122 results found
Motedayen Aval L, Pease JE, Sharma R, et al., 2020, Challenges and opportunities in the clinical development of STING agonists for cancer immunotherapy, Journal of Clinical Medicine, Vol: 9, ISSN: 2077-0383
Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a 'cold' tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.
Matthews S, McKenna S, Malito E, et al., 2020, Structure, dynamics and immunogenicity of a catalytically inactive CXC Chemokine-degrading Protease SpyCEP from Streptococcus pyogenes, Computational and Structural Biotechnology Journal, Vol: 18, Pages: 650-660, ISSN: 2001-0370
Over 18 million disease cases and half a million deaths worldwide are estimated to be caused annually by Group A Streptococcus. A vaccine to prevent GAS disease is urgently needed. SpyCEP (Streptococcus pyogenes Cell-Envelope Proteinase) is a surface-exposed serine protease that inactivates chemokines, impairing neutrophil recruitment and bacterial clearance, and has shown promising immunogenicity in preclinical models. Although SpyCEP structure has been partially characterized, a more complete and higher resolution understanding of its antigenic features would be desirable prior to large scale manufacturing. To address these gaps and facilitate development of this globally important vaccine, we performed immunogenicity studies with a safety-engineered SpyCEP mutant, and comprehensively characterized its structure by combining X-ray crystallography, NMR spectroscopy and molecular dynamics simulations. We found that the catalytically-inactive SpyCEP antigen conferred protection similar to wild-type SpyCEP in a mouse infection model. Further, a new higher-resolution crystal structure of the inactive SpyCEP mutant provided new insights into this large chemokine protease comprising nine domains derived from two non-covalently linked fragments. NMR spectroscopy and molecular simulation analyses revealed conformational flexibility that is likely important for optimal substrate recognition and overall function. These combined immunogenicity and structural data demonstrate that the full-length SpyCEP inactive mutant is a strong candidate human vaccine antigen. These findings show how a multi-disciplinary study was used to overcome obstacles in the development of a GAS vaccine, an approach applicable to other future vaccine programs. Moreover, the information provided may also facilitate the structure-based discovery of small-molecule therapeutics targeting SpyCEP protease inhibition.
Anderson C, Patel P, Viney J, et al., 2020, A degradatory fate for CCR4 suggests a primary role in Th2 inflammation, Journal of Leukocyte Biology, Vol: 107, Pages: 455-466, ISSN: 0741-5400
CCR4 is the sole receptor for the chemokines CCL22 and CCL17. Clinical studies of asthmatic airways have shown levels of both ligands and CCR4+ Th2 cells to be elevated, suggestive of a role in disease. Consequently, CCR4 has aroused much interest as a potential therapeutic target and an understanding of how its cell surface expression is regulated is highly desirable. To this end, receptor expression, receptor endocytosis, and chemotaxis were assessed using transfectants expressing CCR4, CCR4+ human T cell lines, and human Th2 cells polarized in vitro. CCL17 and CCL22 drove rapid endocytosis of CCR4 in a dose‐dependent manner. Replenishment at the cell surface was slow and sensitive to cycloheximide, suggestive of de novo synthesis of CCR4. Constitutive CCR4 endocytosis was also observed, with the internalized CCR4 found to be significantly degraded over a 6‐h incubation. Truncation of the CCR4 C‐terminus by 40 amino acids had no effect on cell surface expression, but resulted in significant impairment of ligand‐induced endocytosis. Consequently, migration to both CCL17 and CCL22 was significantly enhanced. In contrast, truncation of CCR4 did not impair constitutive endocytosis or degradation, suggesting the use of alternative receptor motifs in these processes. We conclude that CCR4 cell surface levels are tightly regulated, with a degradative fate for endocytosed receptor. We postulate that this strict control is desirable, given that Th2 cells recruited by CCR4 can induce the further expression of CCR4 ligands in a positive feedback loop, thereby enhancing allergic inflammation.
Lloyd C, Puttur F, Denney L, et al., 2019, Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans, Science Immunology, Vol: 4, ISSN: 2470-9468
Group 2 innate lymphoid cells (ILC2s) are enriched in mucosal tissues (e.g., lung) and respond to epithelial cell–derived cytokines initiating type 2 inflammation. During inflammation, ILC2 numbers are increased in the lung. However, the mechanisms controlling ILC2 trafficking and motility within inflamed lungs remain unclear and are crucial for understanding ILC2 function in pulmonary immunity. Using several approaches, including lung intravital microscopy, we demonstrate that pulmonary ILC2s are highly dynamic, exhibit amoeboid-like movement, and aggregate in the lung peribronchial and perivascular spaces. They express distinct chemokine receptors, including CCR8, and actively home to CCL8 deposits located around the airway epithelium. Within lung tissue, ILC2s were particularly motile in extracellular matrix–enriched regions. We show that collagen-I drives ILC2 to markedly change their morphology by remodeling their actin cytoskeleton to promote environmental exploration critical for regulating eosinophilic inflammation. Our study provides previously unappreciated insights into ILC2 migratory patterns during inflammation and highlights the importance of environmental guidance cues in the lung in controlling ILC2 dynamics.
Goldblatt J, Hoffland A, Lawrenson RA, et al., 2019, A requirement for neutrophil glycosaminoglycans in chemokine:receptor interactions is revealed by the streptococcal protease SpyCEP, Journal of Immunology, Vol: 202, Pages: 3246-3255, ISSN: 1550-6606
To evade the immune system, the lethal human pathogen Streptococcus pyogenes produces SpyCEP, an enzyme that cleaves the C-terminal α-helix of CXCL8, resulting in markedly impaired recruitment of neutrophils to sites of invasive infection. The basis for chemokine inactivation by SpyCEP is, however, poorly understood, as the core domain of CXCL8 known to interact with CXCL8 receptors is unaffected by enzymatic cleavage. We examined the in vitro migration of human neutrophils and observed that their ability to efficiently navigate a CXCL8 gradient was compromised following CXCL8 cleavage by SpyCEP. SpyCEP-mediated cleavage of CXCL8 also impaired CXCL8-induced migration of transfectants expressing the human chemokine receptors CXCR1 or CXCR2. Despite possessing an intact N terminus and preserved disulfide bonds, SpyCEP-cleaved CXCL8 had impaired binding to both CXCR1 and CXCR2, pointing to a requirement for the C-terminal α-helix. SpyCEP-cleaved CXCL8 had similarly impaired binding to the glycosaminoglycan heparin. Enzymatic removal of neutrophil glycosaminoglycans was observed to ablate neutrophil navigation of a CXCL8 gradient, whereas navigation of an fMLF gradient remained largely intact. We conclude, therefore, that SpyCEP cleavage of CXCL8 results in chemokine inactivation because of a requirement for glycosaminoglycan binding in productive chemokine:receptor interactions. This may inform strategies to inhibit the activity of SpyCEP, but may also influence future approaches to inhibit unwanted chemokine-induced inflammation.
Pease JE, Williams TJ, 2018, Tipping the balance: a biased nanobody antagonist of CCR3 with potential for the treatment of eosinophilic inflammation, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 552-553, ISSN: 0091-6749
Evans RJ, Hernandez-Gil J, Mohri Z, et al., 2018, DEVELOPING NEW TARGETED MOLECULAR CONTRAST AGENTS FOR IMAGING INFLAMMATION OF VULNERABLE PLAQUES, Annual Meeting of the British-Atherosclerosis-Society (BAS), Publisher: OXFORD UNIV PRESS, Pages: S3-S4, ISSN: 0008-6363
Pontejo S, Murphy P, Pease JE, 2018, Chemokine subversion by human herpesviruses, Journal of Innate Immunity, Vol: 10, Pages: 465-478, ISSN: 1662-811X
Viruses use diverse molecular mechanisms to exploit and evade the immune response. Herpesviruses, in particular, encode functional chemokine and chemokine receptor homologs pirated from the host, as well as secreted chemokine-binding proteins with unique structures. Multiple functions have been described for herpesvirus chemokine components, including attraction of target cells, blockade of leukocyte migration, and modulation of gene expression and cell entry by the virus. Here we review current concepts about how human herpesvirus chemokines, chemokine receptors, and chemokine-binding proteins may be used to shape a proviral state in the host.
Amir NASBM, Mackenzie AE, Jenkins L, et al., 2018, Evidence for the existence of a CXCL17 receptor distinct from GPR35, Journal of Immunology, Vol: 201, Pages: 714-724, ISSN: 0022-1767
The chemokine CXCL17 is associated with the innate response in mucosal tissues but is poorly characterized. Similarly, the G protein-coupled receptor GPR35, expressed by monocytes and mast cells has been implicated in the immune response, although its precise role is ill-defined. A recent manuscript reported that GPR35 was able to signal in response to CXCL17, which we set out to confirm in this study. GPR35 was readily expressed using transfection systems, but failed to signal in response to CXCL17 in assays of β-arrestin recruitment, inositol phosphate production, calcium flux and receptor endocytosis. Similarly, in chemotaxis assays, GPR35 did not confirm sensitivity to a range of CXCL17 concentrations above that observed in the parental cell line. We subsequently employed a real time chemotaxis assay (TAXIScan) to investigate the migratory responses of human monocytes and the monocytic cell line, THP-1 to a gradient of CXCL17. Freshly isolated human monocytes displayed no obvious migration to CXCL17. Resting THP-1 cells showed a trend towards directional migration along a CXCL17 gradient, which was significantly enhanced by overnight incubation with the prostaglandin PGE2. However, pretreatment of PGE2-treated THP-1 cells with the well characterized GPR35 antagonist ML145 did not significantly impair their migratory responses to CXCL17 gradient. CXCL17 was susceptible to cleavage with chymase although this had little effect its ability to recruit THP-1 cells.We therefore conclude that GPR35 is unlikely to be a bona fide receptor for CXCL17 and that THP-1 cells express an as yet unidentified receptor for CXCL17.
Pease JE, Kausar F, Day A, et al., 2018, CXCL4/Platelet Factor 4 is an agonist of CCR1 and drives human monocyte migration, Scientific Reports, Vol: 8, ISSN: 2045-2322
Activated platelets release micromolar concentrations of the chemokine CXCL4/Platelet Factor-4. Deposition of CXCL4 onto the vascular endothelium is involved in atherosclerosis, facilitating monocyte arrest and recruitment by an as yet, unidentified receptor. Here, we demonstrate that CXCL4 drives chemotaxis of the monocytic cell line THP-1. Migration and intracellular calcium responses induced by CXCL4 were pertussis toxin-sensitive, implicating a GPCR in signal transduction. Cell treatment with chondroitinase ABC ablated migration, suggesting that cis presentation of CXCL4 by cell surface glycosaminoglycans to a GPCR is required. Although CXCR3 has been previously described as a CXCL4 receptor, THP-1 cells were unresponsive to CXCR3 ligands and CXCL4-induced migration was insensitive to a CXCR3 antagonist, suggesting that an alternative receptor is involved. Interrogating CC-class chemokine receptor transfectants, we unexpectedly found that CXCL4 could induce the migration of CCR1-expressing cells and also induce CCR1 endocytosis. Extending our findings to primary human monocytes, we observed that CXCL4 induced CCR1 endocytosis and could induce monocyte chemotaxis in a CCR1 antagonist-sensitive manner. Collectively, our data identify CCR1 as a previously elusive monocyte CXCL4 receptor and suggest that CCR1 may play a role in inflammation where the release of CXCL4 is implicated.
Pease JE, Williams T, 2018, Eosinophils on trial, Clinical and Experimental Allergy, Vol: 48, Pages: 490-492, ISSN: 0954-7894
Pease JE, 2016, Designing small molecule CXCR3 antagonists., Expert Opinion on Drug Discovery, Vol: 12, Pages: 159-168, ISSN: 1746-045X
INTRODUCTION: By virtue of its specificity for chemokines induced in Th1-associated pathologies, CXCR3 has attracted considerable attention as a target for therapeutic intervention. Several pharmacologically distinct small molecules with in vitro and in vivo potency have been described in the literature, although to date, none have shown efficacy in clinical trials. Areas covered: In this article, the author outlines the rationale for targeting CXCR3 and discusses the potential pitfalls in targeting receptors in poorly understood areas of chemokine biology. Furthermore, they cover emerging therapeutic areas outside of the 'traditional' Th1 arena in which CXCR3 antagonists may ultimately bear fruit. Finally, they discuss the design of recently discovered small molecules targeting CXCR3. Expert opinion: CXCR3 and its ligands appear to play roles in a multitude of diverse diseases in humans. In vitro studies suggest that CXCR3 is inherently 'druggable' and that potent, efficacious small molecules targeting CXCR3 antagonists will find a clinical niche. However, the well-trodden path to failure of small molecule chemokine receptor antagonists in clinical trials suggests that a cautious approach should be undertaken. Ideally, unequivocal evidence elucidating the precise role of CXCR3 should be obtained before targeting the receptor in a particular disease cohort.
Gela A, Kasetty G, Morgelin M, et al., 2016, Osteopontin binds and modulates functions of eosinophil-recruiting chemokines, Allergy, Vol: 71, Pages: 58-67, ISSN: 0105-4538
BackgroundAllergic asthma is characterized by eosinophilic inflammation and airway obstruction. There is also an increased risk of pulmonary infection caused by Streptococcus pneumoniae, in particular during severe asthma where high levels of the glycoprotein, osteopontin (OPN), are present in the airways. Eosinophils can be recruited by chemokines activating the receptor CCR3 including eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26, RANTES/CCL5, and MEC/CCL28. In addition to inducing chemotaxis, several of these molecules have defensin-like antibacterial properties. This study set out to elucidate the functional consequences of OPN binding to eosinophil-recruiting chemokines.MethodsAntibacterial activities of the chemokines were investigated using viable count assays and electron microscopy. Binding studies were performed by means of surface plasmon resonance. The potential interference of OPN with antibacterial, receptor-activating, and lipopolysaccharide-neutralizing abilities of these chemokines was investigated.ResultsWe found that OPN bound all eosinophil-recruiting chemokines with high affinity except for CCL5. The eosinophil-recruiting chemokines all displayed bactericidal activity against S. pneumoniae, but only CCL26 and CCL28 retained high antibacterial activity in the presence of sodium chloride at physiologic concentrations. Preincubation of the chemokines with OPN strongly inhibited their antibacterial activity against S. pneumoniae but did not affect their ability to activate CCR3. All chemokines investigated showed LPS-neutralizing activity that was impaired by OPN only in the case of CCL24.ConclusionsThe data suggest that OPN may impair host defense activities of the chemokines without affecting their eosinophil-recruiting properties. This could be one mechanism explaining the increased vulnerability to acquire pneumococcal infection in parallel with sustained allergic inflammation in asthma.
Anderson CA, Solari R, Pease JE, 2015, Biased agonism at chemokine receptors: obstacles or opportunities for drug discovery?, Journal of Leukocyte Biology, Vol: 99, Pages: 901-909, ISSN: 0741-5400
Gostner JM, Raggl E, Becker K, et al., 2015, Bisphenol A suppresses Th1-type immune response in human peripheral blood mononuclear cells in vitro, IMMUNOLOGY LETTERS, Vol: 168, Pages: 285-292, ISSN: 0165-2478
Denney L, Byrne A, Shea T, et al., 2015, Pulmonary epithelial cell-derived cytokine TGF-β1 Is a critical cofactor for enhanced innate lymphoid cell function, Immunity, Vol: 43, Pages: 945-958, ISSN: 1097-4180
Epithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell-derived cytokine TGF-β had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-β1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-β by expressing the receptor TGF-βRII and ILC chemoactivity was enhanced by TGF-β. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions.
Weiss M, Byrne AJ, Blazek K, et al., 2015, IRF5 controls both acute and chronic inflammation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 112, Pages: 11001-11006, ISSN: 0027-8424
Gela A, Kasetty G, Jovic S, et al., 2015, Eotaxin-3 exerts innate host defense activities that are modulated by mast cell proteases, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Solari R, Pease JE, 2015, Targeting chemokine receptors in disease - a case study of CCR4., European Journal of Pharmacology, Vol: 763, Pages: 167-177, ISSN: 0014-2999
Since their early 1990s, the chemokine receptor family of G protein-coupled receptors (GPCRs) has been the source of much pharmacological endeavour. Best known for their key roles in recruiting leukocytes to sites of infection and inflammation, the receptors present themselves as plausible drug targets for therapeutic intervention. In this article, we will focus our attention upon CC Chemokine Receptor Four (CCR4) which has been implicated in diseases as diverse as allergic asthma and lymphoma. We will review the discovery of the receptors and their ligands, their perceived roles in disease and the successful targeting of CCR4 by both small molecule antagonists and monoclonal antibodies. We will also discuss future directions and strategies for drug discovery in this field.
Blazek K, Eames HL, Weiss M, et al., 2015, IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1 beta production, Journal of Experimental Medicine, Vol: 212, Pages: 845-853, ISSN: 0022-1007
The most studied biological role of type III interferons (IFNs) has so far been their antiviral activity, but their role in autoimmune and inflammatory diseases remains largely unexplored. Here, we show that treatment with IFN-λ2/IL-28A completely halts and reverses the development of collagen-induced arthritis (CIA) and discover cellular and molecular mechanisms of IL-28A antiinflammatory function. We demonstrate that treatment with IL-28A dramatically reduces numbers of proinflammatory IL-17–producing Th17 and γδ T cells in the joints and inguinal lymph nodes, without affecting T cell proliferative responses or levels of anticollagen antibodies. IL-28A exerts its antiinflammatory effect by restricting recruitment of IL-1b–expressing neutrophils, which are important for amplification of inflammation. We identify neutrophils as cells expressing high levels of IFN-λ receptor 1 (IFNLR1)–IL-28 receptor α (IL28RA) and targeted by IL-28A. Our data highlight neutrophils as contributors to the pathogenesis of autoimmune arthritis and present IFN-λs or agonists of IFNLR1–IL28RA as putative new therapeutics for neutrophil-driven inflammation.IFN-λ1, -λ2, and -λ3 (or IL-29, IL-28A, and IL-28B, respectively) are members of the class II cytokine family evolutionarily related to both IL-10 and type I IFNs (IFN-α/β), and are collectively referred to as type III IFNs. IFN-λ1 (IL-29) is the main cytokine of this family produced in human cells, but it is not expressed in mice, where IL-28A/B play the major role. Despite the use of a distinct receptor complex, IFNLR1–IL28RA activates similar signaling pathways to that of the type I IFN receptor (Kotenko et al., 2003; Sheppard et al., 2003), and the most studied biological role of IFN-λs has so far been their antiviral activity. However, there is evidence to suggest that they may also have pleiotropic immune functions. IF
Nedjai B, Viney JM, Li H, et al., 2015, CXCR3 antagonist VUF10085 binds to an intrahelical site distinct from that of the broad spectrum antagonist TAK-779, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 172, Pages: 1822-1833, ISSN: 0007-1188
Gela A, Kasetty G, Jovic S, et al., 2015, Eotaxin-3 (CCL26) exerts innate host defense activities that are modulated by mast cell proteases, ALLERGY, Vol: 70, Pages: 161-170, ISSN: 0105-4538
Solari R, Pease JE, Begg M, 2015, "Chemokine receptors as therapeutic targets: Why aren't there more drugs?", EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 746, Pages: 363-367, ISSN: 0014-2999
Pease JE, Horuk R, 2014, Recent progress in the development of antagonists to the chemokine receptors CCR3 and CCR4, EXPERT OPINION ON DRUG DISCOVERY, Vol: 9, Pages: 467-483, ISSN: 1746-0441
Viney JM, Andrew DP, Phillips RM, et al., 2014, Distinct Conformations of the Chemokine Receptor CCR4 with Implications for Its Targeting in Allergy, JOURNAL OF IMMUNOLOGY, Vol: 192, Pages: 3419-3427, ISSN: 0022-1767
Bonner K, Pease JE, Corrigan CJ, et al., 2013, CCL17/thymus and activation-regulated chemokine induces calcitonin gene-related peptide in human airway epithelial cells through CCR4, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 132, Pages: 942-+, ISSN: 0091-6749
Pease JE, Williams TJ, 2013, Editorial: Are all eotaxins created equal?, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 94, Pages: 207-209, ISSN: 0741-5400
Hua R, Pease JE, Cheng W, et al., 2013, Human Labour is Associated with a Decline in Myometrial Chemokine Receptor Expression: The Role of Prostaglandins, Oxytocin and Cytokines, AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Vol: 69, Pages: 21-32, ISSN: 1046-7408
Pease J, Horuk R, 2012, Chemokine Receptor Antagonists, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 55, Pages: 9363-9392, ISSN: 0022-2623
Rummel PC, Arfelt KN, Baumann L, et al., 2012, Molecular requirements for inhibition of the chemokine receptor CCR8-probe-dependent allosteric interactions, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 167, Pages: 1206-1217, ISSN: 0007-1188
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