Fetal Immune Development Research Articles

Effects of intra-amniotic lipopolysaccharide exposure on the fetal lamb lung as gestation advances

Intra-amniotic lipopolysaccharide (LPS) exposure may affect neonatal outcome by altering fetal lung and immune system development. We hypothesized that intra-amniotic LPS exposure would cause persistent fetal pulmonary responses as the lungs develop in utero. Fetal lambs were exposed to intra-amniotic LPS at 118 or at 118 and 123 d of gestational age (GA) with delivery at 125, 133, or 140 d (term = 147 d). Immune responses, PU.1 expression, Toll-like receptor (TLR)-1,2,4,6 mRNA levels, mast cell levels, and pulmonary elastin deposition were evaluated. After a single dose of LPS, pulmonary inflammatory responses were observed with increases of (i) PU.1 and TLR1 at 125 d GA and (ii) monocytes, lymphocytes, TLR2, and TLR6 at 133 d GA. Repetitive LPS exposure resulted in (i) increases of neutrophils, monocytes, PU.1, and TLR1 at 125 d GA; (ii) increases of neutrophils, PU.1, and TLR2 at 133 d GA; and (iii) decreases of mast cells, elastin foci, TLR4, and TLR6 at early gestation. At 140 d GA, only PU.1 was increased after repetitive LPS exposure. The preterm fetal lung can respond to a single exposure or repeated exposures from intra-amniotic LPS in multiple ways, but the absence of inflammatory and structural changes in LPS-exposed fetuses delivered near term suggest that the fetus can resolve an inflammatory stimulus in utero with time.

Neonatal, atopic and infectious disease outcomes among children born to mothers with latent tuberculosis infection

Exposure to microbes may result in maternal immune responses that can affect fetal immune development. Several lines of evidence have shown that mycobacterial antigens can change the onset of atopic disease. We hypothesized that infants born to mothers with a positive tuberculosis (TB) test and a negative chest radiograph, may exhibit differential development of atopic disease during early childhood. The study was designed as a case control study. Birth records for infants born to untreated mothers with a positive TB skin test (TST), as defined by ≥10 mm induration were reviewed (n = 145 cases) and compared to a randomly selected unmatched control cohort of 46 women with a negative TST who delivered during the same time period at Scripps Hospital in San Diego, CA, USA. Childhood outcome parameters reviewed were: (1) the onset of physician diagnosed asthma; (2) lower respiratory tract infection (LRTI) with wheezing, latent tuberculosis infection/wheezing diagnosed on physical examination; (3) nonsurgical hospitalization; (4) atopic disease (eye/skin/nasal-sinus disease); (5) infections: ear, LRTI, sinus. LRTI was defined as an infection of the lower airways, eg, pneumonia. Outcomes at the end of years 1, 2, and 3–5 years combined were analyzed. Fisher exact test, Chi-square analysis or Poisson regression analysis were used as appropriate and a P-value of <0.05 was defined as significant. The cases and controls had similar birth weights, gestational ages, maternal ages: 3.34 versus 3.35 kg; 38.3 versus 39.2 weeks, 27.4 versus 26 years (P = non-significant). The childhood outcome parameters of the new onset of asthma was significantly higher than controls by age 2 years, but not at other ages studied, based on available clinic follow up data (P = 0.02). There was a difference in the risk for lung infection at age 2 and 3–5 years (P < 0.0001). There were no differences in the other outcome parameters studied (P = ns). There were no cases of infants with a positive TST, maternal Bacille Calmette-Guerin vaccination or active maternal TB, based on our study findings. There was a higher occurrence of asthma and lung infections at age 2 years among controls (P = 0.02). Our study defines for the first time a possible influence of maternal latent TB infection on fetal and childhood illness.

Fetal regulatory T cells and peripheral immune tolerance in utero: implications for development and disease.

The developing fetus must actively learn to tolerate benign antigens or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) in the periphery. Fetal CD4(+) T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in fetal tissues. As the fetus nears birth, a crucial transition must occur between the tolerogenic fetal immune system and a more defensive adult-type immune system that is able to combat pathogens. This paper will review the unique tolerogenic nature of fetal T cells and will examine evidence for a novel model of fetal immune development: the layered immune system hypothesis.

Maternal prenatal life events increase risk for atopic disorders in children

Prenatal stress exposure may affect maternal immune adaptation to pregnancy and fetal immune development, predisposing the child to atopic diseases. Significant levels of prenatal maternal anxiety and/or exposure to bereavement during pregnancy have been associated with the development of atopic diseases in offspring, yet insights on the effect of multiple, common prenatal stressors are rare. Moreover, it is also unclear if prenatal stress challenge modifies the risk for atopic diseases in the context of parental atopy. We tested whether women’s experiences of negative prenatal life events during the first or second half of pregnancy predicted the risk of developing atopic disorders in their children, and whether parental atopy moderated this association. Using multivariable logistic regression we calculated the odds of a child having asthma, eczema and/or allergic rhinitis at ages 6 or 14 years associated with maternal prenatal exposure to negative life events in a sample of 1587 children from the Western Australian Pregnancy Cohort (Raine) Study. After adjusting for confounding variables, the likelihood of asthma, allergic rhinitis or eczema at age 14 was significantly increased in the children of mothers who had experienced negative life events during the second half of gestation, suggesting a critical period of fetal immune development. The association between prenatal stress and increased risk for asthma was stronger in children of non-asthmatic compared to asthmatic mothers.

The influence of maternal prenatal and early childhood nutrition and maternal prenatal stress on offspring immune system development and neurodevelopmental disorders.

The developing immune system and central nervous system in the fetus and child are extremely sensitive to both exogenous and endogenous signals. Early immune system programming, leading to changes that can persist over the life course, has been suggested, and other evidence suggests that immune dysregulation in the early developing brain may play a role in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. The timing of immune dysregulation with respect to gestational age and neurologic development of the fetus may shape the elicited response. This creates a possible sensitive window of programming or vulnerability. This review will explore the effects of maternal prenatal and infant nutritional status (from conception until early childhood) as well as maternal prenatal stress and anxiety on early programming of immune function, and how this might influence neurodevelopment. We will describe fetal immune system development and maternal-fetal immune interactions to provide a better context for understanding the influence of nutrition and stress on the immune system. Finally, we will discuss the implications for prevention of neurodevelopmental disorders, with a focus on nutrition. Although certain micronutrient supplements have shown to both reduce the risk of neurodevelopmental disorders and enhance fetal immune development, we do not know whether their impact on immune development contributes to the preventive effect on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which may contribute to a better understanding of preventative mechanisms. Integrating studies of neurodevelopmental disorders and prenatal exposures with the simultaneous evaluation of neural and immune systems will shed light on mechanisms that underlie individual vulnerability or resilience to neurodevelopmental disorders and ultimately contribute to the development of primary preventions and early interventions.

Modeling the maternal infection risk factor for schizophrenia and autism in mice

Several types of maternal infection (influenza, rubella, genital and reproductive system viruses, bacteria) are associated with increased risk of schizophrenia or autism in the offspring. Modeling this risk factor in mice using influenza infection or activation of the dam's immune system by injection of the double stranded, synthetic RNA, poly(I:C) yields offspring with characteristic features of these disorders. These include behaviors (enhanced anxiety and stereotyped/compulsive behaviors, and deficits in social interaction, communication, prepulse inhibition, latent inhibition, learning) and neuropathology (parvalbumin and Purkinje cell deficits, enlarged ventricles). The cytokine IL-6 is a key mediator of the effects of poly(I:C)-induced maternal immune activation (MIA) on the fetus, as shown by blocking or genetically inactivating IL-6 in the MIA dam. Moreover, MIA activates downstream IL-6 signaling pathways in the placenta, leading to important changes in placental immune cells and endocrine functions. In addition, IL-6 and several other cytokines are induced in both the placenta and fetal brain. Consistent with reports of alterations in the immune system in schizophrenia and autism, we find that MIA leads to significant changes in lymphocytes from the spleen and mesenteric lymph node of adult offspring. As is the case a subset of autistic children, MIA offspring also exhibit gastrointestinal pathology. Thus, the MIA model has face and construct validity for schizophrenia and autism, and is proving useful for exploring the mechanism of how the maternal infection risk factor alters fetal brain and immune system development.

Astma ir nėštumas: prenatalinė epigenetinė sąveika

Nėštumas – itin svarbus raidos programavimo laikotarpis. Straipsnyje nagrinėjami mechanizmai, kurie įrodo motinos sveikatos būklės bei gyvenimo būdo svarbą epigenetiškai slopinant arba aktyvinant besiformuojančio vaisiaus genus. Tyrimai, nagrinėję metų laikų įtaką pradėjimo momentu, nustatė, kad spalio ir lapkričio mėnesiais gimę vaikai turi dukart didesnę tikimybę iki keturių metų amžiaus tapti alergiškais maistui nei tie, kurie gimė birželį arba liepą. Tai susiję su augalų žiedadulkių poveikiu embrionui jautriu nėštumo laikotarpiu. Naujausias tyrimas pateikė duomenų apie folio rūgšties, kaip metilo grupės šaltinio, svarbą genų hipermetilinimo procese. Tyrimai su gyvūnais leido padaryti naujas išvadas, kad nuo alergijos apsaugantis mechanizmas, sąlygotas mikrobų ekspozicijos nėštumo metu, gali būti sąlygotas vaisiaus Th1 genų slopinimo juos metilinant. Pastarųjų metų moksliniai tyrimai, rodantys prenatalinių veiksnių (mitybos tipo, mikrobinio kontakto, rūkymo, vaistų) svarbą vystantis vaisiaus imuninei sistemai bei polinkiui sirgti astma ir kitomis alerginėmis ligomis, suteikia galimybes imtis pirminės profilaktikos mažinant alerginių ligų atsiradimo tikimybę.

Protein supplementation in the first 100 days of gestation fails to enhance resistance of weaned Merino lambs against Haemonchus contortus

The aims of this study were to investigate the effects of a high-protein maternal diet on the fetal immune system development, and subsequently on resistance to the abomasal blood sucking parasite Haemonchus contortus in lambs after weaning. Merino ewes (n=39) of mixed age and parity were fed either a normal protein diet (12% CP) or a high-protein diet (21% CP) for the first 100 day of their 150 day gestation. The lambs were weaned at 3 months old and infected at 6 months of age with 10,000 L3 H. contortus larvae. No significant differences were found between the groups fed a normal protein diet and a high-protein diet in any of the variables measured in lambs (birth weight, fleece weight or fecal parasite egg counts) However, there were differences in hematological variables, except lymphocytes and monocytes, between lambs born to ewes fed 12% or 21% protein during the first 100 day of gestation. Fetal exposure to a maternal high-protein diet during the first 100 day of gestation did not appear to influence lamb susceptibility to experimental H. contortus infection in Merino lambs.

Highway to health; or How prenatal factors determine disease risks in the later life of the offspring

Fetal development is largely dependent on the mother. However, pregnancy maintenance and consequently fetal development are highly vulnerable and sensitive to disruption, triggered by, for example, prenatal stress challenge. Such prenatal stress challenge modulates the maternal endocrine and immune responses during pregnancy e.g. by decreasing levels of progesterone. Prenatal stress also has negative repercussions for the child's health later in life. It has been reported that prenatal stress increases the risk of the child to develop chronic immune diseases such as allergies and asthma. We therefore propose that prenatal stress challenge - associated with a decrease in maternal progesterone - impairs fetal immune development (immune ontogeny). Such impaired immune ontogeny carries over into postnatal life, rendering the child more prone to developing chronic immune diseases. This purported association urgently requires a fresh evaluation in order to identify biomarkers and cascades of events. In the present review, we outline candidate biomarkers involved in fetal immune ontogeny, which may be targets of prenatal stress challenge and subsequently determine offspring disease risk. Identification of these stress-sensitive biomarkers may allow detection of pregnant women at risk to deliver chronic immune disease-prone offspring. The creation of therapeutic interventions designed to prevent negative consequences of prenatal stress would then be within reach.

Exposure to air pollution in critical prenatal time windows and IgE levels in newborns

The objective of this study was to analyze the mechanisms by which exposure to ambient air pollutants influences respiratory health may include altered prenatal immune development. To analyze associations between elevated cord serum Immunoglobulin E (IgE) levels and maternal air pollution exposure during each month of gestation. Total cord serum IgE was determined by the CAP system and mothers' total IgE levels by nephelometry for 459 births in the Czech Republic from May 1994 to mid-January 1997. Concentrations of polycyclic aromatic hydrocarbons (PAHs) and particulate matter <2.5 microns in diameter (PM(2.5) ) were measured in ambient air, and arithmetic means were calculated for each gestational month. Log binomial regression models were used to estimate prevalence ratios (PR) for elevated cord serum IgE (≥0.9 IU/ml) adjusting for district of residence, year of birth, and in further models, for maternal IgE (a surrogate for atopy) and gestational season. Heterogeneity by maternal atopy status was evaluated for associations of air pollution and of cigarette smoke. In adjusted models, PAH and PM(2.5) exposures in the second month of gestation were each associated with a lower prevalence of elevated cord serum IgE. For an average increase of 100 ng/m(3) of PAHs, the PR was 0.69 (95% confidence interval (CI): 0.50, 0.95); for 25 μg/m(3) increase in PM(2.5) , the PR was 0.77 (95% CI: 0.55, 1.07). Conversely, exposures later in gestation were associated with a higher prevalence of elevated cord IgE: in the fifth month, the PR for PAH exposure was 1.64 (95% CI: 1.29, 2.08), while for PM(2.5) in the sixth month, it was 1.66 (95% CI: 1.30, 2.13). In analyses stratified by maternal atopy, air pollutants were associated with altered cord serum IgE only among neonates with non-atopic mothers. Similarly, an association of cigarette smoke with elevated cord serum IgE was found only in non-atopic mothers. PAHs and PM(2.5) , constituents of both ambient air pollution and cigarette smoke, appear to influence fetal immune development, particularly among infants whose mothers are not atopic.

Air pollution exposure during critical time periods in gestation and alterations in cord blood lymphocyte distribution: a cohort of livebirths

BackgroundToxic exposures have been shown to influence maturation of the immune system during gestation. This study investigates the association between cord blood lymphocyte proportions and maternal exposure to air pollution during each gestational month.MethodsCord blood was analyzed using a FACSort flow cytometer to determine proportions of T lymphocytes (CD3+ cells and their subsets, CD4+ and CD8+), B lymphocytes (CD19+) and natural killer (NK) cells. Ambient air concentrations of 12 polycyclic aromatic hydrocarbons (PAH) and particulate matter < 2.5 micrometer in diameter (PM2.5) were measured using fixed site monitors. Arithmetic means of these pollutants, calculated for each gestational month, were used as exposure metrics. Data on covariates were obtained from medical records and questionnaires. Multivariable linear regression models were fitted to estimate associations between monthly PAH or PM2.5 and cord blood lymphocytes, adjusting for year of birth and district of residence and, in further models, gestational season and number of prior live births.ResultsThe adjusted models show significant associations between PAHs or PM2.5 during early gestation and increases in CD3+ and CD4+ lymphocytes percentages and decreases in CD19+ and NK cell percentages in cord blood. In contrast, exposures during late gestation were associated with decreases in CD3+ and CD4+ fractions and increases in CD19+ and NK cell fractions. There was no significant association between alterations in lymphocyte distribution and air pollution exposure during the mid gestation.ConclusionsPAHs and PM2.5 in ambient air may influence fetal immune development via shifts in cord blood lymphocytes distributions. Associations appear to differ by exposure in early versus late gestation.

Allergic disease: understanding howin uteroevents set the scene

Events and exposures in pregnancy can have critical effects on fetal development with lasting implications for subsequent health and disease susceptibility. There is growing interest in how modern environmental changes influence fetal immune development and contribute to the recent epidemic of allergy and other immune disorders. Rising rates of allergic disease in early infancy, together with pre-symptomatic differences in immune function at birth, suggest that antenatal events play a predisposing role in the development of disease. A number of environmental exposures in pregnancy can modify neonatal immune function including diet, microbial exposure and maternal smoking, and there is emerging evidence from animal models that these factors may have epigenetic effects on immune gene expression and disease susceptibility. Furthermore, functional genetic polymorphisms also alter individual vulnerability to the effects of these environmental exposures, highlighting the complexity of gene-environmental interactions in this period. All these observations underscore the need for ongoing research to understand the pathogenesis and rising incidence of disease in the hope of better strategies to reverse this.

Session 1: Allergic disease Nutrition as a potential determinant of asthma

Asthma is characterised by chronic lung airway inflammation, increased airway responsiveness and variable airflow obstruction. In Westernised countries asthma is a public health concern because of its prevalence, associated ill health and high societal and healthcare costs. In recent decades there has been a marked increase in asthma prevalence, particularly in Westernised countries. It has been proposed that changing diet has contributed to the increase in asthma. Several dietary hypotheses exist; the first relates the increase in asthma to declining dietary antioxidant intake, the second to decreased intake of long-chain n-3 PUFA and increasing intake of n-6 PUFA. Vitamin D supplementation and deficiency have also been hypothesised to have contributed to the increase in asthma. Observational studies have reported associations between asthma and dietary antioxidants (vitamin E, vitamin C, carotenoids, Se, flavonoids, fruit), lipids (PUFA, butter, margarine, fish) and vitamin D. However, supplementing the diets of adults with asthma with antioxidants and lipids has minimal, if any, clinical benefit. There is growing interest in the possibility that childhood asthma is influenced by maternal diet during pregnancy, with studies highlighting associations between childhood asthma and maternal intake of some nutrients (vitamin E, vitamin D, Se, PUFA) during pregnancy. It has been suggested that maternal diet during pregnancy influences fetal airway and/or immune development. Further intervention studies are needed to establish whether modification of maternal nutrient intake during pregnancy can be used as a healthy low-cost public health measure to reduce the prevalence of childhood asthma.

Asthma and pregnancy: emerging evidence of epigenetic interactions in utero

Pregnancy is arguably the most critical period of developmental programming. Here, we particularly focus on the emerging paradigm that disease propensity is epigenetically determined by maternal exposures that have the capacity to activate or silence fetal genes through alterations in DNA and histone methylation, histone acetylation, and chromatin structure. The most notable recent candidate to emerge in this role has been dietary folate, a methyl donor clearly associated with changes in gene expression and disease susceptibility through gene hypermethylation. Animal studies also provide the first evidence that the allergy protective effects of microbial exposure in pregnancy may be mediated by changes in methylation of Th1 genes of the offspring. There is also emerging evidence that perinatal differences in immune function of allergy-prone newborns extend beyond previously recognized differences in effector T cell (Th1/Th2) function, to also include differences in neonatal regulatory T cell (Treg) and Th17 function, and moreover, that these pathways are also epigenetically regulated. New studies reinforce the importance of in-utero exposures (including dietary nutrients, microbial products, cigarette smoking, and certain maternal mediations) in fetal immune development and in programming the susceptibility to asthma and allergic disease.

Maternal mood scores in mid-pregnancy are related to aspects of neonatal immune function

Background Although there are recognised associations between psychological and immune function, the effects of maternal depressive symptoms on fetal immune development have not been investigated. Methods This study examined the relationship between maternal depression scores as assessed by the Beck Depression Inventory (BDI) in the second trimester and measure of neonatal immune function measured in cord blood. This study was conducted in a cohort of women ( n = 83) who had received either fish oil containing 3.7 g/day n-3 polyunsaturated fatty acid ( n-3PUFA) or a placebo from 20 weeks gestation as part of a randomised controlled trial. Results At 20 weeks gestation, prior to the intervention, 22% of women in the study manifested mild to moderate depressive symptoms (BDI ⩾10). Neonates of these women had higher lymphoproliferative responses to a range of stimuli (including egg ovalbumin and cat allergen) compared with neonates of women with normal BDI scores (<10). These neonates also showed higher spontaneous cytokine production including (IL-6 and IL-10) and higher stimulated cytokine responses to both bacterial antigens and allergens. These patterns were evident after allowing for maternal age and education, parity, gestation, infant gender, delivery method and neonatal n-3/ n-6 PUFA status. Conclusion This exploratory study supports the notion that maternal mood in pregnancy may have the potential to influence fetal immune development. Further studies are needed to determine the significance of this.

Impact of PUFA on early immune and fetal development

It has recently been reported that the increased prevalence in childhood allergy may be linked to deviations in fetal immune development. One reason may be impaired nutrient supply. Hence, a well-differentiated placenta together with an optimal fetal nutrition via the mother are important prerequisites for the establishment of a functional immune system with normal immune responses. Fatty acids and their derivatives can influence both the early immune development and immune maturation by regulating numerous metabolic processes and the gene expression of important proteins such as enzymes and cytokines. The present review summarises the impact of nutritional fatty acids on the development of the immune system as well as the fetal development. It describes the mechanisms of action of PUFA, trans fatty acids and conjugated linoleic acids in programming the fetus with regard to its risk of acquiring atopic diseases in childhood.

Expression of Molecules Involved in Fetal-Maternal Tolerance Allows Human Mesenchymal Stem Cells to Engraft at High Levels across Immunologic Barriers

The ability of HLA-G to inhibit NK cells, cytotoxic T cells, and the maturation of dendritic cells is thought to play a crucial role in the maintenance of fetomaternal tolerance during pregnancy. Recent studies have provided evidence that MSC are not as immuno-inert as once thought, since they are capable of expressing HLA-II if stimulated by IFN-γ and of activating and serve as targets of NK-mediated lysis. Here we investigated whether transducing human MSC with a retroviral vector encoding HLA-G1 (MSC-G1) or G5 (MSC-G5) would render these cells and their differentiated progeny undetectable by the immune system, and thereby allow efficient engraftment into immuno-competent xenogeneic recipients. Mixed lymphocyte reactions showed that HLA-G1 expression reduced MSC's ability to stimulate human and sheep lymphocytes by at least 80%, while HLA-G5 expression reduced activation of human lymphocytes by 35–63% and sheep lymphocytes by 48–64%. Furthermore, MSC-G1 exhibited a 35–60% reduction in NK cell lysis depending on the effector:target ratio, and MSC-G5 exhibited NK cell inhibition of 12–44%. These results indicated that cell contact-mediated NK cell inhibition by the transmembrane form of HLA-G (HLA-G1) was more effective than inhibition mediated by the soluble HLA-G5. To assess whether these in vitro results were indicative of true immune-evasion ability, we next transplanted (Tx) 105 unMSC, MSC-G1, or MSC-G5 into fetal sheep recipients during the pre-immune period (55 days; n=9), or after immunocompetence was achieved at 82 days (n=10) or 104 days (n=8) of gestation. Evaluation of the recipients' hematopoietic system at 42 days post-transplant for the presence of human cell engraftment revealed that Tx at 55 days resulted in similar levels of engraftment for all cell types (MSC:4±0.9; MSC-G1:6±0.3; MSC-G5:5±0.3%). In contrast, while unMSC engrafted at very low levels at 82d and 104d, Tx of MSC-G1 and-G5 at these later time points resulted in levels of engraftment that were considerably higher than those achieved during the pre-immune period (82d:7±1;18±2.% and 104d:12±2;16±2%). A similar outcome was seen with liver engraftment and hepatic differentiation, with MSC-G1 and MSC–G5 giving rise to 3–5 times more hepatocytes than unMSC at later time points. However, even at the early Tx time point of 55days, MSC-G1 and MSC–G5 gave rise to, respectively, 5 times and 2 times more donor-derived hepatocytes than their unMSC counterpart, suggesting that, even at the earlier stages of development, the fetus may not be completely immuno-naive. Moreover, while no donor cells were found in the lungs of animals that received the Tx at 56 days of gestation, donor cells were consistently observed primarily within the epithelium and the fibro-elastic layer in the lungs of animals that received either MSC-G1 or MSC-G5 at 82 and 104 days of gestation, and engraftment efficiency appeared to increase as a function of gestational age at the time of Tx. Serial sectioning of these tissues demonstrated that transduced cells engrafting within the lung produced HLA-G and Prosurfactant B, suggesting differentiation to alveolar Type II cells. Our studies demonstrate that the forced expression of HLA-G1 or G5 enables MSC to evade a competent recipient immune system and engraft at significant levels at times in gestation when donor cells are normally rejected. These findings suggest this approach could enable the treatment of diseases affecting tissues that develop after fetal immune development such as cystic fibrosis and may allow broadening of the use of MSC to diseases in which an underlying MSC defect precludes the use of the patient's own MSC

Maternal diet during pregnancy: an emerging risk factor for childhood asthma

Evaluation of: Willers SM, Wijga AH, Brunekreef B et al. Maternal food consumption during pregnancy and the longitudinal development of childhood asthma. Am. J. Respir. Crit. Care Med. 178, 124–131 (2008).It has been hypothesized that the recent marked increase in the prevalence of asthma may, in part, be a consequence of changing diet. There is increasing interest in the possibility that childhood asthma may be influenced by maternal diet during pregnancy and an increasing number of studies have highlighted associations between childhood asthma and maternal intake of certain foods (e.g., fish, fruits and vegetables) and nutrients (e.g., vitamin E, vitamin D, zinc and polyunsaturated fatty acids) during pregnancy. Maternal diet during pregnancy has the potential to influence fetal immune and airway development during a critical period of life with long-term irreversible consequences, such as childhood asthma. Further research, particularly intervention studies, needs to be carried out to establish whether dietary intervention during pregnancy can be used as a healthy, low-cost, public-health measure to reduce the prevalence of childhood asthma.

Prenatal nutrition and asthma: hope or hype?

David Barker’s “fetal origins” hypothesis has changed the way we think about the aetiology of adult onset diseases, such as coronary heart disease and type 2 diabetes.1 Underpinning the epidemiological...

Increased activation of GATA‐3, IL‐2 and IL‐5 of cord blood mononuclear cells in infants with IgE sensitization

Risk of allergic diseases has been linked to abnormal patterns of fetal immune development, suggesting that priming of the immune system may occur in utero. The aim of the study was to investigate whether the pattern of immune response in cord blood mononuclear cells (CBMC) shows association with allergic diseases and IgE sensitization at 2 yr of age, and to study the effect of maternal probiotic supplementation on CBMC immune responses. CBMC were isolated from 98 neonates in a randomized double-blinded intervention study. CBMC were stimulated with beta-lactoglobulin, and phytohemaglutinin (PHA). Secretion of interferon-gamma (IFN-gamma), interleukin-5 (IL-5), and IL-13 was measured by an ELISA; IL-2, IL-4, and IL-10 by a cytokine bead assay. T-cell polarization-associated IL-4 receptor and IL-12R expressions, and the respective transcription factors GATA-3 and T-bet were analyzed with RT-PCR. The above responses were compared with the development of allergic diseases and IgE sensitization at 2 yr of age, and with the maternal probiotic or placebo supplementation. PHA-stimulated GATA-3 expression and IL-2 secretion in CBMC were higher in IgE-sensitized children at an age of 2 yr than in the non-sensitized, non-allergic children (p = 0.03 and 0.026). PHA-induced expression of GATA-3 correlated with IL-5 (p = 0.003, r = 0.300) and IL-13 (p = 0.007, r = 0.278) secretion of CBMC, and IL-5 secretion of beta-lactoglobulin-stimulated CBMC was higher in IgE-sensitized children at 2 yr of age than in the non-sensitized, non-allergic children (p = 0.013). Probiotic bacteria had no effect on CBMC immune responses. In CBMC-enhanced induction of GATA-3, which activates several Th2 cytokines genes, was a risk factor for IgE sensitization. The immune deviation towards Th2-type immunity developed already in utero and seemed to modulate the pattern of immune response favoring an IgE response to environmental antigens.