Invited Symposium: Novel Cellular and Molecular Mechanisms in Allergic Inflammation
Allergen-specific T-cell priming
T-CELL PRIMING AGAINST ENVIRONMENTAL ALLERGENS: LYMPHOPROLIFERATIVE STUDIES IN CORD BLOOD (CB)
In relation to the aetiology of atopy, the central question is accordingly: how are these divergent cytokine response patterns programmed into long term immunological memory, in atopics and non-atopics?
In addressing this issue, one research stream that is growing rapidly in the current literature relates to the initial confrontations between the naive immune system and environmental allergens, which occur in very early life. As discussed below, the outcome of these early responses appear likely to play a major role in determining patterns of allergen reactivity in later life.
The initial findings suggestive of transplacental priming against environmental allergens date back to the 1970s from studies with ragweed pollen (8, 9). These findings were not followed up until comparatively recently, but have now been confirmed by a number of groups, employing a range of dietary and inhalant allergens (e.g. (10-15)). The interpretation of these results has been widely disputed, given the possible contamination of CB with maternal T-cells. However, a recent study from our group employing DNA genotyping of CB-derived allergen-specific T-cell clones has formally demonstrated their fetal origin (16).
The issue of whether there are quantitative or qualitative differences in this initial T-cell priming process between atopic family history positive (FH positive) and FH negative subjects remains controversial. There are some published data on lymphoproliferation suggesting that fetal priming is associated with atopic risk (17), whereas our recent studies, in particular those on CB cytokine responses (detailed below), suggest a more complex picture.
Postnatal maturation of T-cell immunity
POSTNATAL MATURATION OF ALLERGEN-SPECIFIC T-CELL IMUNITY: DIVERGENCE OF RESPONSE PATTERNS FOR DIETARY VERSUS INHALANT ALLERGENS
It is of interest to note in this context that low-level IgE production against allergens such as OVA is common in FH positive and FH negative infants (peak levels generally higher in the FH positive group), typically peaking before one year of age and declining to below detectable limits by age 2 years, except in a small subset of children who develop persistent food allergy (20, 21). This contrasts with findings relating to inhalants, where the typical response pattern involves initiation of IgE responses beyond age one, and with a much higher frequency of these responses persisting into later childhood (20, 21).
We have suggested (15, 22) that these disparate patterns of postnatal immune responsiveness may reflect the operation of two distinct classes of T-cell regulatory mechanisms, high zone tolerance (T-cell anergy and/or deletion) driven by high level exposure to dietary allergens, versus low zone tolerance (immune deviation) in the case of low level exposure to inhalants.
CROSS-SECTIONAL STUDIES ON ALLERGEN-SPECIFIC CYTOKINE RESPONSES DURING CHILDHOOD
In experiments focusing on these responses in older age groups, we have demonstrated that at age 18 months, allergen responsiveness within the population segregates on the basis of FH, with FH positive subjects typically manifesting a mixed (Th0-like) cytokine pattern including IL-4, IL-5 and IFNg, in contrast to much weaker cytokine responses amongst FH negative subjects which most frequently do not attain statistical significance (19). By age 5-6 years, <2% of 5-6 yr olds are SPT positive to the dietary allergen OVA, and in vitro PBMC cytokine responses are restricted to IL-6 (of non T-cell origin) and low level T-cell derived IL-10 (unpublished observations). In contrast, approximately 30% of the 5-6 yr old population are SPT positive to inhalants such as HDM, and their responses are dominated by the cytokines IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13, often with low level IFNg, whereas the responses in the SPT negative non-atopic population are principally IFNg in combination with IL-10 (19, 24). IL-10 production here is principally of T-cell origin (24), possibly from the same Th1 cells which are producing the IFNg.
These findings collectively are consistent with the generalised model (illustrated in (22)) referred to above, in which initial T-cell priming against allergens occurs within the Th2-polarised fetal microenvironment, with these responses subsequently being reshaped via high zone/low zone tolerance mechanisms which are driven by postnatal allergen exposure. “Normality” in this context equates to functional silencing of the bulk of food allergen reactivity during early infancy, versus immune deviation towards the Th1 (or Th0) cytokine phenotype for responses to inhalants; atopy in the context of Th2-mediated allergy to inhalants can thus be viewed as a failure of this latter immune deviation process.
Genetic basis for atopic risk
MECHANISM(S) UNDERLYING GENETIC PREDISPOSITION TO ATOPY: CLUES FROM IN VITRO CYTOKINE STUDIES IN NEONATES AND INFANTS
We have hypothesized that the delayed postnatal maturation of Th1-associated function(s) in children with the atopic genotype may compromise their capacity to immune deviate fetally-primed allergen-specific Th2 responses towards the Th1 cytokine phenotype, resulting in the consolidation of Th2-polarised immunological memory during early postnatal life (22, 31). This hypothesis is currently being tested in a series of prospective studies, the first of which is described briefly below.
PROSPECTIVE STUDIES ON ALLERGEN-SPECIFIC T-CELL IMMUNITY DURING EARLY CHILDHOOD
A recent study from our group (31) provides significant new information relevant to the mechanisms underlying this process. In this study, a cohort of subjects were followed to age 2 years, and two groups selected who expressed definite atopic disease at the outcome age (n=18) or who were symptom free (n=13). Allergen-specific T-cell responses in these subjects were then analysed employing cryopreserved PBMC samples which had previously been collected at 6 month intervals commencing with CBMC.
Several findings emerged from the study. Firstly, it was clear that CBMC from children who did not develop atopy expressed higher allergen-specific cytokine responses measured either as protein (IL-6, IL-10, IL-13) or mRNA (IL-4, IL-5 and IL-9), relative to their atopic counterparts. However, the postnatal course followed by these responses varied markedly between the two groups, the atopics demonstrating age-dependent increases in IL-4 and IL-13, in marked contrast to the inverse pattern (age-dependent decrease) in the group who did not develop atopy. Moreover, the non-atopic group exhibited rapid postnatal upregulation of allergen specific IFNg mRNA responses, compared to a very slow rise in the atopics.
Additionally, APC-independent stimulation of purified CD4+ T-cells from CB samples from both groups revealed markedly reduced IFNg production in the group who subsequently developed atopy, confirming earlier observations made on unfractionated CBMC (28).
These findings are consistent with the general model proposed above i.e. that the postnatal development of atopy is associated with a failure to “silence” (or immune deviate) fetally primed allergen-specific Th2 responses, which is in turn associated with deficient expression of Th1 function during the neonatal period.
Further prospective studies are in progress to analyse this model in more detail.
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14. Szepfalusi, Z., W.D. Huber, C. Ebner, G. Granditsch, and R. Urbanek. 1995. Early sensitization to airborne alllergens. Int Arch Allergy Immunol. 107:595 598.
15. Holt, P.G., P.O. O'Keeffe, B.J. Holt, J.W. Upham, M.J. Baron-Hay, C. Suphioglu, B. Knox, G.A. Stewart, W.R. Thomas, and P.D. Sly. 1995. T-cell "priming" against environmental allergens in human neonates: sequential deletion of food antigen specificities during infancy with concomitant expansion of responses to ubiquitous inhalant allergens. Ped Allergy Immunol. 6:85-90.
16. Prescott, S.L., C. Macaubas, B.J. Holt, T. Smallacombe, R. Loh, P.D. Sly, and P.G. Holt. 1998. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T-cell responses towards the Th-2 cytokine profile. J Immunol. 160:4730-4737.
17. Warner, J.A., A.C. Jones, M.E. A, and J.O. Warner. 1996. Prenatal sensitisation. Ped Allergy Immunol. 7:98-101.
18. Upham, J.W., B.J. Holt, M.J. Baron-Hay, A. Yabuhara, B.J. Hales, W.R. Thomas, R.K.S. Loh, P. O'Keeffe, P. Palmer, P. Le Souef, P.D. Sly, P.R. Burton, B.W.S. Robinson, and P.G. Holt. 1995. Inhalant allergen-specific T-cell reactivity is detectable in close to 100% of atopic and normal individuals: covert responses are unmasked by serum-free medium. Clin Exp Allergy. 25:634-642.
19. Yabuhara, A., C. Macaubas, S.L. Prescott, T. Venaille, B.J. Holt, W. Habre, P.D. Sly, and P.G. Holt. 1997. Th-2-polarised immunological memory to inhalant allergens in atopics is established during infancy and early childhood. Clin Exp Allergy. 27:1261-1269.
20. Holt, P.G. 1995. Environmental factors and primary T-cell sensitisation to inhalant allergens in infancy: reappraisal of the role of infections and air pollution. Pediatr Allergy Immunol. 6:1-10.
21. Hattevig, G., B. Kjellman, and B. Björksten. 1993. Appearance IgE antibodies to ingested and inhaled allergens during the first 12 years of life in atopic and non-atopic children. Ped Allergy Immunol. 4:182-6.
22. Holt, P.G., and C. Macaubas. 1997. Development of long term tolerance versus sensitisation to environmental allergens during the perinatal period. Curr Opin Immunol. 9:782-787.
23. Prescott, S.L., C. Macaubas, A. Yabuhara, T.J. Venaille, B.J. Holt, W. Habre, R. Loh, P.D. Sly, and P.G. Holt. 1997. Developing patterns of T cell memory to environmental allergens in the first two years of life. Int Arch Allergy Immunol. 113:75-79.
24. Macaubas, C., P.D. Sly, P. Burton, K. Tiller, A. Yabuhara, B.J. Holt, T.B. Smallacombe, G. Kendall, M. Jenmalm, and P.G. Holt. Regulation of Th-cell responses to inhalant allergen during early childhood. Clin Exp Allergy. Submitted.
25. Holt, P.G., J.B. Clough, B.J. Holt, M.J. Baron-Hay, A.H. Rose, B.W.S. Robinson, and W.R. Thomas. 1992. Genetic 'risk' for atopy is associated with delayed postnatal maturation of T-cell competence. Clin Exp Allergy. 22:1093-9.
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27. Rinas, U., G. Horneff, and V. Wahn. 1993. Interferon-g production by cord blood mononuclear cells is reduced in newborns with a family history of atopic disease and is independent from cord blood IgE-levels. Pediatr Allergy Immunol. 4:60-4.
28. Tang, M.L.K., A.S. Kemp, J. Thorburn, and D.J. Hill. 1994. Reduced interferon g secretion in neonates and subsequent atopy. Lancet. 344:983-86.
29. Liao, S.Y., T.N. Liao, B.L. Chiang, M.S. Huang, C.C. Chen, C.C. Chou, and K.H. Hsieh. 1996. Decreased production of IFNg and increased production of IL-6 by cord blood mononuclear cells of newborns with a high risk of allergy. Clin Exp Allergy. 26:397-405.
30. Martinez, F.D., D.A. Stern, A.L. Wright, C.J. Holberg, L.M. Taussig, and M. Halonen. 1995. Association of interleukin-2 and interferon-g production by blood mononuclear cells in infancy with parental allergy skin tests and with subsequent development of atopy. J Allergy Clin Immunol. 96:652-60.
31. Prescott, S.L., C. Macaubas, T. Smallacombe, B.J. Holt, P.D. Sly, and P.G. Holt. Fetal allergen-specific Th2 responses persist in atopic infants but are rapidly suppressed in non-atopics. Lancet. In press.
32. Shirakawa, T., T. Enomoto, S. Shimazu, and J.M. Hopkin. 1997. Inverse association between tuberculin responses and atopic disorder. Science. 275:77-79.
33. Prescott, S.L., P.D. Sly, and P.G. Holt. 1998. Raised serum IgE associated with reduced responsiveness to DPT vaccination during infancy. Lancet. 351:1489.
34. Piccinni, M.-P., L. Beloni, L. Giannarini, C. Livi, G. Scarselli, S. Romagnani, and E. Maggi. 1996. Abnormal production of T helper 2 cytokines interleukin-4 and interleukin-5 by T cells from newborns with atopic parents. Eur J Immunol. 26:2293-2298.
35. Martinez, F.D. 1994. Role of viral infections in the inception of asthma and allergies during childhood: could they be protective? Thorax. 49:1189-1191.
36. Holt, P.G., P.D. Sly, and B. Björksten. 1997. Atopic versus infectious diseases in childhood: a question of balance? Ped Allergy & Immunol. 8:53-58.
37. Baldini, M., I.C. Lohman, M. Halonen, R.P. Erickson, P.G. Holt, and F.D. Martinez. A polymorphism in the 5' - flanking region of the CD14 gene is associated with circulating soluble CD14 levels with total serum IgE. Am J Resp Cell Mol Biol. In press
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|Holt, PG; (1998). Ontogeny of Atopy. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/denburg/holt0863/index.html|
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