Prof. Stella C Knight

Background

Studies in basic immunology of the human gut^1,2,3and the role of dendritic cells(DC) are being extended and used as a base to inform the nature of immune changes in inflammatory bowel disease and cancer and to identify routes to immunotherapy. Our laboratories are located within the footprint of St Mark’s Hospital and Academic Institute for Colorectal Diseases enabling collaborative links and the rare opportunity for effective study of human immunology.

Current research
Dendritic cell diversity
The hypothesis under study is that full characterisation of the properties of blood DC, studied initially in relation to DC and disease in different parts of the human gut, will aid definition of the type of disease, its location and severity, will be informative in diagnosis and allocation of suitable treatments, as early indicators of effectiveness of treatment and as direct targets for immunotherapy.

Effect of obesity and uptake of fat into dendritic cells

Some differences in DC properties and functions are related to obesity and to the distribution of fat. Increased scavenger receptor expression and fat-storage in DC have been found particularly in cancer and contribute to loss of DC stimulatory function and suppression of immune activity by DC^4,5. Systemic differences in fat and fat metabolism in DC themselves in gut inflammation⁶ and in colorectal cancer which affect their immune functions are being identified⁴.

Interactions of dendritic cells and the microbiome

A major programme of work is to study the impact of different commensal/probiotic bacteria on the functioning of antigen presenting cells. Looking at the effects of different commensal bacteria on different subsets of DC is underway. Our evidence also indicates that products of commensal bacteria, as well as the bacteria themselves, have immunomodulatory function^7-9. The role of the peptideSTp produced by the commensal bacterium Lactobacillusplantarum, is patented as a potential therapeutic agent for IBD. It is currently under study in preclinical trials as a treatment for mouse colitis.

Recent publications

1. Mann, E. R. et al. Compartment-specific immunity in the human gut: properties and functions of dendritic cells in the colon versus the ileum. Gut 65, 256-270, doi:10.1136/gutjnl-2014-307916 (2016).
2. Bernardo, D. et al. CCR2 mediates dendritic cell recruitment to human colon but is not responsible for differences observed in dendritic cell subsets, phenotype and function between proximal and distal colon. Cellular and Molecular Gastroenterology and Hepatology 2, 23-39 (2016).
3. Vora, R. et al. Age-related alterations in blood and colonic dendritic cell properties. Oncotarget, doi:10.18632/oncotarget.7799 (2016).
4. Malietzis, G. et al. Body composition of the host influences dendritic cell phenotype in patients treated for colorectal cancer. Tumour Biol, doi:10.1007/s13277-016-5009-y (2016).
5. Herber, D. L. et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nature Medicine 16, 880-U857 (2010).
6. Al-Hassi, H. O. et al. A mechanistic role for leptin in human dendritic cell migration: differences between ileum and colon in health and Crohn's disease. Mucosal Immunol 6, 751-761, doi:Doi 10.1038/Mi.2012.113 (2013).
7. Bernardo, D. et al. Microbiota/Host Crosstalk Biomarkers: Regulatory Response of Human Intestinal Dendritic Cells Exposed to Lactobacillus Extracellular Encrypted Peptide. PloS one 7, doi:ARTN e36262 DOI 10.1371/journal.pone.0036262 (2012).
8. Al-Hassi, H. O. et al. Altered human gut dendritic cell properties in ulcerative colitis are reversed by Lactobacillus plantarum extracellular encrypted peptide STp. Mol Nutr Food Res 58, 1132-1143, doi:DOI 10.1002/mnfr.201300596 (2014).
9. Mann, E. R. et al. Dysregulated circulating dendritic cell function in ulcerative colitis is partially restored by probiotic strain Lactobacillus Casei Shirota. Mediators Inflamm 2013, 573576, doi:10.1155/2013/573576 (2013).

Dr Alistair Noble

Background

Inflammation in IBD is primarily mediated by the T cells of the immune system, which infiltrate the tissues of the intestine and produce inflammatory cytokines. T cell responses are driven by dendritic cells, which are present in the intestinal tissue and sense bacteria growing in the gut or invasive organisms infiltrating the tissues. In addition, dendritic cells recognise inflammatory or “danger” signals generated by tissue damage or activation of epithelial cells. Once activated, dendritic cells migrate to local lymphoid tissue where they induce development of antigen-specific T cells and program them to migrate back to the intestine. These T cells can develop into either pathogenic subsets, which cause disease through excessive cytokine release, or regulatory subsets that maintain a healthy gut by excluding bacteria from the tissues.

Current research
We are studying the T cells and dendritic cells that reside in the colonic tissues of healthy people and those with IBD. These cells may be specific for gut bacteria or result from immunity to other antigens. We are investigating how these cells contribute to gut health or respond to alterations in the bacterial populations of the gut contents, which is characteristic of IBD. Our aim is to develop vaccines or bacterial therapy that could be used in IBD treatment or in the prevention/treatment of colorectal cancer.

Recent publications
See Dr Alistair Noble’s publications