. This review summarises recent information on cell based therapies for ocular disease, with special emphasis on ocular inflammatory disease, and explores current uses, potential and limitations.
    Progress in Retinal and Eye Research 03/2013; DOI:10.1016/j.preteyeres.2013.02.002 · 9.90 Impact Factor
  • John V Forrester
    Investigative ophthalmology & visual science 03/2013; 54(3):2258-65. DOI:10.1167/iovs.12-10897 · 3.66 Impact Factor

Publication Stats

10k Citations
1,349.25 Total Impact Points

Institutions

  • 1987–2015
    • University of Aberdeen
      • • Institute of Medical Sciences
      • • Division of Applied Medicine
      • • School of Engineering
      Aberdeen, Scotland, United Kingdom
  • 1992–2011
    • University of Western Australia
      • • Lions Eye Institute
      • • School of Anatomy, Physiology and Human Biology
      Perth City, Western Australia, Australia
  • 2008
    • Charité Universitätsmedizin Berlin
      • Department of Ophthalmology
      Berlín, Berlin, Germany
  • 2007
    • Royal Perth Hospital
      Perth City, Western Australia, Australia
  • 2005
    • Charles University in Prague
      Praha, Praha, Czech Republic
  • 2003
    • Moorfields Eye Hospital NHS Foundation Trust
      Londinium, England, United Kingdom
    • University of Bristol
      Bristol, England, United Kingdom
  • 2002
    • VU University Amsterdam
      • Department of Molecular Cell Biology and Immunology
      Amsterdamo, North Holland, Netherlands
  • 2000
    • University of Birmingham
      • School of Mathematics
      Birmingham, ENG, United Kingdom
  • 1981–1987
    • University of Glasgow
      Glasgow, Scotland, United Kingdom