Interrogating immune-mediated inflammatory disease via cutaneous human immune challenge

Project No: #OxKEN-2023/22
Intake: OxKEN 2023

project overview

Human immune challenge (HIC), where an exogenous stimulant is employed to transiently induce normally quiescent pathways, cell populations and genes in healthy volunteers (HV), permits unique insights into fundamental biology at high temporal and spatial resolution. Through the elicitation of disease-relevant targets or biomarkers they additionally allow the therapeutic potential of existing and novel drug candidates to be evaluated, rapidly confirming pre-clinical data and gaining early proof-of-mechanism and pharmacology, including at the biophase (target tissue) of interest, prior to entering a patient population. Despite clear scientific and economic advantages over alternate approaches (e.g. animal models) HIC remains under utilised in both discovery biology and drug development programmes largely through insufficient characterization, heterogeneity in methodology and a historical failure to exploit the access to mechanism-related end-points they afford.

Several cutaneous HIC paradigms exist that induce a self-resolving inflammatory reaction via chemical (e.g. cantharidin), physical (e.g. UV-light) or pathogen-derived (e.g. endotoxin) stimuli. The subsequent immunological response can then be quantified clinically over time and the humoral and cellular elements accessed via blistering or skin biopsy. These approaches can be used not only to 'model' inflammatory dermatological conditions such as psoriasis or atopic dermatitis, but also to employ the skin as an exemplar tissue bed: gaining insight into pathological processes that occur in others (e.g. the lung or kidney). The problem is that we do not currently have a clear idea which stimuli best induce pathways relevant to different immune-mediated inflammatory diseases (IMID), what dose of stimuli to employ and both when and how to sample the skin to derive the greatest biological insight and optimally inform drug development decisions.

This experimental medicine project seeks to directly address this gap, comparing the response to alternate cutaneous HIC stimuli both within and between HV, hypothesizing that they will selectively elicit immunological pathways relevant to different IMID (e.g. rheumatoid arthritis or Crohn's). Further, it will seek to explore the immune response over time from the acute phase through resolution, using different sampling methods (blister vs. biopsy) to catalogue the infiltrating cells and explore their interaction with the local milieu. Finally, the relative sensitivity of the HIC paradigms to both locally and systemically administered immunomodulatory drugs will be explored ex and in vivo: a key step in validating their transaltional relevance.

Specifically, the molecular, cellular and transcriptional profile of samples (blood and skin) arising from discrete human skin challenges including cantharidin, endotoxin, imiquimod, UV-light and keyhole limpet haemocyanin (following immunization, to induce delayed type hypersensitivity) will be sequentially interrogated down to single cell resolution (spectral flow cytometry and RNA sequencing) and compared to library samples from patients with IMID. The utility and relevance of each approach to specific disease states will be determined and a tissue atlas formed to inform future drug development and translational science programs. Within-subject studies using medicines with established mechanisms and known biological effects (e.g. corticosteroids, anti-IL6 agents) will then be conducted to determine the different HIC paradigms response characteristics and suitability for evaluating novel therapeutics.

Left Panel (Belson et al 2016, https://doi.org/10.1007/s00011-016-0923-4). Delayed type hypersensitivity response following antigen rechallenge. Right panel. Erythema, vascular reactivity and histology following imiquimod challenge (Van der Kolk et al 2020, https://doi.org/10.1111/cts.12563)

keywords

Experimental medicine; immunomodulation; autoimmune diseases; drug development; pharmacology

training opportunities

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 conjunction with clinically qualified colleagues 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 an experimental medicine trial. To achieve this they will be supported, trained and mentored by experienced clinicians and clinical/industrial science experts 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 and Prof Buckley. Regular attendance and participation at both Prof Buckley and Prof Mark Coles’ (Stromal Immunology, https://www.kennedy.ox.ac.uk/team/mark-coles) lab meetings and those of the Oxford Centre for Clinical Therapeutics (led by Prof Duncan Richards, https://www.ndorms.ox.ac.uk/team/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 https://www.kennedy.ox.ac.uk/about/translational-research/atap) and industrial collaborations (e.g. Oxford-Bristol Myers Squibb Fellowship), with associated expertise and funding.

key publications

Buters et al. Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers. Br J of Clinical Pharmacology, 2022 https://doi.org/10.1111/bcp.14999
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
Van der Kolk et al. Comprehensive, Multimodal Characterization of an Imiquimod-Induced Human Skin Inflammation Model for Drug Development. Clin Transl Sci 2018. https://doi.org/10.1111/cts.12563
Jenner et al. Characterisation of leukocytes in a human skin blister model of acute inflammation and resolution. PLoS One, 2014. https://doi.org/10.1371/journal.pone.0089375