A5103473467- IL-33, ST2, and ILC Pathways
- Eosinophilic Esophagitis
- Asthma and respiratory diseases
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Pediatric health and respiratory diseases
- Immune Response and Inflammation
- Respiratory and Cough-Related Research
- T-cell and B-cell Immunology
- Genetic Associations and Epidemiology
- Allergic Rhinitis and Sensitization
- Genomics and Rare Diseases
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Immunodeficiency and Autoimmune Disorders
- vaccines and immunoinformatics approaches
- Psoriasis: Treatment and Pathogenesis
- Galectins and Cancer Biology
- Cytokine Signaling Pathways and Interactions
- Epigenetics and DNA Methylation
- Transgenic Plants and Applications
- Systemic Lupus Erythematosus Research
- Immunotherapy and Immune Responses
- Rheumatoid Arthritis Research and Therapies
- Telomeres, Telomerase, and Senescence
AstraZeneca (United Kingdom)
2019-2024
AstraZeneca (Brazil)
2020
Aimmune Therapeutics (United Kingdom)
2014-2019
University of Cambridge
1995-2018
PredictImmune
2018
Nanjing Medical University
2016
Hacettepe University
2011
Jenner Institute
2003
University of Dundee
1992
MRC Protein Phosphorylation and Ubiquitylation Unit
1992
Abstract Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution rare to disease remains relatively unexplored. The UK Biobank contains detailed phenotypic data linked medical records for approximately 500,000 participants, offering an unprecedented opportunity evaluate effect variation on a broad collection traits 1,2 . Here we study relationships between protein-coding and 17,361 binary 1,419 quantitative phenotypes...
Abstract In response to infections and irritants, the respiratory epithelium releases alarmin interleukin (IL)-33 elicit a rapid immune response. However, little is known about regulation of IL-33 following its release. Here we report that biological activity at receptor ST2 rapidly terminated in extracellular environment by formation two disulphide bridges, resulting an extensive conformational change disrupts binding site. Both reduced (active) bonded (inactive) forms can be detected lung...
Integrating human genomics and proteomics can help elucidate disease mechanisms, identify clinical biomarkers discover drug targets1-4. Because previous proteogenomic studies have focused on common variation via genome-wide association studies, the contribution of rare variants to plasma proteome remains largely unknown. Here we associations between protein-coding 2,923 protein abundances measured in 49,736 UK Biobank individuals. Our variant-level exome-wide study identified 5,433...
Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and promising target for treatment of disease. Here, we describe the identification tozorakimab (MEDI3506), potent, human anti-IL-33 monoclonal antibody, which inhibit reduced IL-33 (IL-33red) oxidized (IL-33ox) activities through distinct serum-stimulated 2 (ST2) receptor advanced glycation end products/epidermal growth factor (RAGE/EGFR complex) signalling...
The paired helical filament (PHF), which comprises the major fibrous element of neurofibrillary tangle Alzheimer's disease, is composed abnormally phosphorylated microtubule‐associated protein tau. Here we show that p42 MAP kinase phosphorylates recombinant tau and converts it to a form similar PHF Of serine/threonine phosphatases found in mammalian tissues only phosphatase 2A (PP2A) could dephosphorylate this manner, with PP2A 1 being most effective enzyme.
Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in interleukin-33 (IL-33) pathway. Here, we identified H. Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant...
Mast cell localization within the airway smooth muscle (ASM)-bundle plays an important role in development of hyper-responsiveness (AHR). Genomewide association studies implicate 'alarmin' IL-33 asthma, but its mast cell-ASM interactions is unknown.We examined expression and functional bronchial biopsies patients with without ex vivo ASM, cells, cocultured cells a mouse model system.IL-33 protein was assessed human tissue from 9 healthy controls, 18 mild-to-moderate 12 severe asthmatic by...
BackgroundExacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous.ObjectiveWe sought to investigate the sputum cellular, mediator, microbiome profiles both COPD exacerbations.MethodsPatients with severe or moderate-to-severe were recruited prospectively a single center. Sputum mediators available in 32 asthmatic patients 73 assessed at exacerbation. Biologic clusters determined by using factor cluster analyses on panel mediators. Patterns clinical...
Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases.We sought to determine, in terms of their sputum cellular mediator profiles, the extent which they represent distinct or overlapping conditions supporting either "British" "Dutch" hypotheses airway pathogenesis.We compared clinical physiological characteristics mediators between 86 subjects with severe asthma 75 moderate-to-severe COPD. Biological subgroups were determined using factor cluster analyses on 18...
Group-2 innate lymphoid cells (ILC2), type-2 cytokines, and eosinophils have all been implicated in sustaining adipose tissue homeostasis. However, the interplay between stroma adipose-resident immune is less well understood. We identify that white tissue–resident multipotent stromal (WAT-MSCs) can act as a reservoir for IL-33, especially after cell stress, but also provide additional signals ILC2. Indeed, we demonstrate WAT-MSCs support ICAM-1–mediated proliferation activation of...
Interleukin (IL)-33 is an IL-1 family alarmin released from damaged epithelial and endothelial barriers to elicit immune responses allergic inflammation via its receptor ST2. Serine proteases neutrophils, mast cells cytotoxic lymphocytes have been proposed process the N-terminus of IL-33 enhance activity. Here we report that processing full length can occur in mice deficient these cell protease activities. We sought alternative mechanisms for proteolytic activation discovered exogenous...
Abstract Dysregulated hematopoiesis occurs in several chronic inflammatory diseases, but it remains unclear how hematopoietic stem cells (HSCs) the bone marrow (BM) sense peripheral inflammation and contribute to tissue damage arthritis. Here, we show HSC gene expression program is biased toward myelopoiesis differentiation skewed granulocyte-monocyte progenitors (GMP) during joint intestinal experimental spondyloarthritis (SpA). GM-CSF-receptor increased on HSCs multipotent progenitors,...
Background Epithelial damage, repair and remodelling are critical features of chronic airway diseases including obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation IL-33 to a non-ST2-binding form (IL-33 ox ) is thought limit activity. We investigated whether has functional activities that independent ST2 in the epithelium. Methods In vitro epithelial damage assays...
Telomeres protect chromosome ends from damage and their length is linked with human disease aging. We developed a joint telomere metric, combining quantitative PCR whole-genome sequencing measurements 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of length. Exome-wide rare-variant gene-level collapsing association studies identified 64 variants 30 genes significantly associated length, including allelic series...
This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti-interleukin (IL)-33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data.
IL-13 is a pleiotropic Th2 cytokine considered likely to play pivotal role in asthma. Here we describe the preclinical vitro and vivo characterization of CAT-354, an IL-13-neutralizing IgG4 monoclonal antibody (mAb), currently clinical development.In potency, specificity species selectivity CAT-354 was assayed TF-1 cells, human umbilical vein endothelial cells HDLM-2 cells. The ability modulate disease-relevant mechanisms tested measuring bronchial smooth muscle calcium flux induced by...
<h3>Objective</h3> Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)–GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for treatment of rheumatoid arthritis (RA). Therefore, we investigated cellular expression GM-CSFRα in RA synovial tissue and effects anti-GM-CSFRα antibody vitro vivo preclinical model RA. <h3>Methods</h3> We compared on macrophages positive CD68 or CD163 biopsy samples from patients with psoriatic (PsA) to...
The IL-33-ST2 pathway is an important initiator of type 2 immune responses. We previously characterised the HpARI protein secreted by model intestinal nematode Heligmosomoides polygyrus, which binds and blocks IL-33. Here, we identify H. polygyrus Binds Alarmin Receptor Inhibits (HpBARI) HpBARI_Hom2, both consist complement control (CCP) domains, similarly to immunomodulatory Hp-TGM proteins. HpBARI murine ST2, inhibiting cell surface detection preventing interactions, IL-33 responses in...
Tozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)‐33. IL‐33 broad‐acting epithelial “alarmin” cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first‐in‐human, phase I, randomized, double‐blind, placebo‐controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics (PKs), immunogenicity, target engagement, and pharmacodynamics (PDs) tozorakimab. was 3‐part study. In part 1, 56 healthy...
<h3>Background:</h3> Granulocyte–macrophage colony-stimulating factor (GM-CSF) has been implicated as an important mediator in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). However, expression GM-CSF its receptor airway samples COPD across severity needs to be further defined. <h3>Methods:</h3> Sputum was measured 18 control subjects, 45 subjects with 47 COPD. Enumeration GM-CSF+ cells bronchial submucosa smooth muscle bundle performed 29 36 10...
Immunoglobulin E (IgE) plays a key role in allergic asthma and is clinically validated target for monoclonal antibodies. Therapeutic anti-IgE antibodies block the interaction between IgE Fc epsilon (Fcε) receptor, which eliminates or minimizes phenotype but does not typically curtail ongoing production of by B cells. We generated high-affinity (MEDI4212) that have potential to both neutralize soluble eliminate IgE-expressing B-cells through antibody-dependent cell-mediated cytotoxicity....
Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived promotes their differentiation into RPM precursors, pre-RPMs. However, requirements mature RPMs remain unknown. Here, we have demonstrated that interleukin (IL)-33 associated with erythrocytes co-cooperated heme promote generation through activation MyD88 adaptor protein ERK1/2 kinases downstream IL-33...
Abstract Idiopathic Pulmonary Fibrosis (IPF) is a devastating form of respiratory disease with life expectancy 3–4 years. Inflammation, epithelial injury and myofibroblast proliferation have been implicated in initiation and, recently, epithelial-fibroblastic crosstalk has identified as central driver. However, the ability to interrogate this limited due absence vitro models that mimic physiological conditions. To investigate IPF dysregulated cross-talk, primary normal human bronchial (NHBE)...
In this study, we used in vitro protein evolution with ribosome and phage display to optimize the affinity of a human IL-13-neutralizing antibody, therapeutic candidate for treatment asthma, >150-fold 81 pM by using affinity-driven stringency selections. Simultaneously, antibody potency inhibit IL-13-dependent proliferation cell-based functional assay increased 345-fold an IC50 229 pM. The panoply different optimized sequences resulting from complementarity-determining region-targeted...