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Professor Mick Bailey

The effects of early-life environment on development of the mucosal immune system

Summary

The mucosal immune system is exposed to pathogens but also to food and commensal bacteria, and must produce active immune responses or tolerance, respectively. The ability to discriminate accurately between the two is important, since making the wrong decision can result in allergy or in susceptibility to infectious diseases. There is increasing evidence that events during early life can influence individual susceptibility to allergy, by affecting the process of colonisation of the intestine with commensal microbiota, exposure to pathogenic organisms, or through the level of exposure to food antigens before weaning. Similar early-life events affecting microbial colonisation are also now thought to contribute to a number of metabolic diseases in humans. Our studies use piglets, since they develop transient immune responses to food antigens at weaning, and since they are commercially reared in a range of different environments including extensive, outdoor systems and intensive, indoor systems. In addition, their nutrition and metabolism is perceived as very comparable to that of humans.

 

Pigs in different environments

 

Over several years, we have demonstrated that the immune system of young piglets is initially poorly developed and that it matures over time. Antigen presenting cells with the characteristics of dendritic cells enter the intestine in the first week, followed by CD4+ T-cells when the pigs are 2 to 4 weeks old, and CD8+ T-cells from 4 weeks old onwards, and the mature intestinal architecture is not achieved until at least six weeks old. 

 

 DC and T-Reg

Dendritic Cell                                                       T-reg cell 

Key Findings/ Activities

Our current studies suggest that rearing environment affects the way that the mucosal immune system develops. Using piglets reared in a range of different environments, we have demonstrated significant correlations between the type of complex microbiotas which establish in the intestine and the early appearance of dendritic cells. We have developed robust, quantitative approaches to analysing expression, distribution and co-localisation of immunologically-relevant molecules in tissues. Using this approach, we have demonstrated direct interactions between antigen-presenting cells and CD4 +ve T-cells in intestinal mucosa. Since these interactions are MHC class II dependant, we presume that they involve T-cells scanning APC for cognate peptide. In mature animals, the interactions are exclusively with cells with characteristics of dendritic cells, whereas endothelial cells are involved in a significant proportion of the interactions in neonates. Our current hypothesis is that the involvement of endothelial cells in T-cell-dendritic cell interactions in young animals is driven by the developing microbiota and accounts for the tendency of neonates to over-react to harmless food antigens.

 

MHCII Endothelial cell

 

Our recent research has extended these observations to show that early-l ife events have significant, long-term effects on the functions of mucosal antigen-presenting cells and T-cells, and that this influences responses to food antigens. Studies using 'probiotic' strains of bacteria suggest that it is possible to manipulate the way both the immune and metabolic systems develop in young piglets. We have now begun to address the links between these two systems, and the way that diet, environment and probiotic intervention can interact to promote enteric 'health'. Integrating results from our studies with those in humans and mice strongly suggests that attempts to manipulate the immune system of mature animals are likely to be less successful than interventions in neonates. In addition, each type of nutritional intervention (including different pro- and pre-biotics) is likely to have a specific, different effect on metabolism and immunity in the target species. Currently, nutritional interventions like probiotics are used empirically and indiscriminately. In future, it seems likely that we will use them more like antibiotics, targeted at specific problems on individual farms with characterised core microbiotas. Further, we may need to intervene early, immediately after birth or at weaning, and to plan their effects over generations.

 

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Research keywords

  • Mucosal immunology
  • T-cell
  • dendritic cell
  • allergy
  • microbiota

Research findings

Using piglets reared in a range of different environments, we have demonstrated significant correlations between the type of complex microbiotas which establish in the intestine and the early appearance of dendritic cells. We have demonstrated direct interactions between antigen-presenting cells and CD4 +ve T-cells in intestinal mucosa. Since these interactions are MHC class II dependant, we presume that they involve T-cells scanning APC for cognate peptide. In mature animals, the interactions are exclusively with cells with characteristics of dendritic cells, whereas endothelial cells are involved in a significant proportion of the interactions in neonates.

Our current hypothesis is that the involvement of endothelial cells in T-cell-dendritic cell interactions in young animals may be driven by the developing microbiota and may account for the tendency of neonates to over-react to harmless food antigens.

Collaborations

  • Chris Stokes
  • Wendy Gibson