Age-related changes in microenvironmental inflammation and their influence on adaptive immunity

With human life expectancy almost doubling over the past two centuries the proportion of older adults in society has increased rapidly, those over 65 now constituting nearly 20% (11 million) of the UK population. Ageing is a major risk factor for a plethora of chronic diseases and is associated with both increased susceptibility to infection and reduced vaccine efficacy. The unifying pathophysiology underlying these disparate effects appears to be a dysregulated immune system. Changes in both innate and adaptive immunity with age are well documented, as is an altered inflammatory response. To date however, the biological mechanisms linking these observations has eluded us.

It is now established that ageing results in a low-grade chronic systemic inflammatory phenotype termed ‘inflammageing’. Specifically, inflammation is more easily triggered in older humans and does not resolve appropriately. This phenomenon has been linked to impaired immune responses to pathogens individuals have previously been exposed to (e.g. herpes zoster and shingles). What is less clear is the impact of ‘inflammageing’ on the establishment of memory responses to new pathogens/antigens (e.g. upon vaccination) and what impact this ultimately has on immune competence and clinical outcomes

This project consequently seeks to explore the link between aging and innate and adaptive immunity, ultimately aiming to understand whether functional assessment of inflammation can be used as a biomarker to inform the immunisation schedules of older people for clinical benefit.

To do this, we will utilise novel human immune challenge (HIC) models to investigate and compare inflammation in the skin of young and older people in vivo. We will use different stimuli injected into the skin of volunteers and assess the inflammatory outcomes using multiple novel non-invasive imaging techniques. We will use these measures to determine the variability of the inflammatory response in the different groups and subsequently examine the local immune environment using skin blisters and biopsies. Crucially, we will then test the impact of observed dysregulation in innate immunity on adaptive immunity through immunisation with a neo-antigen (stimulating a T-cell dependent response) and subsequent cutaneous re-challenge. Fine needle aspirates of draining lymph nodes will explore stromal innate/adaptive interactions. You will learn cutting edge cellular immunology techniques and analysis paradigms as part of a strong team focused on human immunology and understanding the ageing process.

Keywords

Ageing, inflammation, immunology, immunisation, human immune challenge

Training

The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease and their treatment. The successful applicant will benefit from regular hands-on training and supervision by experienced laboratory and clinical scientists both at the Kennedy Institute and Botnar Research Centre. As well as developing core ‘wet lab’ skills (flow cytometry, cell culture etc) they will gain exposure to a range of cutting-edge techniques (including single-cell RNA sequencing) and analysis. Most uniquely, they will work in the new NIHR Experimental Medicine Clinical Research Facility to undertake and obtain samples from the HIC paradigms; literally moving from ‘bed to benchside’.

The development of outstanding communication and project management skills is expected as they take on the significant responsibility of establishing and running experimental medicine studies. To achieve this they will be supported, trained and mentored throughout. Daily interaction with fellow clinical and non-clinical PhD students and post-doctoral researchers will be supplemented by frequent supervisory meetings with Dr Fullerton, Dr De Maeyer and Dr Alsaleh. Regular attendance and participation at lab meetings and those of the Oxford Centre for Clinical Therapeutics (led by Prof Duncan Richards) will be required. Presentation at international conferences and publication in leading biomedical journals is expected. The quality, relevance and impact of the students work will be guaranteed by the inter-linked nature of this work with existing research programmes (e.g. A-TAP) and industrial collaborations (e.g. Oxford-Bristol Myers Squibb Fellowship), with associated expertise and funding.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. Students will also be required to attend regular seminars within the Department and those relevant in the wider University.

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

How to apply

The Department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or NDORMS Graduate Studies (graduate.studies@ndorms.ox.ac.uk) who will be able to advise you of the essential requirements.

Interested applicants must have a medical qualification (e.g. MBChB, MBBS) and will also need to provide evidence of English language competence (where applicable).

The application guide and form is found online and the DPhil or MSc by research will commence in October 2023.

Applications should be made to one of the following programmes using the specified course code:

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

Key publications 

De Maeyer et al. Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat Immunol 2020. https://doi.org/10.1038/s41590-020-0646-0

Chambers et al. Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging. Nat Aging 2021. https://doi.org/10.1038/s43587-020-00010-6

Florian et al. Translational drug discovery and development with the use of tissue-relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy. Exp Dermatol 2020. https://doi.org/10.1111/exd.13942

Saghari et al. A randomized controlled trial with a delayed-type hypersensitivity model using keyhole limpet haemocyanin to evaluate adaptive immune responses in man. Br J of Clinical Pharmacology, 2020. https://doi.org/10.1111/bcp.14588 

Studentship Details

This studentship provides a stipend of up to £30,00 per annum for 3 years, covers fees at the home level and provides consumable costs for the research. Any overseas applicants would need to cover the difference between home and overseas fees from alternative funding sources.

Closing date 

Applications must be complete by noon on Friday 7th April 2023.

Interview date 

Thursday 20^th April 2023.