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To investigate the influence of maternal experience of dietary antigen on the subsequent immune status of their offspring

Project Code: T07026;
Publication:

Haverson, K., Corfield, G., Jones, P. H., Kenny, M., Fowler, J., Bailey, M., Stokes, C. R. and Miller B. G. (2009). Effect of oral antigen and antibody exposure at birth on subsequent immune status: a study in neonatal pigs. International Archives of Allergy and Immunology. 150: 192-204.

31/08/2006

Bristol University Veterinary School, Department of Clinical Veterinary Science, University of Bristol
Miller, B ; Corfield, G; Kenny, M; Jones, P; Haverson, K; Bailey, M; Stokes, C

Background

In 1998 the Department of Health, Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment recommended that pregnant women and breast-feeding mothers may wish to avoid eating peanuts and foods containing peanut products. These recommendations were made in the belief, that whilst genotype will have a major effect on whether a child develops allergy, the conditions and timing of exposure (the route, extent and duration of exposure, and the age at first exposure) play an important, but as yet poorly defined, role in the acquisition of sensitization to food proteins (Kimber and Dearman, 2002). Specific research objectives were therefore identified:

1. The influence of maternal nutrition and neonatal feeding practices on the development of food intolerance in atopic and non-atopic children.

2. The effect of exposure to food proteins via maternal sources in the development of food allergy in infants.

3. Determine the impact of age and route of exposure on the development of food allergy.

Rationale and Objectives

The objective of this project was to identify in an animal model whether exposure to antigen, antibody or immune complex (where the antibody is bound to its antigen) at birth affected subsequent immune development. The pig was chosen as the animal model since pigs in contrast to the human, is born devoid of any maternal antibody or maternally derived dietary antigen since the placenta of the pig lacks the ability to transfer large molecules such as proteins. As such, by exposing the pig at birth it is possible to mimic the in utero exposure which occurs in humans. The pig therefore offers an almost unique opportunity (not available in rodent models) to manipulate very early immune exposure.

Detailed information on the effects of very early exposure (in utero or at birth) to either antigen or antibodies will add to the body of evidence to inform any discussion both by the FSA and clinicians concerning the COT advice.

Approach

Pigs were removed from a commercial farm at birth (prior to suckling their dams) and transferred to the University of Bristol Specific Pathogen Free intensive care unit for piglets. They were then cared for individually and fed hourly artificial milk. Immediately upon arrival within the unit, pigs were given orally either physiologically buffered saline (control group) or a solution containing either ovalbumin (egg allergen), anti-ovalbumin antibody or a complex of the two. The anti-ovalbumin antibody, having previously been prepared by either injection (hyperimmune) or feeding with ovalbumin (tolerant), to a separate group of pigs and subsequently collection of their sera. The pigs are defined as hyperimmune because they respond to injected antigen in contrast to the tolerant group who are orally tolerant following feeding and thus fail to respond to injected antigen.

At 16 days of age the isolator reared piglets were exposed to ovalbumin either by injection or by feeding and their subsequent immune response assessed. The aim being to determine whether the early immune exposure had affected the way the piglets at 16 days responded to antigen presented either systemically (injection) or at the gut mucosa (feeding). Two methods of antigen exposure were utilized given that it is well established that immune responses at a mucosal surface can be significantly different from systemic challenge. Several markers of immune function were monitored including serum antibody responses, phenotypic analysis and culture of isolated immune cells from the gut, spleen and blood along with both conventional histology and immunohistochemistry of the small intestine.

Outcome/Key Results Obtained

The results from the immune function assays conducted on the different treatments of pigs clearly indicated that oral exposure at birth to 1gm of ovalbumin, suppressed any subsequent immune response when exposed to ovalbumin whether by injection or orally at 16 days of age. Lower doses of 100mg or 1mg had respectively only a marginal or no affect. The conclusion being that the higher level of early exposure to ovalbumin induces oral tolerance in neonatal pigs. No affects of antibody given alone at birth (whether derived from hyper-immune or tolerant pigs) on subsequent immunity were observed. It is important to note that these antibodies were derived from non-atopic pigs who had no observable clinical symptoms when fed ovalbumin. Serum from atopic pigs may be significantly different from non-atopic pigs and thus any effect upon immune development when given to neonatal pigs may also be different. Arguably an atopic pig model would be a better model for human allergy. Pigs given complexes (antibody plus Ovalbumin) at birth showed minimal responsiveness when subsequently challenged either orally or by injection with ovalbumin, indicating that oral tolerance may have been induced.

What it means and why it’s important

The results inform the discussion of the current COT advice since they infer that neonatal antigen exposure induces oral tolerance. However caution must be exercised since the pig model used may not reflect the response of children from allergic human mothers. The observations should therefore be confirmed using serum from sows made atopic and it established whether exposure to antigen at birth also induces oral tolerance in these animals.

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