Understanding immune biomarkers for use in nutrition interventions

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1 NIHR Southampton Biomedical Research Centre in nutrition Understanding immune biomarkers for use in nutrition interventions Philip C. Calder Professor of Nutritional Immunology University of Southampton The NIHR Southampton Biomedical Research Centre in nutrition is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton

2 Many stakeholders are interested in immune claims. Industry Scientists Regulators Consumers

3 What does the immune system do and how does it work?

4 Exclusion barrier Identification of non-self /Tolerance of self and benign non-self Elimination Memory

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6 Interaction amongst immune cells B Activate Th Activate Activate NK Antibodies Activate Antigen presentation Tc Antigen presentation Lysis Bacteria Phagocyte Virus infected cell

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9 The immune system is very complex It involves many different cell types, chemical mediators and interactions It is dispersed throughout the body It changes its activity according to what it encounters

10 How can we assess immune function in human trials?

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12 Measure immune markers in blood or other accessible sites (e.g. there are certain antibodies in saliva) Isolate immune cells from blood and then study those cells in culture -> can measure functional responses

13 Give a person an immune challenge (e.g. a vaccination) and follow the response Look at pattern of infections do they occur, how severe are they, how long do they last

14 Biomarkers of immune function - ex vivo Phagocytosis - blood neutrophils & monocytes Respiratory burst blood neutrophils & monocytes Natural killer (NK) cell activity - killing of target tumour cells Cytotoxic T cell activity - killing of target virally infected or tumour cells Lymphocyte proliferation Cytokine production Antibody production Cell surface expression of molecules involved in antigen presentation, in cell interaction and cell activation

15 Biomarkers of immune function - in vivo Size [and cellularity] of lymphoid organs Number and type of immune cells in the circulation (there are normal reference values) Cell surface expression of molecules involved in antigen presentation, in cell interactions and in cellular activation Circulating concentrations of total Ig and of Ig subclasses (there are normal reference values) Circulating concentrations of antigen-specific Ig after antigen challenge (primary & secondary responses) e.g. vaccination Concentration of secretory IgA in saliva, tears, and intestinal washings Circulating concentrations of cytokines DTH (cell-mediated immune) response to intradermal application of antigen to which the individual is sensitised Resistance to challenge with live pathogens (survival vs. mortality; duration; number of pathogens in spleen, liver, lungs etc.)

16 % of cells active Cytokine concentration (ng/ml) There is significant variation in immune responses among healthy individuals Phagocytosis Resp Phagocytosis Resp burst burst 0 TNF-a IL-1b IL-6 Neutrophils Monocytes Healthy males, aged 40 to 65 years (n = 50 to 83) Kew et al. (2003) Am. J. Clin. Nutr. 77,

17 There is great variation between individuals in any immune parameter measured considered the sources of variation Different aspects of immunity may respond differently (or with different dose responses) to nutritional intervention

18 It is possible to measure many different immune parameters There is large variation among individuals in most immune parameters that are measured Several sources of such variation are known Both the variation and the sources of variation need to be considered when doing trials Sufficient sample size needed ( power ) Heterogeneity of the study population -> heterogeneity of immune response Also heterogeneity of the study population -> heterogeneity of response to the nutritional intervention Inclusion/exclusion criteria

19 ILSI Europe Nutrition & Immunity in Man Task Force & Expert Group activity reported in 2005 The present review summarises the immune function assays used as markers in human intervention studies and evaluates their biological relevance, sensitivity, and practical feasibility. Based on these criteria markers were classified into three categories with high, medium or low suitability.

20 Vaccine-specific serum antibodies, delayed-type hypersensitivity response, vaccine-specific or total secretory IgA in saliva and the response to attenuated pathogens were classified as markers of HIGH suitability. Markers with MEDIUM suitability include natural killer cell cytotoxicity, oxidative burst of phagocytes, lymphocyte proliferation and the cytokine pattern produced by activated immune cells. No single marker allows conclusions to be drawn about modulation of the whole immune system, except for the clinical outcome of infection itself, combining markers with high and medium suitability is currently the best approach to measure immunomodulation in human nutrition intervention studies.

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22 No single marker is available to predict the effect of a dietary intervention on different aspects of immune function Defined criteria to evaluate usefulness of immune function markers -> over 75 markers were scored within the contexts of defence against pathogens, avoidance or mitigation of allergy, control of low-grade (metabolic) inflammation The most useful markers were subsequently classified depending upon their clinical significance Five hypothetical scenarios were considered to describe potential changes in values of markers compared with a relevant reference range Finally, a flow chart was developed to aid interpretation of studies assessing the effects of nutrition on immune function

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26 The five scenarios considered

27 Flow chart to aid the interpretation of changes in immune function markers in nutrition studies

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29 Intestinal Immune System Constant and masive antigenic stimulation Invasive pathogens Strong protective immunity Food proteins and commensal bacteria Oral tolerance Mowat (2003) Nature Reviews Immunology 3,

30 Overall summary There is considerable stakeholder interest in health claims around immune function The immune system is complex and highly variable between individuals There is no single biomarker of immune response that can be used in healthy subjects Attempts have been made to document and evaluate markers of relevance in order to identify those that will be most useful in nutrition intervention studies in humans The gut-associated immune system is very important but is difficult to assess