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Immunomodulation - A Cure for Allergic Disease?

Early Prevention of Allergy Disease

John A. Warner
Southampton General Hospital
Southampton, United Kingdom

John Warner has been Professor of Child Health at the University of Southampton for the last 14 years. Prior to that, he was Senior Lecturer, Reader and Honorary Consultant in paediatric chest medicine at the Royal Brompton National Heart & Lung Hospital and received his training in paediatric allergy and respiratory disease both in Sheffield and at the Hospital for Sick Children in Great Ormond Street. He has published over 300 papers on paediatric chest medicine and allergy. He is Editor-in-Chief of the Journal of Pediatric Allergy & Immunology. The main focus of his research has been on the early life origins of asthma and related allergic disorders.

Very few treatments have been shown to modify the allergic march from atopic eczema through to allergic rhinitis and asthma and no cure has been identified for any of the conditions. Thus the best predictors of continuing asthma into adulthood are early age of onset, early allergic sensitisation to inhalants, abnormal lung function and bronchial hyperresponsiveness in early life. This suggests that the disease process starts in very early life and research must focus on understanding the way in which it evolves in order to identify targets for future prevention.

The fetus is not immunologically naïve. Even at 16 weeks' gestation, the cellular immune response is active in the fetal bowel and by 22 weeks, circulating peripheral blood mononuclear cells demonstrate proliferative responses to environmental antigens and surface IgM can be demonstrated on B cells. In some respects, the immune response of the fetus is allergically biased as a consequence of protective mechanisms initiated by the placenta to prevent the mother mounting a rejecting Th-1 mediated immune response to the fetus. After birth, the fetal pattern of an allergy Th-2 biased immune response is rapidly reversed primarily as a consequence of exposure to environmental factors, of which bacteria, viruses and other parasites may be particularly important. This latter sequence is the mechanistic basis for the so-called hygiene hypothesis which suggests that failure to be exposed to such organisms leads to a persistence of the allergic response as a consequence of excessive hygiene.

Many factors have been identified to have an impact on the very subtle interaction between the mother, the placenta and the fetus during pregnancy and the environment of the mother and baby in the first months of life. Thus, there are variations in nutrition and programmed fetal growth, maternal health, particularly in relation to her own allergic status, exposure to environmental tobacco smoke and other pollutants. Such factors are only operative in situations where there is genetic susceptibility to allergy as demonstrated by a range of gene polymorphisms. Postnatal influences have focused on allergen exposure in the microbial environment. Particular attention has been paid to the bacteria that first colonised the infant's gut.

Potential intervention strategies based on the above understanding of mechanisms include optimisation of nutrition of the mother during pregnancy, with perhaps lipid, antioxidant, mineral, and vitamin supplementation. Modification of allergen exposure in pregnancy may either be to avoid completely or, alternatively, to induce tolerance by high level exposure. Avoidance of maternal smoking during pregnancy will significantly reduce wheezing illnesses, particularly in infancy, though the effect on allergy is less clear. Postnatally, breast feeding may well reduce the risk of allergy, though there are some conflicting outcomes from studies in relation to this. Immune modulation by the use of DNA vaccines, pro- or pre-biotics, may modify the risk of allergy if administered very early in life. Once the allergic march has commenced, the ability to interfere with progression diminishes appreciably. However, there have been 3 trials of specific antihistamines which have been shown to prevent the development of asthma in infants who have already developed atopic eczema and have particular inhalant allergen sensitivities. Similarly, early treatment of allergic rhinitis with pollen immunotherapy may delay or prevent the onset of asthma.

Given the dramatic increase in the prevalence of allergic diseases, including asthma, it is reasonable to hypothesise that early life research will have the potential to turn back the clock 30 years and reduce prevalence rates by several orders of magnitude.


Warner JO. The early life origins of asthma and related allergic disorders. Arch. Dis. Child. 2004;89:97-102.

Thornton CA , Holloway JA, Popplewell EJ, Shute JK, Boughton J, Warner JO. Fetal exposure to intact immunoglobulin E occurs via the gastrointestinal tract. Clin. Exp. Allergy. 2003;33:306-311.

Jones CA, Holloway JA, Warner JO. Does atopic disease start in fetal life? Allergy. 2000;55:2-10.

Warner JO, Warner JA. Preventing asthma. In: Childhood Asthma & Other Wheezing Disorders. 2 nd Edit. Ed. Silverman M. Oxford University Press Inc., London , UK . 2002:401-413.

Jones CA, Holloway JA, Popplewell EJ et al. Reduced soluble CD14 levels in amniotic fluid and breast milk are associated with the subsequent development of atopy, eczema or both. J. Allergy Clin. Immunol. 2002;109:858-866.

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