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.
Organisations
- University of Oxford, United Kingdom (Collaboration, Fellow, Lead Research Organisation)
- University of Copenhagen, Denmark (Collaboration)
- Karolinska Institute, Sweden (Collaboration)
- Keio University, Japan (Collaboration)
- Royal Veterinary College, United Kingdom (Collaboration)
- Oxford University Hospitals NHS Foundation Trust, Headington (Collaboration)
- University of Kentucky (Collaboration)
- University of Birmingham, United Kingdom (Collaboration)
People |
ORCID iD |
| Christopher O'Callaghan (Principal Investigator / Fellow) |
| 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 | 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018 |
| 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 |