Immunobiology and Immunopathology

Translating Understandings of Immunity for Clinical Benefit

The immune system provides defence against pathogens such as viruses and bacteria and underpins a wide range of non-communicable diseases from allergy to cancer. A proper functioning immune system is therefore fundamental to health and wellbeing. Our approach is to elaborate the basic science of immunity and translate this to clinical benefit. This is achieved through research efforts to better understand cellular and molecular mechanisms driving immune cell function and identify how these pathways become dysregulated in association with disease. In parallel, we seek better diagnostics and therapeutics based on these insights and through interdisciplinary collaborations to improve health.

Immunobiology and Immunopathology Research Focus

The Immunobiology and Immunopathology Sub-theme are focussed on a variety of immunity related areas, exploring the changes in immune function in pregnancy, the metabolic reprogramming and immune system evasion in Cancer.

Linked to our work on novel diagnostics in obstetrics our goal is to ensure that any tests we develop are accessible and applicable to pregnant women in low and middle-income countries. This means working closely with countries such as Uganda and Viet Nam to develop and test our technologies and to elaborate the underpinning biology of differences in disease prevalence in pregnant women of different ethnicity. Our efforts chime with the aspirations of UN Sustainable Development Goal 3 to promote good health and wellbeing at all ages.

Fundamentals of immunometabolism

How cells use sugars, fats and amino acids via metabolism is a key determinant of cell fate and function. These metabolic pathways are now recognised to be integrally linked to all aspects of the immune response. Understanding immunometabolic processes in multiple immune cell types is critical for elaborating how immune cells function, how these functions might be perturbed in disease and how these perturbations can be targeted therapeutically.

Immunology of Pregnancy

Changes in immune function are a normal feature of a healthy pregnancy. Understanding this natural immune plasticity has three main benefits:

Directly related to pregnancy, such insight can help us understand adverse pregnancy outcomes such as miscarriage and gestational diabetes.
Related to immune programming and risk of immune-mediated diseases in childhood, such insight can reveal the role of the maternal immune response to environmental exposures and support interventions to limit childhood disease.
Understanding human immunology, such insight can reveal the broad spectrum of human immune responses that can guide the development of new disease treatments.

Cancer and immunometabolism

Metabolic reprogramming and immune evasion are two critical hallmarks of cancer. This metabolic reprogramming ultimately leads to a ‘metabolic tug-of-war’ between the anti-tumour immune cell populations and the tumour itself. Understanding how tumours rewire metabolic pathways to support uncontrolled proliferation, invasion and migration of tumour cells will reveal novel therapeutic targets. We are interested in:

Repurposing drugs to metabolically target various adult and paediatric haematological cancers and solid tumours.
Understanding how immune cell dynamics are altered throughout the course of haematological cancers and solid tumours (i.e. relapse, remission and therapy resistance).
Using 3D cancer models to explore how cancer cells evade detection by immune cells in the tumour-microenvironment.

Early life origins of disease

Immune system development during intrauterine and early extrauterine life might be a key determinant of the development of numerous immune-mediated disorders in childhood including allergic, inflammatory bowel and autoimmune diseases. These disorders are driven by the interaction of environmental factors and genetic susceptibility. The environmental pressures in pregnancy that are the focus of our research efforts are maternal obesity and exposure to air and plastic pollution.

Novel diagnostics in obstetrics

Working closely with the local health board and international partners we are applying vibrational spectroscopy to the analysis of blood to develop better ways of identifying women with pregnancy disorders such as gestational diabetes, preeclampsia and cholestasis. The goal is community-based testing that can be easily accessed by all pregnant women.

Identifying biomarkers to predict invasive infections in humans and animals

The global burden of disease is dominated by microorganisms that cause severe invasive infections (e.g sepsis) and are associated with high morbidity and mortality. We focus on assessing host and microbial cell responses to identify patterns in local (skin, lung or gut) infections that predict the likelihood of progression to severe infections (blood). Our research identifies biomarkers that will help the NHS predict those at risk for developing severe infections and help save lives.

Research Outcomes

We have recently identified that the sugar fructose supports heightened inflammation by a key population of cells known as monocytes. These cells have an important role in our early immune response to pathogens and are associated with an increased inflammatory state in obesity and are linked to obesity-associated diseases. We also found that these hyperinflammatory cells could be killed more easily and we are now exploring whether this can be exploited as therapy for COVID-19.

The Impact of Fructose on the Immune System

Fructose is commonly found in sugary drinks, sweets and processed foods and is used widely in food production. However, understanding the impact of fructose on the immune system of people who consume it in high levels, has been limited until now. We show that fructose causes the immune system to become inflamed and that process produces more reactive molecules which are associated with inflammation. The research also brings a deeper understanding about how fructose could be linked to diabetes and obesity - as low- level inflammation is often associated with obesity.

Protecting tissues against bacteria

Tissue damage is a common feature of bacterial diseases. Many species of pathogenic bacteria produce toxins that form holes in cell membranes, which can cause cell death. However, tissue cells vary in their ability to protect themselves against these toxins. We are uncovering the mechanisms that cells use to prevent damage.

We have found hormones and drugs that increase the resilience of cell membranes to the toxins. We aim to develop novel approaches to protect tissue cells against bacterial toxins to treat and prevent disease.

Associated Collaborative and Industry Partners

Swansea Bay University Health Board
Joint Clinical Research Facility
Cardiff University
Celgene (Bristol Myers Squibb)
Bristol University
Trinity College Dublin
Makerere University (Uganda)

Associated Research Projects

Metabolic approaches to abolishing cytokine storm in COVID-19; MRC (MR/V037013/1); CA Thornton, N Jones, C Battle (SBU HB), L Newey (SBU HB), A Finall (SBU HB), A Byrne (Imperial College London)
Harnessing pregnancy-associated immunoinflammatory responses to SARS-CoV-2 for mechanistic insight and therapeutic benefit; Ser Cymru II (Welsh Government); CA Thornton, A Finall (SBU HB), M Nair (SBU HB)
Building research capacity in functional genomics in life, health and environmental sciences; Ser Cymru II (Welsh Government); Thornton CA, Cronin JG, Conlan RS, Coates C (Bioscience), S Consuegra (Bioscience), C Garcia de Leaniz (Bioscience)
Regulation of immunometabolism in multiple myeloma and the effects of IMiDs; Celgene (Bristol Myers Squjibb); CA Thornton, N Jones, H Sati (SBU HB)
Disrupting the diagnostic paradigm for gestational diabetes using blood-based Raman spectroscopy; Diabetes UK; CA Thornton, PR Dunstan (Physics), E Dudley
Repurposing approved drugs to target metabolic flexibility in ovarian cancer cells in the tumour microenvironment; Health and Care Research Wales. Cronin JG, Jones N

Associated Sub-Theme Publications

Jones N, Blagih J, Zani F, Rees A, Hill D, Jenkins BJ, Bull C, Moreira D, Bantan A, Cronin JG, Avancini D, Jones G, Finlay D, Vousden K, Vincent E, Thornton CA. Fructose reprograms glutamine-dependent oxidative metabolism to support LPS-induced inflammation. Nature Communications. Accepted
Chaney HL, Grose LF, Charpigny G, Behura SK, Sheldon IM, Cronin JG, Lonergan P, Spencer TE, Mathew DJ. Conceptus-induced, interferon tau dependent gene expression in bovine endometrial epithelial and stromal cells†. Biol Reprod. Epub ahead of print.
Sala A, Spalding KE, Ashton KM, Board R, Butler HJ, Dawson TP, Harris DA, Hughes CS, Jenkins CA, Jenkinson MD, Palmer DS, Smith BR, Thornton CA, Baker MJ. Rapid analysis of disease state in liquid human serum combining infrared spectroscopy and "digital drying". J Biophotonics. 2020;13(9):e202000118.
Jones N, Vincent EE, Felix LC, Cronin JG, Scott LM, Hole PS, Lacy P, Thornton CA. Interleukin-5 drives glycolysis and reactive oxygen species-dependent citric acid cycling by eosinophils. Allergy. 2020;75(6):1361-1370.
Piasecka J, Thornton CA, Rees P, Summers HD. Diffusion Mapping of Eosinophil-Activation State. Cytometry A. 2020;97(3):253-258.
Ruiz-de-Angulo A, Bilbao-Asensio M, Cronin J, Evans SJ, Clift MJD, Llop J, Feiner IVJ, Beadman R, Bascarán KZ, Mareque-Rivas JC. Chemically Programmed Vaccines: Iron Catalysis in Nanoparticles Enhances Combination Immunotherapy and Immunotherapy-Promoted Tumor Ferroptosis. iScience. 2020;23(9):101499.
Tse C, Warner A, Farook R, Cronin JG. Phytochemical Targeting of STAT3 Orchestrated Lipid Metabolism in Therapy-Resistant Cancers. Biomolecules. 2020;10(8):1118.
Nassar M, Doan M, Filby A, Wolkenhauer O, Fogg DK, Piasecka J, Thornton CA, Carpenter AE, Summers HD, Rees P, Hennig H. Label-Free Identification of White Blood Cells Using Machine Learning. Cytometry A. 2019; 95(8):836-842.
Jones N, Vincent EE, Cronin JG, Panetti S, Chambers M, Holm SR, Owens SE, Francis NJ, Finlay DK, Thornton CA. Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation. Nature Communications. 2019;10(1):2042
Oo YH, Ackrill S, Cole R, Jenkins L, Anderson P, Jeffery HC, Jones N, Jeffery LE, Lutz P, Wawman RE, Athwal AK, Thompson J, Gray J, Guo K, Barton D, Hirschfield GM, Wong T, Guest P, Adams DH. Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis. JHEP Rep. 2019;1(4):286-296.
Lutz P, Jeffery HC, Jones N, Birtwistle J, Kramer B, Nattermann J, Spengler U, Strassburg CP, Adams DH, Oo YH. NK Cells in Ascites From Liver Disease Patients Display a Particular Phenotype and Take Part in Antibacterial Immune Response. Front Immunol. 2019 ;10:1838.
Jenkins CA, Jenkins RA, Pryse MM, Welsby KA, Jitsumura M, Thornton CA, Dunstan PR, Harris DA. A high-throughput serum Raman spectroscopy platform and
methodology for colorectal cancer diagnostics. Analyst. 2018;143(24):6014-6024.
Jones N, Cronin JG, Dolton G, Panetti S, Schauenburg AJ, Galloway SAE, Sewell AK, Cole DK, Thornton CA, Francis NJ. Metabolic Adaptation of Human CD4+ and CD8+ T-Cells to T-Cell Receptor-Mediated Stimulation. Front Immunol. 2017;8:1516.
Bryant AH, Bevan RJ, Spencer-Harty S, Scott LM, Jones RH, Thornton CA. Expression and function of NOD-like receptors by human term gestation-associated tissues. Placenta. 2017;58:25-32.
Carneiro LC, Bedford C, Jacca S, Rosamilia A, de Lima VF, Donofrio G, Sheldon IM, Cronin JG. Coordinated Role of Toll-Like Receptor-3 and Retinoic Acid- Inducible Gene-I in the Innate Response of Bovine Endometrial Cells to Virus. Front Immunol. 2017;8:996.
Scott LM, Bryant AH, Rees A, Down B, Jones RH, Thornton CA. Production and regulation of interleukin-1 family cytokines at the materno-fetal interface. Cytokine. 2017;99:194-202.
Bryant AH, Menzies GE, Scott LM, Spencer-Harty S, Davies LB, Smith RA, Jones RH, Thornton CA. Human gestation-associated tissues express functional cytosolic nucleic acid sensing pattern recognition receptors. Clin Exp Immunol. 2017;189(1):36-46.