Maize food allergy: a double‐blind placebo‐controlled study

Background Maize allergy is not very common especially in Europe. The number of studies that address IgE mediated maize allergy is all too few. Objective Evaluate subjects with a history of maize allergy by double‐blind, placebo‐controlled food challenge; identify the spectrum of symptoms manifested during challenge; determine the lowest provocation dose (PD) during challenge; determine the performance characteristics of maize skin prick test and specific IgE. Methods Twenty‐seven patients with a history of maize allergy were enrolled to be evaluated by skin test, specific IgE and double‐blind placebo‐controlled maize challenge. Results Forty‐eight percent of the patients were challenge positive. PD range was 0.1–25 g. Fifty‐four percent of the maize allergic subjects had a PD that was 2.5 g; two subjects reacted to 100 mg of maize. Comparison of maize specific IgE levels and skin test results to the challenge results revealed the following (specific IgE level/skin testing): sensitivity 1.00/0.846, specificity 0.077/0.384, positive predictive value 0.520/0.579, and negative predictive value 1.00/0.714. Conclusion Maize is a cause of IgE‐mediated allergic reactions to foods in adults and children. Nearly half of the subjects recruited were confirmed by challenge to be allergic to maize. Twenty‐three percent of the positive challenge patients manifested symptoms that involved two organ systems, thus fulfilling the criteria for maize induced anaphylaxis. Maize is allergenic and can pose a risk for symptomatic food allergy at a dose of 100 mg.     

Impaired Toll‐like receptor 2 signalling in monocytes from 5‐year‐old allergic children

The relative composition of the two major monocytic subsets CD14⁺CD16⁻ and CD14⁺CD16⁺ is altered in some allergic diseases. These two subsets display different patterns of Toll-like receptor levels, which could have implications for activation of innate immunity leading to reduced immunoglobulin E-specific adaptive immune responses. This study aimed to investigate if allergic status at the age of 5 years is linked to differences in monocytic subset composition and their Toll-like receptor levels, and further, to determine if Toll-like receptor regulation and cytokine production upon microbial stimuli is influenced by the allergic phenotype. Peripheral blood mononuclear cells from 5-year-old allergic and non-allergic children were stimulated in vitro with lipopolysaccharide and peptidoglycan. Cells were analysed with flow cytometry for expression of CD14, Toll-like receptors 2 and 4 and p38-mitogen-activated protein kinase (MAPK). The release of cytokines and chemokines [tumour necrosis factor, interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70] into culture supernatants was measured with cytometric bead array. For unstimulated cells there were no differences in frequency of the monocytic subsets or their Toll-like receptor levels between allergic and non-allergic children. However, monocytes from allergic children had a significantly lower up-regulation of Toll-like receptor 2 upon peptidoglycan stimulation. Further, monocytes from allergic children had a higher spontaneous production of IL-6, but there were no differences between the two groups regarding p38-MAPK activity or cytokine and chemokine production upon stimulation. The allergic subjects in this study have a monocytic population that seems to display a hyporesponsive state as implicated by impaired regulation of Toll-like receptor 2 upon peptidoglycan stimulation.     

Suppressive effects of nitric oxide‐releasing prednisolone NCX‐1015 on the allergic pleural eosinophil recruitment in rats

Background The addition of a nitric oxide (NO)‐releasing moiety to prednisolone was shown to enhance the anti‐inflammatory activity of this glucocorticoid in some experimental conditions, but its effectiveness in the context of eosinophilic inflammation remains to be elucidated. Objective This study compared the anti‐inflammatory effect of prednisolone to a NO‐releasing derivative of prednisolone, NCX‐1015, using a model of allergen‐evoked eosinophil recruitment in rats. The efficacy of a NO‐donor compound, DETA‐NONOate, was also assessed for comparison. Methods Wistar rats were actively sensitized with Al(OH)₃ plus ovalbumin and 14 days later challenged with antigen intrapleurally. Treatments were performed locally 1 h before challenge. Cysteinyl‐leucotrienes (Cys‐LT) and eotaxin were measured by ELISA. Results Antigen challenge induced an eosinophil infiltration at 12 h, maximal at 24 h. It also caused an increase in the levels of Cys‐LTs in the pleural exudate and in the expression of 5‐lipoxygenase (5‐LO) in infiltrated leucocytes at 6 h, peaking at 12 h and persisting for at least 24 h. Treatment with equimolar doses of prednisolone and NCX‐1015 inhibited the late eosinophil infiltration, although the dose required to produce maximal inhibition was about one‐tenth that of prednisolone. Cys‐LT generation and 5‐LO expression were inhibited by NCX‐1015 but not by prednisolone. Treatment with prednisolone combined with the NO‐donor DETA‐NONOate led to a greater inhibition of the eosinophilia and Cys‐LT generation as compared with either drug alone. Administration of the steroid receptor antagonist RU 486, 1 h before prednisolone and NCX‐1015, abolished the inhibitory effect of the former, under conditions where it only partially affected the latter. Conclusions Our findings indicate that NCX‐1015 provided a greater anti‐inflammatory effect than prednisolone on the allergic eosinophil recruitment in rats, suggesting that NO‐releasing steroids can be considered as a promising therapeutic approach to allergic diseases.     

Cytotoxic T lymphocyte antigen 4‐immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy

Allergen‐specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen‐specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses of the allergen, thereby reducing the risk of anaphylactic reactions. Cytotoxic T lymphocyte antigen 4–immunoglobulin (CTLA‐4–Ig) has been shown to induce immunological tolerance in autoimmunity and allograft transplantation by blocking T cell co‐stimulation and induction of the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO). Previously, we showed that CTLA‐4–Ig treatment at the time of allergen inhalation induced tolerance to subsequent allergen exposure in a mouse model of asthma. In this study, we test the hypothesis that CTLA‐4–Ig acts as an adjuvant for experimental SIT. We evaluated the adjuvant effects of CTLA‐4–Ig on SIT in a mouse model of ovalbumin‐driven asthma. We used both wild‐type and IDO‐deficient mice to assess the role of IDO in the adjuvant effects of CTLA‐4–Ig. Co‐administration of CTLA‐4–Ig strongly increased SIT‐induced suppression of airway hyperreactivity (AHR), specific IgE in serum, airway eosinophilia and Th2 cytokine levels. Moreover, we found that CTLA‐4–Ig, as an adjuvant for SIT, is equally effective in IDO‐deficient and wild‐type mice, demonstrating that the effect of CTLA‐4–Ig is independent of IDO expression. We show that CTLA‐4–Ig acts as a potent adjuvant to augment the therapeutic effects of SIT. As the adjuvant activity of CTLA‐4–Ig is independent of IDO, we conclude that it acts by blocking CD28‐mediated T cell co‐stimulation.     

Pollen‐derived low‐molecular weight factors inhibit 6‐sulfo LacNAc+ dendritic cells' capacity to induce T‐helper type 1 responses

Background Evidence is accumulating that the pollen exsudate contains an array of non‐allergenic, pro‐inflammatory and immunomodulatory substances acting on the innate and adaptive immune system. In this context, pollen‐associated E₁‐phytoprostanes (PPE₁) were shown to licence human monocyte‐derived dendritic cells for T‐helper type 2 (Th2) polarization of naïve T cells. Objective This study aims at analysing the impact of pollen‐associated lipid mediators on cytokine secretion and maturation of 6‐sulfo LacNAc⁺ dendritic cells (slanDCs), the most abundant native dendritic cell (DC) in human peripheral blood, and further dissecting the biologically active substance(s) within aqueous pollen extracts. Results Aqueous birch pollen extracts dose‐dependently inhibited the lipopolysaccharide (LPS)‐induced IL‐12 p70 production, while the levels of IL‐6 remained unaffected. PPE₁ inhibited secretion of both IL‐12 p70 and IL‐6. Aqueous pollen extracts, but not PPE₁ or F₁‐phytoprostanes significantly reduced the LPS‐induced surface expression of the maturation markers CD80, CD83, CD40 and CCR‐7, an effect that was independent of proteins and that was still present in a 3 kDa cut‐off fraction of the pollen extract. These effects were observed irrespective of the atopy status of the donors. Finally, slanDCs exposed to aqueous pollen extracts were impaired in eliciting an IFN‐γ response in naïve CD4⁺ T cells. Conclusion Our data show that slanDCs, a subset of human blood DCs with constitutively high potency to induce Th1 responses, are susceptible to the Th2 polarizing effect of low molecular weight, non‐protein factors derived from pollen. Cite this as: S. Gilles, D. Jacoby, C. Blume, M. J. Mueller, T. Jakob, H. Behrendt, K. Schaekel and C. Traidl‐Hoffmann, Clinical & Experimental Allergy, 2010 (40) 269–278.     

Antigen presenting cell‐derived IL‐6 restricts Th2‐cell differentiation

The identification of DC‐derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen‐loaded, IL‐6‐deficient DCs to naïve mice induced an exacerbated Th2 response, characterized by the differentiation of GATA‐3‐expressing T lymphocytes secreting high levels of IL‐4, IL‐5, and IL‐13. Coinjection of wild type and IL‐6‐deficient bone marrow‐derived dendritic cells (BMDCs) confirmed that IL‐6 exerted a dominant, negative influence on Th2‐cell development. This finding was confirmed in vitro, where exogenously added IL‐6 was found to limit IL‐4‐induced Th2‐cell differentiation. iNKT cells were required for optimal Th2‐cell differentiation in vivo although their activation occurred independently of IL‐6 secretion by the BMDCs. Collectively, these observations identify IL‐6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity.     

Natural evolution of skin‐test sensitivity in patients with IgE‐mediated hypersensitivity to cephalosporins

There are studies demonstrating that skin‐test sensitivity to penicillins can decrease over time and that allergic patients may lose sensitivity if the responsible compounds are avoided. With regard to subjects with IgE‐mediated hypersensitivity to cephalosporins, however, such studies are lacking. We evaluated prospectively in a 5‐year follow‐up 72 cephalosporin‐allergic patients. After the first evaluation, patients were classified into two groups according to their patterns of allergologic‐test positivity: to both penicillins and cephalosporins (group A), or only to cephalosporins (group B). Skin tests and serum‐specific IgE assays were repeated 1 year later and, in case of persistent positivity, 3 and 5 years after the first allergologic examination. Seven (43.7%) of the 16 subjects of group A and 38 (67.8%) of the 56 patients of group B became negative; one was lost to follow‐up. Patients of group B became negative sooner and more frequently than group A subjects.