Biomarkers of immunity and inflammation for use in nutrition interventions: ILSI Europe work on selection criteria and interpretation

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1 NIHR Southampton Biomedical Research Centre in nutrition Biomarkers of immunity and inflammation for use in nutrition interventions: ILSI Europe work on selection criteria and interpretation 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 To cover Background to ILSI Europe EG activity in the area of immune biomarkers Description of the activity and output from two EGs on immune biomarkers and one EG on biomarkers of inflammation

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

5 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

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7 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.

8 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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10 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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14 The five scenarios considered

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

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18 The approach used to identify candidate biomarkers Identified general and disease specific markers of inflammation within the circulation and within tissue sites Considered metabolic, immune mediated, allergic and neurodegenerative inflammatory conditions Identified soluble (plasma/serum), blood cellular, and tissue markers for each condition Identified markers that are common across conditions (these must be generic markers of inflammation)

19 Soluble markers Cytokines/chemokines TNF, TNFR, IL-6, IL-1β, IL-8, IFN-γ, CCL2, CCL3, CCL5 Acute phase proteins CRP, SAA, Fibrinogen, vwf, anti-chymotrypsin, C3, IL-1ra, PAI-1, spla2 Adhesion molecules VCAM-1, ICAM-1, E-selectin, P-selectin Adipokines Leptin, Adiponectin

20 Total leukocytes Total neutrophils Total T cells Total eosinophils Total monocytes Blood cellular markers

21 There is wide variation in any of the soluble or blood cellular markers of inflammation even amongst normal, fairly healthy individuals

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24 The inflammatory response is dynamic

25 Challenge models Most often markers measured in a resting state (e.g. in fasted blood) are used Such measurements can identify persons with overt inflammatory diseases from those without and can identify effects of some modifiers But such measurements do not provide information about an individual s ability to respond to an inflammatory challenge -> may be a more meaningful measure

26 Challenge models considered Oral glucose load Oral fat load Acute exercise iv or im administration of LPS, TNF or IL-6 UVB exposure Vaccination

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28 Emerging markers of inflammation Cell surface markers CD11b on granulocytes CD66b on monocytes CD11c on monocytes Clusters of markers Cell stress markers Heat shock proteins and other chaperones MicroRNA

29 Emerging technologies Omics technologies Identification of new markers Clusters or patterns as markers Imaging

30 Biomarkers of inflammation: Summary 1 Acute inflammation is a normal physiological response crucial for maintaining homeostasis but when it becomes chronic, inflammation contributes to pathology Common soluble and blood cellular markers can be identified The same markers are involved in acute and chronic inflammatory processes and so cannot be used to distinguish these processes There are a number of exogenous and endogenous modifiers that influence the levels of inflammatory markers

31 Biomarkers of inflammation: Summary 2 Inflammatory responsiveness or resilience to challenges may provide a more sensitive and meaningful indication of inflammatory state than the assessment of markers during the steady state There is a need to standardise challenges and subsequent assessments It is likely that a combination of multiple inflammatory markers and integrated readouts based on kinetic analysis following challenge will be the most informative biomarker of inflammation Novel markers are emerging

32 Overall summary There is considerable stakeholder interest in health claims around immunity and inflammation The immune system, including its inflammatory component, is complex and highly variable between individuals There is no single biomarker of immune response or inflammation that can be used in healthy subjects ILSI Europe EGs have sought to document and evaluate markers of relevance in order to identify those that will be most useful in nutrition intervention studies in humans Significant progress has been made in this area