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  • Project No: #OxKEN-2021/10
  • Intake: OxKEN

PROJECT OVERVIEW

Inflammation represents an evolutionarily conserved host response to noxious stimuli. Whilst vital to help combat infection and trigger healing from injury, significant inter- and intra-individual variability in the magnitude and duration of a response is recognised, which in itself may be pathogenic. This may relate to insufficiency (failure to clear an infection), over-exuberance (sepsis, severe Covid-19), lack of regulation (auto-immunity) or chronicity (e.g. atherlosclerosis). In the case of bacterial infections, the character and kinetics of the reaction - both local and systemic - relate to properties of both the pathogen and host, and their subsequent interaction.

The majority of work undertaken to study the fundamental biology of inflammation and the associated immune response has been undertaken in non-human species. Whilst possessing some clear advantages, this approach has well-recognised translational limitations, especially in relation to drug development. Human experimental medicine approaches, where healthy or diseased individuals are deliberately (but safely) exposed to stimuli and/or drugs represent a crucial, if under-utilised, method to interrogate basic molecular and cellular pathways, explore inter-individual variability and elucidate pharmacology in the target species for most therapeutics.

With regards to inflammation, it’s regulation and how it may be pharmacologically manipulated, skin challenge models have found a particular role, the response being visible, measurable and accessible. To date, several approaches have been taken to trigger a local inflammatory response: chemical (cantharidin), heat, UV light, physical (negative pressure), allergic (house dust mite) and abrasion. A recently developed and particularly promising approach is injection of UV-killed bacteria intra-dermally with subsequent biopsy or suction blister formation over the site. This permits acquisition of both the infiltrating cells and associated humoral mediators at different phases of the inflammatory response to a relevant stimulus in an intact tissue matrix in vivo. To date, this has only been conducted with E.coli and E.coli-derived endotoxin, a Gram-negative bacteria that is not associated with clinical skin infection.

This project seeks to develop this model further, employing UV-killed Gram-positive Staphylococcal species (S. aureus and S. epidermidis), including substrains with known discrete pathogenic factors, as stimuli for the local inflammatory response. These common skin commensals are of direct pathogenic relevance in different clinical populations and alternate Staphylococcal colonisation patterns, as well as their host-recognition and handling, are associated with allergic skin disease. The response to intra-dermal injection will be temporally characterised locally and systemically, clinically, physiologically and immunologically, and divergences in response explored. Once established, it is anticipated that these standardised models will be employed by the student in both pre-defined populations to explore clinically-relevant biology (e.g. age-related changes in immune function), and in healthy vs. diseased cohorts (e.g. atopic dermatitis) to detect drivers of an alternate response and thus potential therapeutic targets. The highly translational nature of this project is expected to be of immediate impact, being of relevance in both academia and also the industrial setting, where it is anticipated to be of value in both pre-clinical and early phase studies seeking to establish proof-of-mechanism.

KEYWORDS

Experimental medicine

Immunology

Inflammation

Clinical pharmacology

Dermatology

TRAINING OPPORTUNITIES

The successful applicant will benefit from a supervisory team comprised of experts in immunology, clinical pharmacology, early phase drug discovery and human in vivo challenge models. They will be encouraged to integrate these disciplines to generate novel, impactful paradigms that promote translational science and accelerate the discovery of therapeutics. Independent thought and the challenging of established dogma will be actively encouraged.

The student would be based at the Botnar Research Centre but with access to the MRC Weatherall Institute of Molecular Medicine. Experimental studies will be conducted initially at the NIHR Clinical Trials Unit (Nuffield Orthopaedic Centre). At all sites there are excellent core facilities, infrastructure and expertise readily available.  The student would receive training in experimental medicine approaches (including associated clinical skills), molecular and cellular techniques and would gain experience in handling human skin biopsies and skin tissue fluid and cells, with concomitant assays including imaging (e.g. Hyperion), RNAseq, rtPCR and cytokine bead array. Initial hands-on support will enable the rapid accruing of skills and the ability to undertake work independently. The student would also learn about regulatory issues surrounding the use and storage of human samples including ethics, hospital R&D, GCP and HTA.  The student would attend GCP, statistical courses and relevant conferences as well as the excellent internal and guest speaker programmes available in Oxford. They will be expected to present data regularly to the department, attend and disseminate data at national and international conferences as well as publish in high-impact journals.

KEY PUBLICATIONS

  1. Motwani MP, Flint JD, De Maeyer RP, Fullerton JN et al. Novel translational model of resolving inflammation triggered by UV-killed E. coli. The Journal of Pathology Clinical Research 2016;2(3):154-65
  2. De Maeyer RPH, van de Merwe RC, Louie R, et al. Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat Immunol 2020;21(6):615-25.
  3. Chen YL, … Ogg G. Re-evaluation of human BDCA-2+ DC during acute sterile skin inflammation. J Exp Med. 2020 Mar 2;217(3)
  4. Hardman CS, … Ogg G. CD1a presentation of endogenous antigens by group 2 innate lymphoid cells. Sci Immunol. 2017 Dec 22;2(18):pii: eaan5918
  5. Jarrett R, … Ogg G. Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite derived phospholipase. Science Translational Medicine. 2016;8:325ra18 

CONTACT INFORMATION OF ALL SUPERVISORS

James Fullerton

Graham Ogg

Duncan Richards