Distinguishing healthy and diseased cells for immune destruction: function and structure of MHC class I Homologues

Lead Research Organisation: University of Oxford
Department Name: Unlisted

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

I am studying the molecular mechanisms by which diseased cells identify themselves to the immune system for destruction. Rapid destruction of diseased cells is essential if tumour cells are not to proliferate into cancers and if pathogen-infected cells are not to spread their infections to other cells. Adaptive or ‘learnt‘ immunity can be effective, but takes time to develop. In contrast, natural killer cells can rapidly destroy diseased cells. Diseased cells send molecules to their surfaces which act as flags to identify them as diseased to natural killer cells. The importance of natural killer cell recognition is highlighted by recent observations that viruses such as cytomegalovirus, have evolved multiple mechanisms to evade them.

Publications

10 25 50

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Chakera A (2010) A lucky fall? Case report. in Transplantation proceedings

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Dahlmann F (2015) Analysis of Ebola Virus Entry Into Macrophages. in The Journal of infectious diseases

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O'Callaghan CA (2009) Chronic kidney disease--assessing the impact. in QJM : monthly journal of the Association of Physicians

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O'Callaghan C (2008) CLEC-2 in AfCS-Nature Molecule Pages

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Hughes CE (2010) CLEC-2 activates Syk through dimerization. in Blood

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Watson AA (2008) Crystal structure of rhodocytin, a ligand for the platelet-activating receptor CLEC-2. in Protein science : a publication of the Protein Society

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Watson AA (2005) Crystallization and X-ray diffraction analysis of human CLEC-2. in Acta crystallographica. Section F, Structural biology and crystallization communications

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Watson AA (2010) Crystallization and X-ray diffraction analysis of human CLEC5A (MDL-1), a dengue virus receptor. in Acta crystallographica. Section F, Structural biology and crystallization communications

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Aslam A (2006) Defining the T cell antigen proteome of wasp venom. in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

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Watson AA (2011) Expression, purification and crystallization of the human UL16-binding protein ULBP1. in Protein expression and purification

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Reschen M (2012) Floating-Harbor syndrome and polycystic kidneys associated with SRCAP mutation. in American journal of medical genetics. Part A

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O'Callaghan CA (2008) Kidney transplantation--the long term view. in QJM : monthly journal of the Association of Physicians

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O'Callaghan C (2009) NKG2D in AfCS-Nature Molecule Pages

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McCarthy MT (2014) PeaKDEck: a kernel density estimator-based peak calling program for DNaseI-seq data. in Bioinformatics (Oxford, England)

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McCarthy MT (2018) Purine nucleotide metabolism regulates expression of the human immune ligand MICA. in The Journal of biological chemistry

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McCarthy MT (2018) Purine nucleotide metabolism regulates expression of the human immune ligand MICA. in The Journal of biological chemistry

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Christou CM (2008) Renal cells activate the platelet receptor CLEC-2 through podoplanin. in The Biochemical journal

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O'Callaghan CA (2004) Renal manifestations of systemic autoimmune disease: diagnosis and therapy. in Best practice & research. Clinical rheumatology

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Chakera A (2010) Reversible renal impairment caused by thyroid disease. in Scandinavian journal of urology and nephrology

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Brown J (2007) Structure of the fungal beta-glucan-binding immune receptor dectin-1: implications for function. in Protein science : a publication of the Protein Society

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Davison LJ (2017) The Canine POMC Gene, Obesity in Labrador Retrievers and Susceptibility to Diabetes Mellitus. in Journal of veterinary internal medicine

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Herrington WG (2009) The hyponatraemic hairdresser: highlighting the differentials. in Lancet (London, England)

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Watson AA (2009) The platelet receptor CLEC-2 is active as a dimer. in Biochemistry

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O'Callaghan CA (2009) Thrombomodulation via CLEC-2 targeting. in Current opinion in pharmacology

 
Description National UKCRN renal specialty committee
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description AKC Health Foundation
Amount $14,958 (USD)
Funding ID 02355-A: 02355-A 
Organisation American Kennel Club Canine Health Foundation, Inc. 
Sector Charity/Non Profit
Country United States
Start 08/2017 
End 07/2018
 
Description BHF Project Grant
Amount £120,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2007 
End 11/2009
 
Description BHF project grant
Amount £176,940 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 07/2014
 
Description British Renal Society
Amount £17,360 (GBP)
Funding ID 11-007 
Organisation British Renal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2012 
End 11/2014
 
Description Clarin Postdoctoral Fellowship
Amount £40,000 (GBP)
Organisation Foundation for the Promotion of Applied Scientific Research and Technology in Asturias 
Sector Public
Country Spain
Start 09/2007 
End 09/2008
 
Description Confidence in Concept
Amount £75,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2019 
End 02/2020
 
Description European Foundation for the Study of Diabetes/JDRF European Programme in type 1 diabetes research
Amount € 100,000 (EUR)
Funding ID 96111 
Organisation European Association for the Study of Diabetes (EASD) 
Department European Foundation for the Study of Diabetes (EFSD)
Sector Academic/University
Country Germany
Start 04/2017 
End 04/2018
 
Description Health Services Research scheme
Amount £100,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department Oxfordshire Health Services Research Committee (OHSRC)
Sector Charity/Non Profit
Country United Kingdom
Start 07/2018 
End 06/2021
 
Description MRC Centenary early career award for michael mccarthy
Amount £45,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2013 
End 09/2014
 
Description MRC Clinical Research Training Fellowship for Michael McCarthy
Amount £185,970 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2013
 
Description MRC Clinician Scientist Fellowship for Lucy Davison
Amount £1,896,074 (GBP)
Funding ID MR/R007977/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2018 
End 01/2023
 
Description MRC PhD Studentship
Amount £70,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description NIHR Research Capability Funding (RCF)
Amount £51,960 (GBP)
Funding ID RCf121377 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2013
 
Description Novo Nordisk Fonden Collaborative Grant
Amount kr 40,000,000 (DKK)
Organisation Novo Nordisk Foundation 
Sector Charity/Non Profit
Country Denmark
Start 12/2015 
End 12/2019
 
Description Panamanian research studentship
Amount £30,000 (GBP)
Organisation Government of the Republic of Panama 
Sector Public
Country Thailand
Start 10/2006 
End 10/2009
 
Description Prize Studentship
Amount £100,000 (GBP)
Organisation Joyce Frankland Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2019
 
Description Research Grant
Amount £15,000 (GBP)
Funding ID 15/0005171 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2015 
End 07/2016
 
Description UK Government Overseas Research Studentship
Amount £30,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 10/2008
 
Description UKCRN/TVCLRN NHS R and D
Amount £180,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2010 
End 04/2015
 
Description Wellcome Trust Clinical Research Training Fellowship
Amount £244,488 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Wellcome Trust Veterinary Postdoctoral Fellowship
Amount £423,781 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 10/2015
 
Description Wellcome Trust clinical research training fellowhsip
Amount £226,021 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 10/2014
 
Description Wellcome Trust clinical training fellowship
Amount £244,488 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Title DNA assembly new method 
Description A new method for assembly of DNA fragments up to 200kb. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact Wide interest when presented at a synthetic biology conference. Interest from both academia and industry. Patent filed. 
 
Title Orientated coupling to biosensor surfaces 
Description A technology for the production and application of BirA ( a biotinylating protein) that allows this enzyme to be used to place a biotin molecule on a defined portion of a protein. This allows the protein to be tethered to fluorescently labeled streptavidin derivates. As each streptavidin molecule binds four biotin molecues, a species is created which is tetrameric with respect to the labeled protein. The fluorescent tetrameric protein can then be used in flow cytometry. We further developed this approach 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact A great enhancement in the precision and quality of binding data obtained using surface plasmon resonance. 
 
Title Peak identification algorithm and software 
Description Development of an algorithm and software to identify peaks in high throughput sequencing data and to allow comparison between datasets with differing signal to noise ratios. 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact Publication currently pending. This software has been used to analyse and compare datasets that might not otherwise be useful. 
URL http://www.ccmp.ox.ac.uk/o-callaghan-group
 
Title Protein structures 
Description X-ray crystallographic structures. The co-ordinates are deposited in the PDB public database 
Type Of Material Biological samples 
Year Produced 2007 
Provided To Others? Yes  
Impact The structures can now being used for structure based drug design. 
 
Title Quantitation of transcripts 
Description Solid-phase plate-reader quantification of specific PCR products by measurement of band-specific ethidium bromide fluorescence. 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact Publication of an article in the premier methodology journal Analytical Biochemistry. 
URL http://www.sciencedirect.com/science/article/pii/S0003269713005290
 
Title Spanish version of OxMar software 
Description Spanish language version of software I developed for clinical trial allocation by randomisation with minimisation. 
Type Of Material Improvements to research infrastructure 
Year Produced 2018 
Provided To Others? Yes  
Impact Makes the software, which is open access and free of charge, available to Spanish speaking communities which is relevant to Central and Southern America as well as Spain. 
 
Title Web-based sequence analysis and manipulation tool 
Description A web-based tool for the design of molecular biology cloning experiments and the analysis of nucleic acid sequences. Usable on any platform. 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact We have had positive feed back from other groups on this improved version of our previous DNA analysis tool. 
 
Title antibody to innate immune receptor 1 
Description an antibody was generated to a novel innate immune receptor 
Type Of Material Antibody 
Provided To Others? No  
Impact identification of cells expressing it and their potential disease role 
 
Title antibody to innate immune receptor 2 
Description an antibody was generated to a novel innate immune receptor 
Type Of Material Antibody 
Provided To Others? No  
Impact identification of expression of this receptor and studies of its function. 
 
Title plasmids 
Description A set of around 1000 plasmids for expression or manipulation of innate immune ligands and receptors. 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Publications as listed elsewhere. 
 
Title NGS datasets 
Description Multiple sets of high throughput next generations sequencing relating to immune cells, endothelial cells, vascular smooth muscle cells and induced pluripotent stem cells. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Appreciation of the mechanism of action of GWAS hits. 
 
Description Acute care partnership 
Organisation Oxford University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution We are providing laboratory analysis of clinical samples.
Collaborator Contribution Study recruitment.
Impact Yes, currently a paper is under revision studying factors involved in pulmonary embolism.
Start Year 2018
 
Description Canine Diabetes Genetics Partnership 
Organisation Royal Veterinary College (RVC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in molecular biology, cellular biology, bioinformatics, next generation sequencing.
Collaborator Contribution Veterinary expertise, collection of samples and phenotyping.
Impact Grant funding.
Start Year 2018
 
Description Collaboration with Professor Andrew Morris 
Organisation University of Kentucky
Country United States 
Sector Academic/University 
PI Contribution We have developed assays of macrophages and their lipid metabolism relevant to atherosclerosis.
Collaborator Contribution Our partners have provided us with some help on lipid component characterisation and quantification.
Impact manuscripts in preparation
Start Year 2013
 
Description Collaboration with Professor Paul Moss 
Organisation University of Birmingham
Department Birmingham Cancer Research UK Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided structural data about the NKG2D ligands and structural models of allelic variations that may affect the ligand-receptor interactions.
Impact Paper : PMID 20219610
Start Year 2008
 
Description Collaboration with Professor Steve Watson 
Organisation University of Birmingham
Department College of Medical and Dental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have identified and crystallized a novel receptor which promotes platelet activation and aggregation.
Collaborator Contribution Help with platelet studies.
Impact Publications - PMID 18215137, PMID 20154219
Start Year 2007
 
Description Hedgehog protein studies 
Organisation University of Oxford
Department Division of Structural Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in the analysis of protein-protein interactions using surface plasmon resonance and isothermal titration microcalorimetry.
Collaborator Contribution Expertise in hedgehog ligand biology
Impact Publications PMID 19561611
Start Year 2008
 
Description Immunometabolism collaborative consortium 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution I am a co-applicant on a major consortium grant and am leader of one of the three workstreams.
Collaborator Contribution major scientific and intellectual input to the project.
Impact a major 40 million DK grant
Start Year 2015
 
Description Metabolites and immune cell function with CM, TS and others 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution shared experimental protocols, reagents, exchange visits and projects.
Collaborator Contribution shared experimental protocols, reagents, exchange visits and projects.
Impact none yet.
Start Year 2016
 
Description Metabolites and innate immune cell recognition with SS 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution Collaboration on innate immune cell recognition mechanisms and metabolism.
Collaborator Contribution shared experiments, expertise and reagents
Impact none yet.
Start Year 2016
 
Description Natural killer cell assays 
Organisation University of Oxford
Department Centre for Cellular and Molecular Physiology
Country United Kingdom 
Sector Academic/University 
PI Contribution Developing a flow cytometry-based assay for routine clincal assessment of natural killer cell function.
Collaborator Contribution help with staffing
Impact Paper PMID 20967261
Start Year 2007
 
Description metabolomics 
Organisation Keio University
Department Institute for Advanced Biosciences
Country Japan 
Sector Academic/University 
PI Contribution We undertook experimental work with metabolic interventions.
Collaborator Contribution Our partners undertook metabolomic studies of samples we produced.
Impact Publication in the Journal of Biological Chemistry 2017.
Start Year 2014
 
Title HLA-E Binding 
Description PROBLEM TO BE SOLVED: To provide a method for preventing inhibition of NK cell activity mediated by HLA-E. ; SOLUTION: The method for preventing inhibition of NK cell activity mediated by HLA-E, includes (a) selecting a compound that interferes with the binding of HLA-E to an inhibitory CD94/NKG2 receptor and (b) bringing an NK cell or T cell expressing the inhibitory CD94/NKG2 receptor into contact with the compound. 
IP Reference WO1999028748 
Protection Patent granted
Year Protection Granted
Licensed Yes
Impact High level publication in various journals. Patent granted in US, Europe and Japan.
 
Title OxCKD1- Empowering healthy lifestyle choices. 
Description The OxCKD1 trial is testing the value of a comprehensive range of interventions to help people reduce their dietary salt intake. This includes the use of technology to prompt and promote healthy choices. 
Type Therapeutic Intervention - Psychological/Behavioural
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact The trial is still ongoing. 
URL https://clinicaltrials.gov/show/NCT01552317
 
Title Bioinformatic pipeline development for study of metabolic effects on immune cells 
Description Development of robust bioinformatic tools to analyse next generation sequencing data across the whole genome and establish the impact of metabolite signalling on the transcriptome and on the epigenetics status of the cell and chromatin. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact This now allows us to define the impact of the metabolite signalling on the cells in an unbiased manner and to examine the relationship between these changes and polymorphisms associated with human metabolic disease. 
 
Title OxMaR: Open Source Free Software for Online 
Description Minimization is a valuable method for allocating participants between the control and experimental arms of clinical studies. The use of minimization reduces differences that might arise by chance between the study arms in the distribution of patient characteristics such as gender, ethnicity and age. However, unlike randomization, minimization requires real time assessment of each new participant with respect to the preceding distribution of relevant participant characteristics within the different arms of the study. For multi-site studies, this necessitates centralized computational analysis that is shared between all study locations. Unfortunately, there is no suitable freely available open source or free software that can be used for this purpose. OxMaR was developed to enable researchers in any location to use minimization for patient allocation and to access the minimization algorithm using any device that can connect to the internet such as a desktop computer, tablet or mobile phone. The software is complete in itself and requires no special packages or libraries to be installed. It is simple to set up and run over the internet using online facilities which are very low cost or even free to the user. Importantly, it provides real time information on allocation to the study lead or administrator and generates real time distributed backups with each allocation. OxMaR can readily be modified and customised and can also be used for standard randomization. It has been extensively tested and has been used successfully in a low budget multi-centre study. Hitherto, the logistical difficulties involved in minimization have precluded its use in many small studies and this software should allow more widespread use of minimization which should lead to studies with better matched control and experimental arms. OxMaR should be particularly valuable in low resource settings. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact The software has already been used successfully in one clinical trial - OxCKD1 which has now completed recruitment and is in the follow up phase. 
URL http://sourceforge.net/projects/oxmar/
 
Title PeaKDEck: a kernel density estimator-based peak calling program for DNaseI-seq data 
Description Hypersensitivity to DNaseI digestion is a hallmark of open chromatin, and DNaseI-seq allows the genome-wide identification of regions of open chromatin. Interpreting these data is challenging, largely because of inherent variation in signal-to-noise ratio between datasets. We have developed PeaKDEck, a peak calling program that distinguishes signal from noise by randomly sampling read densities and using kernel density estimation to generate a dataset-specific probability distribution of random background signal. PeaKDEck uses this probability distribution to select an appropriate read density threshold for peak calling in each dataset. We benchmark PeaKDEck using published ENCODE DNaseI-seq data and other peak calling programs, and demonstrate superior performance in low signal-to-noise ratio datasets. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact We have had a number of emails from workers around the world who are using the software and have used it ourselves to analyse high throughput sequencing data. 
URL http://www.ccmp.ox.ac.uk/peakdeck
 
Title Spanish language version of OxMar software 
Description This a revised Spanish language version of my previous software OxMar which provides for clinical trial randomisation with or without minimisation and recruitment tracking. It also has an easy to use highly portable web-interface allowing operation from anywhere with connection to the internet. The conversion of this to a Spanish language version allows it to be used by a large number of people in lower to middle income and other countries. 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact Collaboration with Spanish colleagues. 
URL https://sourceforge.net/projects/oxmar-en-espanol/
 
Description Patient participation in research event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact talks and small group workshops

Real help in designing the research.
Year(s) Of Engagement Activity 2013
 
Description Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Our website provides information to the public about our research activities.

I have received questions from the public.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
URL http://www.ccmp.ox.ac.uk/o-callaghan-group
 
Description school visit - oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 50+ pupils attended a talk which generated lots of questions and interest in the research.

sixth formers expressed interest in research as a career
Year(s) Of Engagement Activity 2013