Fullerton Group | Translational Pharmacology

Comprising a mix of both scientists and clinician scientists we design, develop and use a range of human immune challenge (HIC) approaches to explore in vivo biology, interrogate immune variance and unravel the interplay between disease and immune dysregulation. We also have a particular interest in how HIC can be employed in translational/early clinical drug development to establish mechanistic proof-of-concept and tissue-based pharmacology of both established (enabling repurposing) and novel therapeutics, seeking to enable and catalyse the work of both academic and industrial partners.

Our focus

Our work employs in vivo human immune challenge (HIC) to explore four domains:

Diversity

Interrogate fundamental human immunology, with an emphasis on understanding inter-individual variation in inflammatory and immune responses, and how endogenous or exogenous stimuli influence immunity intra-individually, including over the lifespan.

Disease

Understand how immune variation may influence to risk of acquiring a given disease and contribute to prevalent pathology, and conversely, how disease and the drugs used to treat it impact the immune system.

Drugs

Catalyse the development of novel immunomodulatory therapeutics by providing comprehensive platforms which establish in vivo tissue (biophase) pharmacology and hence proof-of-mechanism during early clinical development, often in healthy volunteers.

Development 

Determine the operational characteristics of established HIC paradigms, iterate these to refine performance and develop new systems that elaborate different or discrete immunological profiles (biomarkers) to permit novel insight.

Ongoing research programmes 

We are currently employing a number of HIC paradigms to obtain unique temporal and spatial insight into tissue immunology in a controlled, repeatable and safe manner. Samples arising from our studies undergo analysis using cutting-edge scientific techniques, often in conjunction with our collaborators, to address important questions related to human health and drug development. Exemplar approaches, methods and research themes are highlighted below.

HIC paradigms

• Immunisation with keyhole limpet haemocyanin (KLH) followed by re-exposure in the skin to elicit a T-cell dependent antibody response (TDAR) and delayed type hypersensitivity (DTH) reaction. This allows exploration of adaptive immunity from antigen exposure through memory formation to effector cell response.
• Intradermal or topical cutaneous challenge with exogenous agents including cantharidin and lipopolysaccharide, amongst others. This system allows the interrogation of inflammation and innate immunity from onset to resolution
• Contrast-enhanced ultrasound (CEUS) to identify lymphatic structures to enable focused sampling. 

Investigation and Analysis

Our approach to analysing the response to immunological perturbation can be broadly divided into:

Invasive techniques. We seek to sample not only blood for standard assays (e.g. serology and ELISpot) but also tissue, believing we will only truly understand biology and pharmacology by looking at the site of inflammation and drug action. Our primary focus here is skin (either via biopsy or blister formation) and lymph node fine needle aspiration (FNA) however we are able to undertake additional approaches (e.g. bone marrow aspiration or synovial biopsy) if required.

Non-Invasive techniques. We have developed a suite of methods to objectively assess immune responses, especially in the skin. This includes the Miravex Antera 3D multi-spectral camera, Moor laser Doppler imaging, state-of-the-art high-frequency Ultrasound (GE), ancillary techniques linked to these, and novel exploratory imaging modalities. We seek to correlate non-invasive data with that obtained invasively to understand the potential of these techniques to replace or refine tissue sampling.

Themes

Current research themes include:

• Can the immune response to a common antigen can be ‘shaped’ by adjuvants to selectively elicit desired biomarker profiles e.g. Th1 vs Th2
• Can CEUS identify sentinel nodes following vaccination at different sites and depths?
• Exploring neutrophilic infiltration: Can we develop HIC models of neutrophil infiltration to elicit disease-relevant phenotypes and activation states?
• Exploring mechanisms of fibrosis: Can we develop HIC models capable of  transiently upregulating pathways relevant to fibrotic disease in vivo?
• How can HIC paradigms be deployed to understand the impact of iron status on immunity?