Dias de Matos Oliveira, João Joaquim; (2025) Interrogating the human immune response via cutaneous inflammatory challenges to aid drug development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Clinical research is continuously under pressure to develop new therapeutic entities whilst containing the spiralling costs of research and development. Obtaining critical data regarding target engagement in relevant tissue, and proof of mechanism in early phase clinical trials, allows evaluation of the efficacy of the asset and thus identifies programmes for termination before the significant economic, health and reputational cost of late-phase failure. Skin blisters allow an easy access for investigating inflamed tissue, where type and level of inflammation can be experimentally adjusted with the use of local inflammatory challenges. Although the technique is in widespread use, the biology behind the inflammatory stimuli driven by cantharidin or suction that results in leukocyte rich blisters is not well understood; nor is the variability of the cellular and soluble components of the resulting blisters both within and between subjects, a crucial element required for the design of well powered in vivo experiments. This research project aims to identify the role of cantharidin in driving the blister reaction and how this compares to the suction model. By drawing samples shortly after challenge, it highlights the primary effect of TNF secretion by stromal cells in response to cantharidin, prior to the formation of an observable blister, and allows the identification of key mediators of the immune response. It also provides a detailed time course of the cellular and humoral components throughout the blister reaction. Also, by using duplicate and repeat challenges in the same subjects, this project allows the determination of inter- and intra-subject variability estimates for the main blister outputs and identifies best practices for the design of clinical trials using these models. To demonstrate the potential of blistering models in drug development, this project showed the effects of steroids in the pharmacological modulation of the local cantharidin blister response, by reducing oedema formation and cell recruitment and highlighted differences in cellular responses to topical and systemic doses of similar compounds in both tissue and circulating leukocytes.

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