Abnormalities in cord blood mononuclear cytokine production as a predictor of later atopic disease...
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EDITORIAL Abnormalities in cord blood mononuclear cytokine production as a predictor of later atopic disease in childhood The escalating prevalence of atopic disease over recent decades [1–6], with associated spiralling social and eco- nomic costs [7–10], has emphasized the urgent need for action which will avert or reverse this trend. Of particular interest is the growing need for the development of primary prevention strategies. Essential to this approach is a clear understanding of the immunological processes in early life which promote TH2-polarized atopic sensitization. Envir- onmental factors implicated in this process, including changes in patterns of childhood infection [11–14], allergen exposure, and dietary intake [15], are currently being addressed. A means of identifying children at risk is important for targeted prevention. Currently the most reli- able way of predicting allergy is atopic heredity, but with the rising disease prevalence, the risk is still substantial for previously unaffected families. For many years there has been a search for a reliable marker for allergy prediction. Although elevated cord blood IgE (CB-IgE) is associated with the development of atopy, asthma [16–18], and ele- vated IgE at 5 years [18], after more than 20 years of research [19–21], it is now widely accepted that CB-IgE is of less value than a positive family history in predicting allergy, and is not of value as a screening test [22]. The paper by Kondo et al. in this issue reports the first long-term prospective study of clinical symptoms in child- ren in relation to capacity to generate IFNg responses at birth [23], and provides tantalizing hints of another possible prognostic marker, i.e. peri-natal T-cell function. Current developments in this area of research started in 1992, when this same group were the first to document allergen-specific proliferative responses in cord blood [24], an observation which promoted a surge of interest in cellular immune responses during the neonatal period. The findings from this and other research in this area have altered current concepts of initial allergen sensitization, which is now generally accepted to begin in utero. In this context, recent work by our own group confirms definitively (by microsatellite genotyping), that these allergen-specific responses by cord blood mononuclear cells (CBMC), noted previously as positive lymphoproliferation by many groups [24–28] are due to allergen-specific fetal T cells, as opposed to maternally-derived contaminants [29]. This work by our group shows that virtually all neonates display TH2-skewed allergen-specific responses at birth [29,30]. In the early post-natal period these TH2 responses are quickly restricted [30,31] by maturing TH1 immunity (a process know as immune deviation) and by 5 years of age normal patterns of TH1 immunity appear established in non-atopic individuals [32]. The central question is: why does this process fail in atopic individuals? There has been accumulating evidence of immaturity in aspects of immune function in atopic children, starting with an earlier report by our group that IFNg responses are defective in T-cell clones isolated from ‘high risk’ infants (with atopic heredity), compared with low risk infants [33]. It is now clear that while many immune functions are normally less mature at birth, these maturational deficien- cies may be more marked in individuals who go on to develop atopy. A large number of studies [25,30,34–37] have documented defective polyclonal IFNg responses by CBMCs from neonates either at risk of atopy, or those who later develop disease. Based on current data from many of the groups cited above, Fig. 1 shows a hypothetical model for the post-natal maturation of polyclonal IFNg responses. Although all neonates have reduced capacity for mitogen stimulated IFNg responses [38–41], this appears more marked in atopic individuals at birth, as discussed above [25,30,34– 37]. In normal non-atopic infants, IFNg responses to mitogenic polyclonal stimulation gradually increase over the first year of life, but at 2 years are still well below adult levels [38]. By 4–5 years of age most normal children have polyclonal IFNg responses approaching adult levels [38]. In contrast, infants with atopic heredity show a more delayed increase in IFNg responses in the early post- natal period, with the capacity for IFNg remaining sig- nificantly reduced compared with low risk children [33]. During this period, responses to vaccine antigen are also weaker in infants with higher serum IgE levels [42]. It is likely that the IFNg responses during this period are important for normal post-natal immune deviation of fetal TH2 responses. Clearly, these observed defects in TH1 immune responses provide a very attractive explana- tion for the persistence of the fetal TH2 responses [30] seen during childhood in association with atopic disease. Other work by our group has shown that the first 2 years of life is a critical period for the development of T helper memory patterns [31,43]. Targeting these TH1 defects in atopic individuals during this early period may provide potential for disease prevention. The developmental patterns of allergen-specific memory are less clear. Very few studies have examined 1313 q 1998 Blackwell Science Ltd Clinical and Experimental Allergy, 1998, Volume 28, pages 1313–1316
Transcript of Abnormalities in cord blood mononuclear cytokine production as a predictor of later atopic disease...
EDITORIAL
Abnormalities in cord blood mononuclear cytokine productionas a predictor of later atopic disease in childhood
The escalating prevalence of atopic disease over recentdecades [1–6], with associated spiralling social and eco-nomic costs [7–10], has emphasized the urgent need foraction which will avert or reverse this trend. Of particularinterest is the growing need for the development of primaryprevention strategies. Essential to this approach is a clearunderstanding of the immunological processes in early lifewhich promote TH2-polarized atopic sensitization. Envir-onmental factors implicated in this process, includingchanges in patterns of childhood infection [11–14], allergenexposure, and dietary intake [15], are currently beingaddressed. A means of identifying children at risk isimportant for targeted prevention. Currently the most reli-able way of predicting allergy is atopic heredity, but withthe rising disease prevalence, the risk is still substantial forpreviously unaffected families. For many years there hasbeen a search for a reliable marker for allergy prediction.Although elevated cord blood IgE (CB-IgE) is associatedwith the development of atopy, asthma [16–18], and ele-vated IgE at 5 years [18], after more than 20 years ofresearch [19–21], it is now widely accepted that CB-IgE isof less value than a positive family history in predictingallergy, and is not of value as a screening test [22].
The paper by Kondoet al. in this issue reports the firstlong-term prospective study of clinical symptoms in child-ren in relation to capacity to generate IFNg responses atbirth [23], and provides tantalizing hints of another possibleprognostic marker, i.e. peri-natal T-cell function. Currentdevelopments in this area of research started in 1992, whenthis same group were the first to document allergen-specificproliferative responses in cord blood [24], an observationwhich promoted a surge of interest in cellular immuneresponses during the neonatal period. The findings fromthis and other research in this area have altered currentconcepts of initial allergen sensitization, which is nowgenerally accepted to beginin utero. In this context,recent work by our own group confirms definitively (bymicrosatellite genotyping), that these allergen-specificresponses by cord blood mononuclear cells (CBMC),noted previously as positive lymphoproliferation by manygroups [24–28] are due to allergen-specific fetal T cells, asopposed to maternally-derived contaminants [29]. Thiswork by our group shows that virtually all neonates displayTH2-skewed allergen-specific responses at birth [29,30]. Inthe early post-natal period these TH2 responses are quicklyrestricted [30,31] by maturing TH1 immunity (a process
know as immune deviation) and by 5 years of age normalpatterns of TH1 immunity appear established in non-atopicindividuals [32]. The central question is: why does thisprocess fail in atopic individuals?
There has been accumulating evidence of immaturity inaspects of immune function in atopic children, starting withan earlier report by our group that IFNg responses aredefective in T-cell clones isolated from ‘high risk’ infants(with atopic heredity), compared with low risk infants [33].It is now clear that while many immune functions arenormally less mature at birth, these maturational deficien-cies may be more marked in individuals who go on todevelop atopy. A large number of studies [25,30,34–37]have documented defective polyclonal IFNg responses byCBMCs from neonates either at risk of atopy, or those wholater develop disease.
Based on current data from many of the groups citedabove, Fig. 1 shows a hypothetical model for the post-natalmaturation of polyclonal IFNg responses. Although allneonates have reduced capacity for mitogen stimulatedIFNg responses [38–41], this appears more marked inatopic individuals at birth, as discussed above [25,30,34–37]. In normal non-atopic infants, IFNg responses tomitogenic polyclonal stimulation gradually increase overthe first year of life, but at 2 years are still well below adultlevels [38]. By 4–5 years of age most normal children havepolyclonal IFNg responses approaching adult levels [38].In contrast, infants with atopic heredity show a moredelayed increase in IFNg responses in the early post-natal period, with the capacity for IFNg remaining sig-nificantly reduced compared with low risk children [33].During this period, responses to vaccine antigen are alsoweaker in infants with higher serum IgE levels [42]. It islikely that the IFNg responses during this period areimportant for normal post-natal immune deviation offetal TH2 responses. Clearly, these observed defects inTH1 immune responses provide a very attractive explana-tion for the persistence of the fetal TH2 responses [30] seenduring childhood in association with atopic disease. Otherwork by our group has shown that the first 2 years of life isa critical period for the development of T helper memorypatterns [31,43]. Targeting these TH1 defects in atopicindividuals during this early period may provide potentialfor disease prevention.
The developmental patterns of allergen-specificmemory are less clear. Very few studies have examined
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Clinical and Experimental Allergy,1998, Volume 28, pages 1313–1316
allergen-specific responses at birth. One small study [25]suggested that low IFNg responses to allergen (bLG) byCBMCs was associated with atopic eczema at 1 year of age.In their present study Kondoet al. [23] document the firstlong-term follow-up (to 6 years of age) on children who hadpreviously had their cord blood cytokine responses ana-lysed. In contrast with the many previous studies of cordblood IFNg, this study measured allergen-stimulatedresponses rather than mitogen-induced responses. Theydemonstrate that low level CBMC IFNg responses to foodallergens are associated with atopic disease at 6 years, andalso with higher cord blood IgE levels. These findings areconsistent with the discussion above.
Clearly, all of these observations are fuelling speculationthat cord blood cytokine responses may represent a markerfor identification of children who are likely to developatopy. Currently this is unfortunately not the case. Whilethere is little doubt from the cited literature that impairedcapacity for neonatal cytokine production (particularlyIFNg) correlates consistently with the development ofatopy in small population studies, this is, as yet, of novalue in predicting atopy at an individual level. It isimportant to stress that, in this context, these cytokinemeasurements are largely experimental, with no currentdiagnostic application. As such, there are no standardizedmethods for detection. Different laboratories use widelyvarying culture conditions; with differences in stimulationmethods, allergens, cell numbers, culture media, culture
durations and methods of detection. There are no ‘normal’values forin vitro cytokine responses, which do not conformto a gaussian distribution, usually show a wide variationbetween individuals, and may be affected by other peri-natalfactors such as trauma and sepsis. The problems with usingsuch measures for prediction in individuals are obvious.Given this, the consistency of the observed deficiencies inIFNg responses by ‘at risk’ neonates is quite remarkable andobviously indicates a very significant underlying geneticdefect. While these observations do not bring us muchcloser to predicting accurately individual atopy, researchin this area remains very important, and has considerablyenhanced current understanding of the kinetics of immuneresponses during the early life period, in both atopic andnon-atopic children.
Thus, the combined efforts of the many groups studyingearly life cytokine responses, have been central to develop-ing a clearer picture of the disease mechanisms which areinitiated during this period. This area of research now needsto extend to examine immunological effects of potentialenvironmental influences, and how these interact withunderlying genetic factors, with a view to interventionbefore persistent TH2 immunity is established. There is anurgent need for more precise data on the nature of the IFNg
defect, which appears an increasingly likely target for earlyintervention and disease prevention. Increasingly, it isbecoming clear that this will only be possible throughcollaborative efforts.
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Fig. 1. Post-natal maturation of polyclonalIFNg responses in atopic and non-atopicinfants.
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S. L. PRESCOTT
P. G. HOLT
TVW Telethon Institute for Child Health ResearchPO Box 855
West Perth 6872Australia
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