Cutaneous human immune challenge for the development and evaluation of therapeutics
LEAD SUPERVISOR: Dr James Fullerton, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences
Co-supervisor: Professor Christopher Buckley, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences
Commercial partner: DJS Antibodies, Oxford
Human immune challenge (HIC), where an exogenous stimulant is employed to transiently induce normally quiescent pathways and cell populations 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 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 an 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 processes that would 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. 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, using the optimal (and optimised) HIC paradigm to expose the target of interest, the efficacy of the industrial partner’s (DJS Antibodies) proprietary immunomodulatory assets will be explored ex (and potentially in) vivo as part of a live drug development programme.
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. Working at DJS, functional assays principally related to the myeloid compartment will be employed to ascertain the pharmacology of their investigational medicinal products and facilitate precision, biomarker-guided follow-on interventional trials exploiting their unique GPCR-targeting technology for patient benefit.
Apply using course: DPhil in Molecular and Cellular Medicine