Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation

Background:  As Th2 type lymphocytes orchestrate the cardinal features of allergic asthma, inhibiting their recruitment to the lungs could be of therapeutic benefit. Although human Th2 cells express the CCR4 chemokine receptor and increased production of CCR4 ligands has been found in asthmatic airways, studies in animals have reached contradictory conclusions on whether blocking this pathway would be beneficial.
Objective:  As a lack of efficacy might be due to differences between mouse and man, we readdressed this question using a humanized severe combined immunodeficiency model of asthma.
Methods:  Mice received peripheral blood mononuclear cells from house dust mite (HDM) allergic asthmatic patients and then underwent bronchial challenge with HDM.
Results:  This resulted in marked allergic inflammation and bronchial hyper-reactivity. Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyperreactivity. In this chimeric system, human CD11c+ dendritic cells (DCs) were the predominant source of CCR4 ligands, suggesting that DC-derived chemokines attract Th2 cells. In separate experiments using human DCs, in vitro exposure to HDM of DCs from HDM allergic patients but not healthy controls caused CCL17 and CCL22 release that resulted in chemoattraction of polarized human Th2 cells in a CCR4-dependent way.
Conclusions:  Taken together, our data provide proof of concept that CCR4 blockade inhibits the salient features of asthma and justify further clinical development of CCR4 antagonists for this disease.     

大鼠发育早期接触变应原对Th1/Th2亚群功能及哮喘发生的影响

目的探讨妊娠期母鼠及其子代接触尘螨点刺液（Derp）对发育后期个体Th1/Th2平衡及哮喘发生的影响。方法Wistar大鼠根据母体妊娠期及新生早期是否接触Derp随机分为对照组、母Derp-仔Derp-组（母鼠和其子代均未接触Derp）、母Derp＋仔Derp＋组（母鼠和其子代均接触Derp）和母Derp＋仔Derp-组（母鼠接触Derp,其子代未接触Derp）,分别皮下注射Derp或生理盐水,30d龄时除对照组外,其余3组以卵白蛋白（OVA）为变应原致敏并雾化吸入,诱发哮喘发生。取血浆检测OVA特异性IgE抗体、收集外周血单个核细胞（PBMC）用ELISA法检测培养上清中细胞因子IL-4和IFN-γ水平,行支气管肺泡灌洗记录支气管肺泡灌洗液（BALF）中嗜酸性粒细胞的计数,留取肺组织行病理学检查。结果母Derp＋仔Derp＋组在哮喘建模后PBMC培养上清中IFN-γ水平显著低于母Derp-仔Derp-组,IL-4水平显著升高,IL-4/IFN-γ比值升高,OVA特异性IgE、BALF中嗜酸性粒细胞计数显著高于母Derp-仔Derp-组;母Derp＋仔Derp-组与母Derp-仔Derp-组IL-4和IFN-γ水平差异均无统计学意义,OVA特异性IgE水平虽有增高,但差异不具统计学意义,BALF中嗜酸性粒细胞计数差异无统计学意义。母Derp＋仔Derp＋组Th2优势显著高于母Derp＋仔Derp-组。结论胎鼠对于Derp跨胎盘的致敏作用可通过母体妊娠期间的免疫来完成,这一过程会根本上导致Th2优势免疫的发生,增加了变态反应性疾病的危险性。     

Peripheral blood mononuclear cell proliferative responses in the first year of life in babies born to allergic parents

Background Raised peripheral blood mononuclear cells (PBMCs) proliferative responses to food allergens have been demonstrated in children with established atopic dermatitis. Objective In this report we investigate the PBMC proliferative responses to inhalant and food allergens from babies at birth, 6 months and 1 year of age, born to atopic and non-atopic parents. Methods PBMCs, separated by density gradient centrifugation. were cultured for 6 days with autologous plasma and a range of allergens (house dust mite [HDM], cat, grass pollen, tree pollen, betalactoglobulin and ovalbumin). Proliferative responses were measured by the uptake of [³H] thymidine added for the final 18 h of culture. Results At birth, infants born to atopic parents who developed allergic disease by 1 year of age had significantly more positive responses (stimulation index ± 2 with a value of ± 1000 cpm above background) to HDM (P = 0.0091), betalactoglobulin (P= 0.0166) and ovalbumin (P = 0.0035) than newborns who did not develop allergy. Tnfants who developed allergy also had significantly more positive responses to HDM (P - 0.03) and ovalbumin (P = 0.0057) than babies, born to non-atopic parents, who did not develop allergies. At 6 months of age a significant fall in response to HDM (P = 0.003) and cat fur extract (P = 0.006) was seen in infants who developed allergic disease by 1 year of age. A similar pattern was seen for proliferative responses to betalactoglobulin and ovalbumin (P = 0.0006. P= 0.004). Conversely, proliferations to grass and tree pollen extracts increased at 6 months (P = 0.04. P = NS) and 1 year (P= NS. P= 0.01) compared with birth which was significant for infants who did not develop allergic disease. Conclusion Proliferative responses to seasonal allergens increased over the first year of life whilst those to perennial allergens, both inhalant and food, fell. This suggests either the induction of a systemic immune tolerance by perennial exposure to antigens or movement of sensitized cells to target organs where allergen exposure occurs. This process may be independent of the development allergic disease.     

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL‐5 and IL‐13. Here, we used a house dust mite (HDM)‐driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T‐cell activation precedes ILC2 induction. During HDM‐driven allergic airway inflammation the accumulation of ILC2s in BALF is IL‐33 independent, although infiltrating ILC2s produce less cytokines in Il33^?/? mice. Transfer of in vitro polarized OVA‐specific OT‐II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T‐cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM‐mediated allergic airway inflammation in mice critically depends on activation of T cells.     

Histamine induces Th2 activation through the histamine receptor 1 in house dust mite rhinitic but not asthmatic patients

Background Effects of mast cell‐released histamine on smooth muscle and endothelial cells are considered as responsible of immediate symptoms of anaphylaxis. However, little is known about histamine effects on Th2 lymphocytes, which orchestrate the allergic reaction upstream of mast cells. Objective We addressed this question in house dust mite (HDM) allergics, according to the presence of rhinitis or asthma and allergen stimulation. Methods Peripheral blood mononuclear cell from 15 rhinitic and 14 asthmatic HDM‐allergic subjects and 16 controls were cultured with Der p 1 or histamine. The effect of Der p 1 on histamine receptor (H1R and H2R) expression was studied. T‐cell cytokine production was studied upon Der p 1 or histamine stimulation. The role of H1R in histamine effects was assessed with levocetirizine. Results H1R and H2R are overexpressed on T cells from asthmatic but not from rhinitic subjects. Der p 1 increases H1R expression on CD4⁺ cells from both allergic groups, and decreases it in controls, on CD4⁺ and CD8⁺ subsets. Der p 1 decreases T‐cell H2R expression in asthmatics. Allergen increases IL‐4 and IL‐13 in both allergic groups. Histamine increases Th2 cytokines in rhinitics only, and levocetirizine abolishes this effect. In asthmatics and controls, histamine decreases T‐cell cytokines through a non‐H1R dependent pathway. Conclusion In rhinitis but not in asthma, histamine is able to increase allergic inflammation by increasing Th2 cytokine production in a positive feedback dependent on H1R. This result could explain in part why H1R antagonists, are very efficient in rhinitis, but not in asthma. Cite this as: K. Botturi, Y. Lacoeuille, D. Vervloet and A. Magnan, Clinical & Experimental Allergy, 2010 (40) 755–762.     

Prevalence of food allergies in young adults and their relationship to asthma, nasal allergies, and eczema.

BACKGROUND: The true prevalence of food allergy in adults is generally thought to be uncommon. It is unknown whether there are any relationships between food allergy and atopic diseases. OBJECTIVE: To determine the prevalence of probable immunoglobulin (Ig)E-mediated food allergy to peanut, shrimp, cow's milk, wheat, and egg as defined by a positive skin prick test result and relevant clinical history to the same food, and to explore the relationship with atopic diseases. METHODS: Cross-sectional epidemiologic study. One thousand one hundred forty-one randomly selected young adults (aged 20 to 45 years) underwent skin prick testing to five common food allergens (cow's milk, peanut, egg white, shrimp, and wheat), completed a detailed questionnaire, including validated items on respiratory symptoms, history of asthma and other allergic conditions, as well as undergoing lung function testing. RESULTS: Just over one percent (1.3%, n = 15) had probable IgE-mediated food allergy. The prevalence of probable IgE food allergy was: <0.27% for wheat, 0.09% (95% confidence interval = 0.0 to 0.49%) each for cow's milk and egg, 0.53% (0.21 to 1.09%) for shrimp, and 0.61% (0.25 to 1.26%) for peanut. Those with probable IgE peanut and shrimp allergy were significantly more likely to have current asthma and doctor-diagnosed asthma. Wheeze and history of eczema were also associated with peanut allergy, whereas nasal allergies were associated with shrimp allergy. CONCLUSIONS: The prevalence of probable IgE-mediated food reactions is rare in young adults. Some positive associations between probable IgE-mediated food allergy and allergic diseases were found, but larger study numbers are required to confirm these results.     

Epicutaneous exposure to peanut protein prevents oral tolerance and enhances allergic sensitization

BACKGROUND: Food allergies are an important cause of life-threatening hypersensitivity reactions. Oral tolerance can be considered the default immune response to dietary antigens, with immune deviation resulting in allergic sensitization. However, primary sensitization to food allergens may not solely be through the gastrointestinal mucosa, as strong T-helper type 2 (Th2)-biased immunity can result from exposure to protein allergens on barrier-disrupted skin. OBJECTIVE: The purpose of this study was to examine whether exposure to allergens through the skin may interfere with the normal development of oral tolerance and promote allergic sensitization to food proteins. METHODS: Female BALB/c mice were exposed epicutaneously to peanut protein and induction of systemic oral tolerance through high dose feeds of peanut protein was subsequently assessed. Other mice were rendered tolerant prior to epicutaneous peanut exposure. Sensitivity to peanut was determined by assessing delayed-type hypersensitivity, proliferative, cytokine and antibody responses. RESULTS: Epicutaneous exposure to peanut protein induced potent Th2-type immunity with high levels of IL-4 and serum IgE. Primary skin exposure prevented the subsequent induction of oral tolerance to peanut in an antigen-specific manner. Upon oral challenge, mice became further sensitized and developed strong peanut-specific IL-4 and IgE responses. Furthermore, animals with existing tolerance to peanut were partly sensitized following epicutaneous exposure. CONCLUSION: Epicutaneous exposure to peanut protein can prevent induction of oral tolerance, and may even modify existing tolerance to peanut. Epidermal exposure to protein allergens selectively drives Th2-type responses, and as such may promote sensitization to food proteins upon gastrointestinal exposure.     

Activation of Peripheral Th17 Lymphocytes in Patients with Asthma

A recently identified interleukin (IL)-17-producing T-helper (Th) lymphocyte subset, which comprises Th17 cells producing hallmark cytokines IL-17A, IL-17F and IL-22, is involved in chronic inflammatory diseases. Elevated gene and protein expressions of IL-17 are manifested in allergic asthma. We further characterized the activation of Th17 cells in asthmatic patients. Peripheral blood mononuclear cells (PBMC) were purified from 31 asthmatic patients and 20 sex- and age-matched control subjects. The number of IL-17A secreting cells in peripheral blood was enumerated by enzyme-linked immunosorbent spot assay. Cell surface expression of Th17-related chemokine receptor CCR6, and plasma level of IL-17A, IL-17F and IL-22, and ex vivo production of IL-17A and IL-22 were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. The number of peripheral Th17 lymphocytes, expression of CCR6 on Th cells, and ex vivo IL-23, anti-CD3 and anti-CD28 induced production of IL-22 by PBMC were significantly elevated in asthmatic patients compared with control subjects (all p < 0.01). This clinical study further confirmed increased number of peripheral Th17 lymphocytes and cell surface expression of CCR6 receptors on Th cells in asthmatic patients. Pro-inflammatory cytokine IL-23 can exacerbate disease severity by activating pathogenic Th17 lymphocytes to release downstream inflammatory cytokine IL-22 in asthma.     

Cord blood mononuclear cell cytokine responses in relation to maternal house dust mite allergen exposure

BACKGROUND: Cord blood mononuclear cells have demonstrated specific immune responses to environmental allergens. OBJECTIVE: To establish whether the nature of this response is related to the level of maternal antenatal exposure to house dust mite (HDM) allergen and, hence, whether antenatal allergen avoidance may have a role in the prevention of allergic sensitization in children. METHODS: Children with a family history of asthma were recruited antenatally as subjects in a randomised controlled trial: the Childhood Asthma Prevention Study. HDM allergen (Der p 1) concentrations were measured in dust collected from the maternal bed at 36 weeks gestation. Cord blood mononuclear cells were stimulated in culture, separately, with phytohaemaglutinin (PHA) and HDM extract. Cytokine IL-4, IL-5, IL-10 and IFN-gamma concentrations in supernatant were measured by ELISA. mRNA signals for these cytokines were measured using RT-PCR. RESULTS: The median concentration of HDM allergen was 18.4 microg/g (interquartile range 7.3-35.3 microg/g). Median concentrations of IL-4, IL-5, IL-10 and IFN-gamma, after PHA stimulation were 4, 19, 401 and 1781 pg/mL, respectively. After HDM allergen stimulation the median concentrations were 0, 0, 20 and 14 pg/mL, respectively. The distribution of mRNA cytokine signals was similar. Neither cytokine protein concentrations nor cytokine mRNA signal levels were correlated with the concentration of HDM allergen in the mothers' beds at 36 weeks gestation. CONCLUSION: These findings do not support the view that the prevention of allergic disease in children requires the institution of HDM avoidance interventions during pregnancy.     

Neonatal interleukin-12 capacity is associated with variations in allergen-specific immune responses in the neonatal and postnatal periods

BACKGROUND AND OBJECTIVES: A reduced capacity of antigen presenting cells (APC) to provide pro-T helper 1 (Th1) signals, such as IL-12, to T cells during early life may be implicated in the development of T helper 2 (Th2)-mediated allergic disease. In this study we examined the relationships between the capacity for IL-12 responses in the neonatal period and atopic risk (family allergy), in vitro T cell responses to allergens, and the subsequent development of allergic disease at 6 years. METHODS: The capacity of circulating neonatal (and maternal) APC to produce IL-12 p70 in response to LPS (and IFN-gamma) stimulation was assessed in a group of 60 children with previously well-characterized immune responses to allergens and atopic outcomes. The IL-12 responses were compared with allergen-induced lymphoproliferation (to house dust mite (HDM) ovalbumin (OVA), cat and beta-lactoglobulin (BLG)) and IL-13 and IFN-gamma cytokine responses (to OVA, HDM and phytohaemaglutinin (PHA)) in the neonatal and postnatal periods. IL-12 responses were also compared according to atopic risk and atopic outcomes (doctor-diagnosed asthma, eczema, food allergies and sensitization as evidenced by skin prick testing) at 6 years clinical follow-up. RESULTS: Maternal peripheral blood mononuclear cells (PBMC) synthesized significantly greater amounts of IL-12 than neonatal PBMC, though within maternal-infant pairs IL-12 responses were significantly correlated (r = 0.4, P = 0.019). Moreover, neonatal IL-12 responses were positively correlated with neonatal allergen proliferation for HDM (r = 0.6, P < 0.0001), OVA (r = 0.55, P < 0.0001), cat (r = 0.5, P = 0.003) and BLG (r = 0.55, P = 0.001), but negatively correlated with neonatal IL-13 responses to both allergens tested (HDM: r = - 0.4, P = 0.03 and OVA: r = - 0.5, P = 0.001). Both neonatal and maternal IL-12 responses were positively correlated with postnatal IFN-gamma responses to HDM at 12, 18 and 24 months of age (responses after age of 2 years were not assessed). There was no relationship between atopic risk and IL-12 capacity in the neonatal period, but there was a (non-significant) trend for neonatal IL-12 responses to be lower in the high-risk children who developed clinical allergy at 6 years (compared with the low risk group) although the number in this analysis was small. CONCLUSIONS: Reduced APC IL-12 production in the perinatal period was associated with reduced T cell activation (lymphoproliferation), stronger neonatal Th2 responses, and weaker Th1 responses to allergen in the postnatal period. This supports the notion that variations in APC function in early life may contribute to altered allergen-specific cytokine responses associated with later allergy.     

Prenatal environmental tobacco smoke exposure increases allergic asthma risk with methylation changes in mice

Allergic asthma remains an inadequately understood disease. In utero exposure to environmental tobacco smoke (ETS) has been identified as an environmental exposure that can increase an individual's asthma risk. To improve our understanding of asthma onset and development, we examined the effect of in utero ETS exposure on allergic disease susceptibility in an asthmatic phenotype using a house dust mite (HDM) allergen‐induced murine model. Pregnant C57BL/6 mice were exposed to either filtered air or ETS during gestation, and their offspring were further exposed to HDM at 6–7 weeks old to induce allergic inflammation. Methylation in the promoter regions of allergic inflammation‐related genes and genomic DNA was quantified. Exposure to HDM resulted in the onset of allergic lung inflammation, with an increased presence of inflammatory cells, Th2 cytokines (IL‐4, IL‐5, and IL‐13), and airway remodeling. These asthmatic phenotypes were significantly enhanced when the mice had been exposed to in utero ETS. Furthermore, prenatal ETS exposure and subsequent HDM (ETS/HDM)‐induced asthmatic phenotypes agree with methylation changes in the selected asthma‐related genes, including IL‐4, IL‐5, IL‐13, INF‐γ, and FOXP3. Global DNA methylation was significantly lower in ETS/HDM‐exposed mice than that of controls, which coincides with the results observed in lung, spleen, and blood DNAs. Prenatal ETS exposure resulted in a severe increase in allergic inflammatory responses after an HDM challenge, with corresponding methylation changes. Prenatal ETS exposure may influence developmental plasticity and result in altered epigenetic programming, leading to an increased susceptibility to asthma. Environ. Mol. Mutagen. 58:423–433, 2017. © 2017 Wiley Periodicals, Inc.     

Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression

Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthma using house dust mite (HDM) allergen. Mice exposed to CDPM+HDM failed to develop a typical asthma phenotype including airway hyper-responsiveness, T-helper type 2 (Th2) inflammation, Muc5ac expression, eosinophilia, and HDM-specific immunoglobulin (Ig) compared with HDM-exposed mice. Although HDM-specific IgE was attenuated, total IgE was twofold higher in CDPM+HDM mice compared with HDM mice. We further demonstrate that CDPM exposure during early life induced an immunosuppressive environment in the lung, concurrent with increases in tolerogenic dendritic cells and regulatory T cells, resulting in the suppression of Th2 responses. Despite having early immunosuppression, these mice develop severe allergic inflammation when challenged with allergen as adults. These findings demonstrate a mechanism whereby CDPM exposure modulates adaptive immunity, inducing specific antigen tolerance while amplifying total IgE, and leading to a predisposition to develop asthma upon rechallenge later in life.     

Lack of association of HLA class II alleles with peanut allergy.

BACKGROUND: Peanut allergy is a common and severe phenotype of food allergy with a strong genetic component; HLA class II polymorphisms are attractive candidate genes for this disorder. Objective: To determine possible genotypic associations of HLA class II with peanut allergy and attempt replication of previously reported associations. METHODS: Sibling pairs discordant for peanut allergy were genotyped (low resolution) by polymerase chain reaction-based methods to 7 DQ and 18 DR allele groups. A chi2 analysis was undertaken against sibling controls with statistical adjustment for multiple analyses. RESULTS: Seventy-three children with confirmed peanut allergy (mean age, 6.5 years; male, 72%; asthma, 58%; atopic dermatitis, 62%; allergic rhinitis, 67%; other food allergies, 41%) and 75 of their siblings who eat peanut (mean age, 8 years; male, 52%; asthma, 12%; atopic dermatitis, 22%; allergic rhinitis, 37%; other food allergy, 7%) were genotyped. Distribution of DQ7 (29% of children with peanut allergy vs 47% sibling controls) was statistically significantly different (P = .04) before statistical correction for multiple comparisons was made by multiplying them by the number of alleles tested (and not statistically significant after correction; P = .30). Distribution of DR11 was nearly statistically significant without statistical adjustment (26% with peanut allergy vs 41% of sibling controls; P = .07; corrected P = 1.3). Alleles that were previously reported to have a weak association with peanut allergy (DRB1 *03, *08; DQB1 *0302, *04) were not verified in this cohort (unadjusted P > .44). CONCLUSIONS: We could not establish an association between the HLA class II alleles evaluated in this cohort of sibling pairs discordant for peanut allergy.     

Beyond allergen avoidance: update on developing therapies for peanut allergy

PURPOSE OF REVIEW: Food allergy has emerged as a significant health problem. Peanut allergy is a major cause of food-induced fatal and near fatal anaphylactic reactions, and the incidence in children is increasing. Attempts to manage peanut allergy by strict avoidance are often unsuccessful. The purpose of this review is to highlight the most promising novel approaches for treating peanut allergy beyond allergen avoidance. RECENT FINDINGS: In the past 5 years much effort has been devoted to developing a treatment for peanut allergy. A recent clinical trial showed that monthly injections of humanized recombinant anti-IgE antibodies increased the threshold for allergic responses of peanut-sensitive individuals, at least to small amounts of peanut protein. However, this treatment cannot cure peanut allergy, and continuous monthly injections are necessary to maintain protection. Developing new therapies for the treatment of peanut allergy is essential. In reviewing publications between 2003 and 2005, several novel therapeutic approaches, tested in the murine model of peanut anaphylaxis appeared promising. Immunotherapy with engineered recombinant peanut protein and bacterial adjuvant significantly protected peanut allergic mice from anaphylaxis. It was also found that a Chinese herbal medicine formula called Food Allergy Herbal Formula-2 completely blocked anaphylaxis up to 5 weeks following therapy. These potent therapeutic effects are associated with immunoregulation of Th1 and Th2 responses. SUMMARY: Although there is no effective and safe therapy for food allergy, many novel approaches are under investigation. Some of these approaches may provide allergists with effective treatments in the near future.     

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4⁺ T cells would exacerbate xenogeneic GVHD (xGVHD) into NOD-scid IL-2Rγ null (NSG) mice. Naive human CD4⁺ T cells were stimulated under Th17-skewing conditions for 8 to 10 days and then coinjected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated toward xGVHD target organs. They also acquired a double-expressing IL-17A⁺IFNγ⁺ profile in vivo. Importantly, cotransfer of Th17-polarized cells (1?×?10⁶) with PBMCs (1?×?10⁶) exacerbated xGVHD compared with transplantation of PBMCs alone (2?×?10⁶). Furthermore, PBMC cotransfer with Th17-polarized cells was more potent for xGVHD induction than cotransfer with naive CD4⁺ T cells stimulated in nonpolarizing conditions (Th0 cells, 1?×?10⁶?+?1?×?10⁶ PBMCs) or with Th1-polarized cells (1?×?10⁶?+?1?×?10⁶ PBMCs). In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model.     

Rising prevalence of food allergies in Taiwan: An epidemiological study

BackgroundFood allergies are becoming more prevalent globally. The purpose of this study was to investigate the epidemiology of food allergies in Taiwan.MethodsIn 2017, a food allergy questionnaire was administered to 6–7-year-old children, 13–14-year-old adolescents, and their parents in Taipei. The results were compared to those from a previous survey conducted in 2004.ResultsA total of 16,200 questionnaires were completed, revealing a rise in the prevalence of food allergies from 7.7% to 10.4% in the pediatric group and from 6.4% to 12.5% in the adult group. Peanut allergies also increased to 1.1%. Shrimp and crabs were the most common allergens, with urticaria being the most common symptom. Shortness of breath or wheezing occurred in 10% of individuals, while 2.1% experienced syncope or shock, and 0.1% were admitted to an intensive care unit. Personal history of allergic rhinitis and atopic dermatitis, as well as family histories of food allergies, were risk factors for food allergy in 6–7-year-old children. In the 13–14-year-old group, personal history of asthma, allergic rhinitis, or atopic dermatitis, recent use of acetaminophen, and living with dogs were risk factors. Females, personal histories of asthma, allergic rhinitis, atopic dermatitis, and moist and damp at home were risk factors in adults. Breastfeeding was a protective factor in 6–7-year-old children.ConclusionThe increasing prevalence of food allergies, including peanut allergies, in Taiwan warrants attention from physicians to provide appropriate care and education to patients with food allergies. The protective effect of breastfeeding against food allergies shall be emphasized.     

Mixed antibody and T cell responses to peanut and the peanut allergens Ara h 1, Ara h 2, Ara h 3 and Ara h 6 in an oral sensitization model

BACKGROUND: Peanut allergy is known for its severity and persistence through life. Several peanut proteins have been identified as allergenic and are indicated as Ara h 1-7. Very little is known about the mechanisms that underlie sensitization to peanut proteins. OBJECTIVE: The purpose of the present study was to reveal the immune responses that are induced against peanut and the peanut allergens Ara h 1, Ara h 2, Ara h 3 and Ara h 6 during sensitization, including the very early responses. METHODS: Humoral and T cell responses against peanut and the peanut allergens were examined in an early and later stage of sensitization in an established murine model of peanut anaphylaxis. Therefore C3H/HeJ mice were orally exposed to two different doses of peanut extract plus cholera toxin. RESULTS: Oral sensitization to peanut was characterized by an antigen-induced mixed cytokine response in the spleen (IL-4, IL-5, IL-10 and IFN-gamma), which could already be observed 7 days after the onset of exposure. Additionally, polyisotypic humoral responses (IgE, IgG1 and IgG2a) against peanut were found in the serum. Moreover, we demonstrated that these T helper (Th)1/Th2 cytokine and antibody responses were also directed specifically against the major peanut allergens Ara h 1, Ara h 2, Ara h 3 and Ara h 6. CONCLUSIONS: This study implicates that both Th1 and Th2 phenomena are involved in the development of peanut allergy in the C3H/HeJ murine model. Furthermore, we show that the present oral model is suitable to examine immune responses to food allergens during different stages of sensitization upon treatment with a whole food extract.     

Associations between antioxidant status, markers of oxidative stress and immune responses in allergic adults

BACKGROUND: There has been growing interest in the role of antioxidant function in controlling inflammatory disease states, such as allergy. This study investigated the relationship between antioxidant status, markers of airways inflammation [exhaled nitric oxide (eNO)], oxidative stress (F(2) isoprostanes) and immune responses in allergic adults. METHODS: Antioxidants (vitamins C, E, beta-carotene and selenium) and total antioxidant capacity (tAC) in serum were examined in relation to eNO, plasma F(2) isoprostanes and peripheral blood mononuclear cell (PBMC) cytokine and lymphoproliferative response to house dust mite (HDM) allergen, Staphylococcus enterotoxin B (SEB), phytohaemaglutinin (PHA) and lipopolysaccharide (LPS) in 54 allergic adults. RESULTS: Firstly, levels of specific vitamins did not correlate with tAC. Secondly, we did not see any evidence that specific vitamin levels (or tAC) were associated with either polarization or attenuation of in vitro immune responses. If anything, there were positive correlations between antioxidant (vitamin C and selenium) levels and HDM allergen responses [lymphoproliferation (selenium; r=0.35, P=0.013) and both Th2 IL13 (vitamin C; tau=0.254, P=0.028) and Th1 IFN-gamma (vitamin C; tau=0.302, P=0.009) responses]. There were also significant positive relationships between antioxidant levels and IL-10 responses to polyclonal stimulation by SEB (r=0.292, P=0.036) and LPS (r=0.34, P=0.015) (beta-carotene) and PHA (r=0.34, P=0.021) (tAC). Thirdly, although airways inflammation (eNO) was associated with both in vitro and in vivo (skin test reactivity) to HDM, we did not see any correlation between eNO and oxidative stress (F(2)-isoprostanes). Finally, there were no consistent relationships between oxidative stress and immune responses. CONCLUSION: There was no evidence that higher antioxidant levels were associated with reduced allergen responsiveness in allergic adults. If anything, antioxidant status was associated with increased immune responsiveness. The significance of this needs to be addressed in future intervention studies.     

Prevention of allergic disease during childhood by allergen avoidance: the Isle of Wight prevention study

BACKGROUND: Early life allergen exposure may increase the risk of childhood allergy, but the protective effect of reduction in allergen exposure remains uncertain. OBJECTIVE: To evaluate the effect of reduction in food and house dust mite (HDM) allergen exposure in infancy in preventing asthma and allergy. METHODS: Infants, at higher risk because of family predisposition, were recruited prenatally and randomized to prophylactic (n = 58) and control (n = 62) groups. Prophylactic group infants were either breast-fed with mother on a low allergen diet or given an extensively hydrolyzed formula. Exposure to HDM was reduced by the use of an acaricide and mattress covers. The control group followed standard advice. Development of allergic diseases and sensitization to common allergens (atopy) was assessed blindly at ages 1, 2, 4, and 8 years in all 120 children. RESULTS: Repeated measurement analysis, adjusted for all relevant confounding variables, confirmed a preventive effect on asthma: adjusted odds ratio (OR), 0.24; 95% CI, 0.09-0.66; P = .005; atopic dermatitis, OR, 0.23; CI, 0.08-0.64; P = .005; rhinitis, OR, 0.42; CI, 0.19-0.92; P = .03; and atopy, OR, 0.13; CI, 0.05-0.32; P < .001. The protective effect was primarily observed in the subgroup of children with persistent disease (symptoms at all visits) and in those with evidence of allergic sensitization. CONCLUSION: Allergic diseases can be reduced, for at least the first 8 years of life, by combined food and HDM allergen avoidance in infancy. CLINICAL IMPLICATIONS: Strict food and HDM allergen avoidance should be considered for prevention of allergy in high-risk infants.