A5086439660- Immune Cell Function and Interaction
- SARS-CoV-2 and COVID-19 Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Asthma and respiratory diseases
- COVID-19 Clinical Research Studies
- Respiratory viral infections research
- S100 Proteins and Annexins
- Diabetes Management and Research
- Diabetes and associated disorders
- Immunotherapy and Immune Responses
- COVID-19 Impact on Reproduction
- Immune cells in cancer
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Immune Response and Inflammation
- Neonatal Respiratory Health Research
- T-cell and B-cell Immunology
- interferon and immune responses
- Invertebrate Immune Response Mechanisms
- Blood disorders and treatments
- Inflammation biomarkers and pathways
- Pancreatic function and diabetes
- Eosinophilic Disorders and Syndromes
- Respiratory Support and Mechanisms
- Influenza Virus Research Studies
- Eosinophilic Esophagitis
University of Cambridge
2012-2024
Addenbrooke's Hospital
2018-2023
National Institute for Health Research
2016-2018
Wellcome Trust
2016-2018
OSE Immunotherapeutics (France)
2018
Juvenile Diabetes Research Foundation
2017
Papworth Hospital
2014-2016
Texas A&M University
2015
Abstract Neutrophils play a central role in the innate immune response and critical bacterial killing. Most studies of neutrophil function have been conducted under conditions ambient oxygen, but inflamed sites where neutrophils operate may be extremely hypoxic. Previous indicate that sense respond to hypoxia via ubiquitous prolyl hydroxylase/hypoxia-inducible factor pathway this can signal for enhanced survival. In current study, human were shown upregulate hypoxia-inducible...
Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting immune response following infection regulate autoreactive effector (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility T1D causes alterations IL-2 pathway, a finding that supports cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses activate...
The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses degranulation are unknown.Following exposure (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or...
Immune cells face constant changes in their microenvironment, which requires rapid metabolic adaptation. In contrast to neutrophils, are known rely near exclusively on glycolysis, the profile of human eosinophils has not been characterized. Here, we assess key parameters peripheral blood-derived using real-time extracellular flux analysis measure acidification rate and oxygen consumption rate, compare these neutrophils. Using this methodology, demonstrate that neutrophils have a similar...
BACKGROUND. Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development autoimmunity pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance immunosuppressive functions. Using a response-adaptive design, we aimed determine optimal regimen aldesleukin (recombinant human IL-2) physiologically enhance Tregs while limiting expansion Teffs.
There are limited effective prophylactic/early treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral entry requires spike protein binding to the angiotensin-converting enzyme-2 receptor and cleavage by transmembrane serine protease (TMPRSS2), a cell surface protease. Targeting of TMPRSS2 either androgen blockade or direct inhibition is in clinical trials early SARS-CoV-2
Inflamed environments are typically hypercellular, rich in pro-inflammatory cytokines, and profoundly hypoxic. While the effects of hypoxia on neutrophil longevity function have been widely studied, little is known about consequences this stimulus eosinophils.We sought to investigate several key aspects eosinophil biology, namely secretion, survival, their sensitivity glucocorticosteroids (GCS), agents that normally induce apoptosis.Eosinophils derived from patients with asthma/atopy or...
To date many clinical studies aim to increase the number and/or fitness of CD4+ CD127lowCD25+ regulatory T cells (Tregs) in vivo harness their potential context treating autoimmune disease. Here, we sought define phenotype and function Tregs expressing highest levels IL-6 receptor (IL-6R). We have identified a population TIGIT− distinguished by elevated IL-6R expression that lacked HELIOS, showed higher CTLA-4 expression, displayed increased suppressive capacity compared IL-6RhiTIGIT+ Tregs....
Abstract Background Pulmonary ionocytes have been identified in the airway epithelium as a small population of ion transporting cells expressing high levels CFTR (cystic fibrosis transmembrane conductance regulator), gene mutated cystic fibrosis. By providing an infinite source epithelial (AECs), use human induced pluripotent stem (hiPSCs) could overcome some challenges studying ionocytes. However, production AEC epithelia containing from hiPSCs has proven difficult. Here, we present...
Abstract Silencing Amblyomma americanum insulin‐like growth factor binding protein‐related protein 1 ( Aam IGFBP‐rP1) mRNA prevented ticks from feeding to repletion. In this study, we used recombinant (r) IGFBP‐rP1 in a series of assays obtain further insight into the role(s) tick regulation. Our results suggest that IGFBP‐1 is an antigenic apparently exclusively expressed salivary glands. We found both males and females secrete host during confirmed female within 24–48 h after attachment....
We provide in this paper a detailed characterization of the human peripheral CD4+ CD127lowCD25+ regulatory T cell (Treg) compartment, with particular emphasis defining population expressing higher levels IL-6 receptor (IL-6R). description phenotype by assessing both surface expression flow cytometry as well their transcriptional profile and functional features. In addition, we also present data describing responsiveness these subsets to signalling vitro IL-2 vivo. The presented support...
Quantitative proteomics is able to provide a comprehensive, unbiased description of changes cells caused by viral infection, but interpretation may be complicated differential in infected and uninfected 'bystander' cells, or the use non-physiological cellular models.
BackgroundCigarette smoking has many serious negative health consequences. The relationship between and SARS-CoV-2 infection is controversial, specifically whether smokers are at increased risk of infection. We investigated the impact cigarette smoke on ACE2 isoform expression in differentiated primary human bronchial epithelial cells air-liquid-interface (ALI). assessed response to CSE therapeutics reported modulate ACE2. exposed ALI cultures extract (CSE) then infected them with...
<h3></h3> Sites of infection and inflammation are profoundly hypoxic, requiring neutrophils to function under low oxygen tensions. Although well adapted can rely on glycolytic metabolism, hypoxia still impairs the neutrophil oxidative burst, reduces bacterial killing delays apoptosis.<sup>1</sup> As proteases have been implicated in lung diseases such as COPD, we hypothesised that might also promote degranulation, with an enhanced potential for neutrophil-mediated tissue injury. Neutrophils...
Abstract Background There are limited effective prophylactic treatments for SARS-CoV-2 infection, and early treatment options. Viral cell entry requires spike protein binding to the ACE2 receptor cleavage by TMPRSS2, a surface serine protease. Targeting of TMPRSS2 either androgen blockade or direct inhibition is already in clinical trials infection. Methods The likely initial cells ciliated upper airway. We therefore used differentiated primary human airway epithelial maintained at...
Summary Background Type 1 diabetes (T1D) results from loss of immune regulation leading to the development autoimmunity pancreatic beta-cells, involving autoreactive T effector cells (Teffs). Regulatory (Tregs), that prevent autoimmunity, require Interleukin-2 (IL-2) for maintenance immunosuppressive functions and, alterations in IL-2 pathway predispose T1D. Using an adaptive trial design we aimed determine optimal regimen aldesleukin (recombinant human IL-2) physiologically enhance Tregs...
<h3>Introduction and objectives</h3> Neutrophils (PMNs) are a key component of the innate immune response to invading pathogens. They accumulate at sites inflammation infection, which typically characterised by low oxygen tensions (e.g. in acute respiratory distress syndrome (ARDS)). Human PMNs undergo constitutive apoptosis, their survival contingent upon pro-survival pro-apoptotic signals derived from microenvironment. Hypoxia profoundly delays PMN resulting persistence inflammatory foci...
Tissues such as the skin and intestinal epithelium experience physiological hypoxia whereas pathological occurs at inflammatory sites. Neutrophils are recruited to infective/inflamed areas thus required operate under low oxygen tensions. We have shown previously that delays neutrophil apoptosis (JEM 2005; 201:105) impairs bacterial killing (J Immunol 2011; 186:453) now studied effect of on release histotoxic proteases. isolated from healthy volunteers were subjected normoxia or (3 kPa)....
Many tissues including the skin, intestinal epithelium and potentially airway operate at ‘physiological’ levels of tissue hypoxia with normal <i>P</i>O<sub>2</sub> values below 3KPa. Both sterile non-sterile inflammation exacerbates degree predicates need for granulocytes eosinophils to efficiently under hypoxia. In these experiments we have examined effects on eosinophil longevity show that a 3KPa severely attenuates pro-apoptotic effect dexamethasone. Human blood were prepared from healthy...
Cigarette smoking has many serious negative health consequences. The relationship between and SARS-CoV-2 infection is controversial, specifically whether smokers are at increased risk of infection. We investigated the impact cigarette smoke on ACE2 isoform expression in differentiated primary human bronchial epithelial cells air-liquid-interface (ALI). assessed response to CSE therapeutics reported modulate ACE2. exposed ALI cultures extract (CSE) then infected them with SARS-CoV-2. measured...