M M Harnett

University of Glasgow, Glasgow, Scotland, United Kingdom

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Publications (151)736.37 Total impact

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    ABSTRACT: ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage. SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria. SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition. SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate. © The Author(s) 2015.
    Lupus 06/2015; DOI:10.1177/0961203315591031 · 2.48 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2(-/-) mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Journal of Autoimmunity 05/2015; 376. DOI:10.1016/j.jaut.2015.04.005 · 7.02 Impact Factor
  • M A Pineda, R J Eason, M M Harnett, W Harnett
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    ABSTRACT: Evidence from human studies suggests that parasitic worm infection can protect humans against rheumatoid arthritis (RA) and this idea is strengthened by data generated in model systems. Although therapeutic use of parasitic worms is currently being explored, there are obvious benefits in pursuing drug development through identification and isolation of the 'active ingredients'. ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae, which we have found to protect against the development of collagen-induced arthritis (CIA) in mice. ES-62 activity is dependent on the inflammatory phenotype of the local environment and protection arises via inhibition of Th17- and γδT cell-dependent IL-17 production. At the same time, NK and NK T cell IL-17 production is left intact, and such selectivity suggests that ES-62 might make a particularly attractive therapeutic for RA. However, as a potentially immunogenic protein, ES-62 is unsuitable for development as a drug. Nevertheless, ES-62 activity is dependent on covalently attached phosphorylcholine (PC) residues and we have therefore produced a library of PC-based drug-like ES-62 small-molecule analogues (SMAs) as an alternative therapeutic strategy. Screening this library, we have found an ES-62 SMA that mirrors ES-62 in protecting against CIA and by the same IL-17-dependent mechanism of action. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    Lupus 04/2015; 24(4-5):400-11. DOI:10.1177/0961203314560004 · 2.48 Impact Factor
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    ABSTRACT: ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following administration before oxazolone sensitisation and after oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered following challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed. Copyright © 2015. Published by Elsevier Inc.
    Experimental Parasitology 03/2015; DOI:10.1016/j.exppara.2015.03.025 · 1.86 Impact Factor
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    ABSTRACT: ES-62 is an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae. Accelerated atherosclerosis frequently occurs in systemic lupus erythematosus (SLE), resulting in substantial cardiovascular morbidity and mortality. We examined the effects of ES-62 in the gld.apoE(-/-) mouse model of this condition. Treatment with ES-62 did not substantially modulate renal pathology but caused decreased anti-nuclear autoantibody levels. Moreover, a striking 60% reduction in aortic atherosclerotic lesions was observed, with an associated decrease in macrophages and fibrosis. We believe that these latter findings constitute the first example of a defined parasitic worm product with therapeutic potential in atherosclerosis: ES-62-based drugs may represent a novel approach to control accelerated atherosclerosis in SLE. Copyright © 2015. Published by Elsevier Ltd.
    International Journal for Parasitology 02/2015; 45(4). DOI:10.1016/j.ijpara.2014.12.006 · 3.40 Impact Factor
  • M. A. Pineda, W. Harnett, M. M. Harnett
    Immunology 12/2014; 143:57-57. · 3.74 Impact Factor
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    ABSTRACT: Objective. The Hygiene Hypothesis suggests that parasitic helminths (worms) protect against development of autoimmune disease as a serendipitous side-effect of worm-derived immunomodulators that concomitantly promote parasite survival and limit host pathology. We therefore investigated whether ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, protects against kidney damage, in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE).Methods. MRL/Lpr mice progressively produce high levels of autoantibodies and the resultant deposition of immune-complexes drives kidney pathology. The effects of ES-62 on disease progression were assessed by measurement of proteinuria and kidney histology, as well as by determination of anti-nuclear antibody (ANA) and cytokine levels and flow cytometric analysis of relevant cellular populations.Results. ES-62 restores the disrupted effector:regulatory B cell balance in MRL/Lpr mice, acting to inhibit plasmablast differentiation with consequent reduction in ANA production and immune complex and C3a deposition in the kidneys. Moreover, by reducing IL-22 production, ES-62 may desensitise downstream effector mechanisms of kidney pathogenesis. Highlighting the therapeutic importance of resetting B cell responses, adoptive transfer of purified splenic B cells from ES-62-treated MRL/Lpr mice mimics the protection afforded by the helminth product. Mechanistically, this reflects downregulation of MyD88 expression by B cells and also kidney cells, resulting in inhibition of pathogenic crosstalk amongst TLR-, C3a- and immune complex-mediated effector mechanisms.Conclusion. This study provides the first demonstration of protection against pathology by a parasitic worm-derived immunomodulator in a model of SLE and suggests therapeutic potential for drugs based on ES-62 mechanism of action. This article is protected by copyright. All rights reserved.
    12/2014; 67(4). DOI:10.1002/art.39004
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    ABSTRACT: ES-62 is a phosphorylcholine (PC)-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that acts to modulate the host immune response to promote the establishment of chronic helminth infection. Reflecting its anti-inflammatory actions, we have previously reported that ES-62 protects mice from developing Collagen-Induced Arthritis (CIA): thus, as this helminth-derived product may exhibit therapeutic potential in Rheumatoid Arthritis (RA), it is important to understand the protective immunoregulatory mechanisms triggered by ES-62 in this model in vivo. We have established to date that ES-62 acts by downregulating pathogenic Th17/IL-17-mediated responses and upregulating the regulatory cytokine IL-10. In addition, our studies have identified that IL-22, another member of the IL-10 family of cytokines, exerts dual pathogenic and protective roles in this model of RA with ES-62 harnessing the cytokine’s inflammation-resolving and tissue repair properties in the joint during the established phase of disease. Here, we discuss the counter-regulatory roles of IL-22 in the murine model of CIA and present additional novel data showing that ES-62 selectively induces γδ T cells with the capacity to induce IL-22 production and that gd T cells with the capacity to produce IL-22, but not IL-17, induced during CIA can be identified by their expression of TLR4. Moreover, we also show that treatment of mice undergoing CIA with the active PC moiety of ES-62, in the form of PC conjugated to BSA, is not only sufficient to mimic the ES-62-dependent suppression of pathogenic IL-17 responses shown previously but also that of the IL-22 and IL-10 up-regulation observed with the parasitic worm product during CIA. These findings not only reinforce the potential of IL-22, firstly described as a Th17-related pro-inflammatory cytokine, as a protective factor in arthritis but also suggest that drugs based on the PC moiety found in ES-62 may be able to harness the joint-protecting activities of IL-22 therapeutically.
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    ABSTRACT: ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, exhibits anti-inflammatory properties by virtue of covalently attached phosphorylcholine (PC) moieties. Screening of a library of ES-62 PC-based small molecule analogues (SMAs) revealed that two compounds, termed 11a and 12b, mirrored the helminth product both in inhibiting mast cell degranulation and cytokine responses in vitro and in preventing ovalbumin-induced Th2-associated airway inflammation and eosinophil infiltration of the lungs in mice. Furthermore, the two SMAs inhibited neutrophil infiltration of the lungs when administered therapeutically. ES-62-SMAs 11a and 12b thus represent starting points for novel drug development for allergies such as asthma.
    International Journal for Parasitology 06/2014; 44(9). DOI:10.1016/j.ijpara.2014.05.001 · 3.40 Impact Factor
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    ABSTRACT: Objective. The parasitic worm-derived immunomodulator, ES-62 protects against disease in the mouse collagen-induced arthritis (CIA) model of Rheumatoid Arthritis (RA) by suppressing pathogenic IL-17 responses. The Th17-associated cytokine, IL-22 also appears to play a pathogenic role in autoimmune arthritis, particularly in promoting pro-inflammatory responses by synovial fibroblasts (SF) and osteoclastogenesis. We therefore investigated whether the protection from joint damage afforded by ES-62 also reflected suppression of IL-22. Methods. The role(s) of IL-22 were assessed by investigating the effects of neutralising anti-IL-22 antibodies and rIL-22 on pro-inflammatory cytokine production, synovial fibroblast responses and joint damage in mice with CIA, exposed to ES-62 or not. Results: Neutralisation of IL-22 during the initiation phase abrogated CIA whilst administration of rIL-22 enhanced synovial fibroblast responses and exacerbated joint pathology. By contrast, after disease onset, anti-IL-22 did not suppress progression; rather, administration of rIL-22 promoted resolution of inflammation. Consistent with these late anti-inflammatory effects, the protection afforded by ES-62 was associated with elevated levels of IL-22 in the serum and joints that reflected a desensitisation of the synovial fibroblast responses. Moreover, neutralisation of IL-22 during the late effector stage of disease prevented ES-62-mediated desensitisation of synovial fibroblast responses and protection against CIA. Conclusion: IL-22 plays a dual role in CIA, being pathogenic during the initiation phase whilst acting to resolve inflammation and joint damage during established disease. Harnessing of the tissue repair properties of IL-22 by ES-62 highlights the potential for joint-targeted therapeutic modulation of SF responses and consequent protection against bone damage in RA. © 2014 American College of Rheumatology.
    06/2014; 66(6). DOI:10.1002/art.38392
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    ABSTRACT: Filarial nematodes cause long-term infections in hundreds of millions of people. A significant proportion of those affected develop a number of debilitating health problems but, remarkably, such infections are often unnoticed for many years. It is well known that parasitic worms modulate, yet do not completely inhibit, host immunological pathways, promoting their survival by limiting effective immune mechanisms. Such immunoregulation largely depends on molecules released by the worms, termed excretory-secretory products (ES). One of these products is the molecule ES-62, which is actively secreted by the rodent filarial nematode Acanthocheilonema viteae. ES-62 has been shown to exert anti-inflammatory actions thorough its phosphorylcholine (PC)-containing moiety on a variety of cells of the immune system, affecting intracellular signalling pathways associated with antigen receptor- and TLR-dependent responses. We summarise here how ES-62 modulates key signal transduction elements and how such immunomodulation confers protection to animals subjected to certain experimental models of inflammatory disease. Finally, we discuss recent results showing that it is possible to synthetize small molecule analogues (SMAs) that mimic the anti-inflammatory properties of ES-62, opening an exciting new drug development field in translational medicine.
    Molecular and Biochemical Parasitology 03/2014; DOI:10.1016/j.molbiopara.2014.03.003 · 2.24 Impact Factor
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    ABSTRACT: We have previously reported that ES-62, a molecule secreted by the parasitic filarial nematode Acanthocheilonema viteae, protects mice from developing collagen-induced arthritis (CIA). Together with increasing evidence that worm infection may protect against autoimmune conditions, this raises the possibility that ES-62 may have therapeutic potential in rheumatoid arthritis and hence, it is important to fully understand its mechanism of action. To this end, we have established to date that ES-62 protection in CIA is associated with suppressed T helper type 1 (Th1)/Th17 responses, reduced collagen-specific IgG2a antibodies and increased interleukin-10 (IL-10) production by splenocytes. IL-10-producing regulatory B cells have been proposed to suppress pathogenic Th1/Th17 responses in CIA: interestingly therefore, although the levels of IL-10-producing B cells were decreased in the spleens of mice with CIA, ES-62 was found to restore these to the levels found in naive mice. In addition, exposure to ES-62 decreased effector B-cell, particularly plasma cell, infiltration of the joints, and such infiltrating B cells showed dramatically reduced levels of Toll-like receptor 4 and the activation markers, CD80 and CD86. Collectively, this induction of hyporesponsiveness of effector B-cell responses, in the context of the resetting of the levels of IL-10-producing B cells, is suggestive of a modulation of the balance between effector and regulatory B-cell responses that may contribute to ES-62-mediated suppression of CIA-associated inflammation and inhibition of production of pathogenic collagen-specific IgG2a antibodies.
    Immunology 03/2014; 141(3):457-66. DOI:10.1111/imm.12208 · 3.74 Impact Factor
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    ABSTRACT: Parasitic worms are able to survive in their mammalian host for many years due to their ability to manipulate the immune response by secreting immunomodulatory products. It is increasingly clear that, reflecting the anti-inflammatory actions of such worm-derived immunomodulators, there is an inverse correlation between helminth infection and autoimmune diseases in the developing world. As the decrease in helminth infections due to increased sanitation has correlated with an alarming increase in prevalence of such disorders in industrialised countries, this "Hygiene Hypothesis" has led to the proposal that worms and their secreted products offer a novel platform for the development of safe and effective strategies for the treatment of autoimmune disorders. Here we review the anti-inflammatory effects of one such immunomodulator, ES-62 on innate and adaptive immune responses and the mechanisms it exploits to afford protection in the murine Collagen Induced Arthritis (CIA) model of rheumatoid arthritis (RA). As its core mechanism involves targeting of IL-17 responses, which despite being pathogenic in RA are important for combating infection, we discuss how its selective targeting of IL-17 production by Th17 and γδ T cells, whilst leaving that of CD49b+ Natural Killer (NK and NK T) cells intact, reflects the ability of helminths to modulate the immune system without immunocompromising the host. Exploiting helminth immunomodulatory mechanisms therefore offers the potential for safer therapies than current biologics, such as "IL-17 blockers", that are not able to discriminate sources of IL-17 and hence present adverse effects that limit their therapeutic potential.
    Clinical & Experimental Immunology 12/2013; DOI:10.1111/cei.12252 · 3.28 Impact Factor
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    ABSTRACT: In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases, and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that (11a) was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL1R transducer, MyD88. (11a) is thus a novel prototype for anti-inflammatory drug development.
    Journal of Medicinal Chemistry 11/2013; 56(24):9982-10002. DOI:10.1021/jm401251p · 5.48 Impact Factor
  • Article: Reply.
    William Harnett, Margaret M Harnett
    Arthritis & Rheumatology 02/2013; DOI:10.1002/art.37886 · 7.87 Impact Factor
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    ABSTRACT: ES-62, an immunomodulator secreted by filarial nematodes, exhibits therapeutic potential in mouse models of allergic inflammation, at least in part by inducing the desensitisation of Fc RI-mediated mast cell responses. However, in addition to their pathogenic roles in allergic and autoimmune diseases, mast cells are important in fighting infection, wound healing, and resolving inflammation, reflecting that mast cells exhibit a phenotypic and functional plasticity. We have therefore characterised the differential functional responses to antigen (via Fc RI) and LPS and their modulation by ES-62 of the mature peritoneal-derived mast cells (PDMC; serosal) and those of the connective tissue-like mast cells (CTMC) and the mucosal-like mast cells derived from bone marrow progenitors (BMMC) as a first step to produce disease tissue-targeted therapeutics based on ES-62 action. All three mast cell populations were rendered hyporesponsive by ES-62 and whilst the mechanisms underlying such desensitisation have not been fully delineated, they reflect a downregulation of calcium and PKC signalling. ES-62 also downregulated MyD88 and PKC in mucosal-type BMMC but not PDMC, the additional signals targeted in mucosal-type BMMC likely reflecting that these cells respond to antigen and LPS by degranulation and cytokine secretion whereas PDMC predominantly respond in a degranulation-based manner.
    Journal of Parasitology Research 02/2013; 2013:961268. DOI:10.1155/2013/961268
  • Verica Paunovic, Margaret M Harnett
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease in which imbalances in pro- and anti-inflammatory cytokines promote the induction of autoimmunity, inflammation and joint destruction. Methotrexate, the standard disease-modifying anti-rheumatic drug (DMARD), has shown a gradual loss of efficacy in a significant proportion of patients, probably due to the onset of drug resistance, and thus it was hoped that the development of biologics would revolutionise RA management. Even though biologics have improved the therapy of patients refractive to DMARDs, they require parenteral administration and may leave patients open to serious infection and cancer. Therefore, attention has also been focused on inhibitors of mitogen-activated protein kinases (MAPKs), signalling enzymes that play key roles in pathogenic cytokine production, and their downstream effector pathways, in order to create safe and effective oral drugs. This article therefore provides an overview of the structure and function of MAPKs and their role in the pathogenesis of RA as context to describing the advances in the development of specific, druggable MAPK inhibitors. Their potential as therapies in the management of RA is also discussed.
    Drugs 02/2013; 73(2). DOI:10.1007/s40265-013-0014-6 · 4.13 Impact Factor
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    ABSTRACT: We previously demonstrated inhibition of ovalbumin (OVA)-induced allergic airway hyper-responsiveness in the mouse using ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode, Acanthocheilonema viteae. This inhibition correlated with ES-62-induced mast cell desensitisation, although the degree to which this reflected direct targeting of mast cells remained unclear as suppression of the Th2 phenotype of the inflammatory response, as measured by eosinophilia and IL-4 levels in the lungs, was also observed. We now show that inhibition of the lung Th2 phenotype is reflected in ex vivo analyses of draining lymph node recall cultures and accompanied by a decrease in the serum levels of total and OVA-specific IgE. Moreover, ES-62 also suppresses the lung infiltration by neutrophils that is associated with severe asthma and is generally refractory to conventional anti-inflammatory therapies, including steroids. Protection against Th2-associated airway inflammation does not reflect induction of regulatory T cell (Treg) responses (there is no increased IL-10 or Foxp3 expression) but rather a switch in polarisation towards increased T-bet expression and IFNγ production. This ES-62-driven switch in the Th1/Th2 balance is accompanied by decreased IL-17 responses, a finding in line with reports that IFNγ and IL-17 are counter-regulatory. Consistent with ES-62 mediating its effects via IFNγ-mediated suppression of pathogenic Th2/Th17 responses, we found that neutralising anti-IFNγ antibodies blocked protection against airway inflammation in terms of pro-inflammatory cell infiltration, particularly by neutrophils and lung pathology. Collectively, these studies indicate that ES-62, or more likely small molecule analogues, could have therapeutic potential in asthma, in particular for those subtypes of patients (e.g. smokers, steroid-resistant) who are refractory to current treatments.
    International journal for parasitology 01/2013; 43(3-4). DOI:10.1016/j.ijpara.2012.12.001 · 3.40 Impact Factor
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    ABSTRACT: Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62. DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA. ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17-producing network, involving signaling between dendritic cells and γ/δ or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL-1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of γ/δ T cells and this was reflected by direct suppression of CD44 up-regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA.
    Arthritis & Rheumatology 10/2012; 64(10):3168-78. DOI:10.1002/art.34581 · 7.87 Impact Factor
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    ABSTRACT: Negative regulation of B cell activation by cognate immune complexes plays an important homeostatic role in suppressing B cell hyperactivity and preventing consequent autoimmunity. Immune complexes co-ligate the BCR and FcγRIIB resulting in both growth arrest and apoptosis. We now show that such apoptotic signalling involves induction and activation of p53 and its target genes, the pro-apoptotic Bcl-2 family members, Bad and Bid, as well as nuclear export of p53. Collectively, these events result in destabilisation of the mitochondrial and lysosomal compartments with consequent activation and interplay of executioner caspases and endosomal-derived proteases. In addition, the upregulation of Fas and FasL with consequent activation of caspase 8-dependent death receptor signalling is required to facilitate efficient apoptosis of B cells. Consistent with this role for Fas death receptor signalling, apoptosis resulting from co-ligation of the BCR and FcγRIIB is defective in B cells from Fas-deficient MRL/MpJ-Fas(lpr) mice. As these mice develop spontaneous, immune complex-driven lupus-like glomerulonephritis, targeting this FcγRIIB-mediated apoptotic pathway may therefore have novel therapeutic implications for systemic autoimmune disease.
    Journal of Autoimmunity 05/2012; 39(4). DOI:10.1016/j.jaut.2012.04.006 · 7.02 Impact Factor

Publication Stats

4k Citations
736.37 Total Impact Points

Institutions

  • 1993–2015
    • University of Glasgow
      • • Institute of Infection, Immunity and Inflammation
      • • BHF Glasgow Cardiovascular Research Centre
      • • Division of Immunology
      • • Division of Biochemistry
      Glasgow, Scotland, United Kingdom
  • 1993–2009
    • University of Strathclyde
      • • Strathclyde Institute of Pharmacy and Biomedical Sciences
      • • Department of Immunology
      Glasgow, Scotland, United Kingdom
  • 1998
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1987–1992
    • MRC National Institute for Medical Research
      Londinium, England, United Kingdom