Dissection of the grass allergen–specific immune response in patients with allergies and control subjects: T-cell proliferation in patients does not correlate with specific serum IgE and skin reactivity☆☆☆★

Würtzen, Peter Adler; Neerven, R. J. Joost van; Arnved, J.; Ipsen, Henrik; Sparholt, S.H.

doi:10.1016/s0091-6749(98)70389-6

Cited by 32 publications

(40 citation statements)

References 45 publications

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“…Studies conducted in mice have demonstrated the development of allergic airway hyperresponsiveness mediated by T cells in the absence of IgE (10,11). Furthermore, data obtained from human studies have demonstrated a lack of correlation between antigen-specific IgE levels and T-cell responses (12)(13)(14)(15)(16).…”

Section: Previously Undescribed Grass Pollen Antigens Are the Major Imentioning

confidence: 99%

Previously undescribed grass pollen antigens are the major inducers of T helper 2 cytokine-producing T cells in allergic individuals

Schulten

Greenbaum

Hauser

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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T cells play an important role in the pathogenesis of allergic diseases. However, the proteins considered as potential immunogens of allergenic T-cell responses have traditionally been limited to those that induce IgE responses. Timothy grass (TG) pollen is a well-studied inhaled allergen for which major IgE-reactive allergens have also been shown to trigger T helper 2 (Th2) responses. Here we examined whether other TG pollen proteins are recognized by Th2 responses independently of IgE reactivity. A TG pollen extract was analyzed by 2D gel electrophoresis and IgE/IgG immunoblots using pooled sera from allergic donors. Mass spectrometry of selected protein spots in combination with de novo sequencing of the whole TG pollen transcriptome identified 93 previously undescribed proteins for further study, 64 of which were not targeted by IgE. Predicted MHC binding peptides from the previoulsy undescribed TG proteins were screened for T-cell reactivity in peripheral blood mononuclear cells from allergic donors. Strong IL-5 production was detected in response to peptides from several of the previously undescribed proteins, most of which were not targeted by IgE. Responses against the dominant undescribed epitopes were associated with the memory T-cell subset and could even be detected directly ex vivo after Th2 cell enrichment. These findings demonstrate that a combined unbiased transcriptomic, proteomic, and immunomic approach identifies a greatly broadened repertoire of protein antigens targeted by T cells involved in allergy pathogenesis. The discovery of proteins that induce Th2 cells but are not IgE reactive may allow the development of safer immunotherapeutic strategies.

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Section: Previously Undescribed Grass Pollen Antigens Are the Major Imentioning

confidence: 99%

Previously undescribed grass pollen antigens are the major inducers of T helper 2 cytokine-producing T cells in allergic individuals

Schulten

Greenbaum

Hauser

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Four replicates of 3 × 10 5 cells/well were stimulated with naturally purified major allergens Phl p 1 (5 µg/ml) and Phl p 5 (5 µg/ml), purified protein derivative (PPD; 25 µg/ml; SSI, Copenhagen, Denmark) or medium control with or without blocking antibodies specific to the IL-10 receptor (aIL-10R: 5 µg/ml, clone 3F9; BD Biosciences, San Jose, Calif., USA), and TGF-β (aTGF-β 1, 2, and 3: 10 µg/ml, clone 1D11; R&D, Minneapolis, Calif., USA) or to the IL-4 receptor (IL-4R: 2.5 µg/ml, clone 25463.111; R&D). Allergens were purified from grass pollen extracts as described elsewhere [27] and concentrations of allergens were selected on the basis of previous studies on grass allergen-specific T cell responses [28,29]. Endotoxin levels were below 2.5 EU/ml in cultures with Phl p 5 and below 0.5 EU/ml in cultures with Phl p 1.…”

Section: Methodsmentioning

confidence: 99%

“…Subsequently, 0.5 µCi/well 3 H-thymidine (New England Nuclear, Boston, Mass., USA) was added and proliferation was measured by counts per minute (cpm) in a β-scintillation counter (Wallax, Pharmacia, Turku, Finland) after an additional 16–20 h of incubation. In previous studies [28,29] and in pilot experiments, these experimental conditions were found to be generally applicable for detection of grass allergen-specific T cell proliferation and detection of Th1 and Th2 cytokines as well as IL-10. The stimulation index (SI) was calculated by the mean cpm of allergen or PPD stimulated cells divided by the mean cpm of cells in medium (median 906 cpm, range 293–4,845 cpm).…”

Section: Methodsmentioning

confidence: 99%

The T Cell Response to Major Grass Allergens Is Regulated and Includes IL-10 Production in Atopic but Not in Non-Atopic Subjects

Domdey

Liu²,

Millner³

et al. 2010

Int Arch Allergy Immunol

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Background: The incidence of allergic diseases is increasing in industrialized countries and the immunological mechanisms leading to tolerance or allergy are poorly understood. Cytokines with suppressive abilities and CD4⁺CD25⁺ regulatory T cells have been suggested to play a central role in allergen-specific responses. The aim was to determine whether major grass allergens induce production of suppressive cytokines in allergic and healthy subjects and to examine the inhibitory effect of these cytokines on allergic responses. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy and grass-allergic donors and stimulated with the major grass allergens Phl p 1 or Phl p 5. The effects of endogenous IL-10 and/or TGF-β on proliferation and cytokine production were determined by use of blocking antibodies. In addition, the number of CD4⁺CD25⁺ T cells and their expression of chemokine receptors were investigated by flow cytometry. Results: Phl p 1 and Phl p 5 induced IL-10 production, which down-regulated proliferation and cytokine production, in PBMC cultures from atopic but not from non-atopic donors. Comparable frequencies of CD4⁺CD25⁺ T cells were present in PBMCs in the two groups, but fewer cells from atopic donors were CD4⁺CD25⁺CCR4⁺ and more cells were CD4⁺CD25⁺CLA⁺ compared to healthy donors. Conclusion:Allergen-specific responses of grass allergic patients but not in non-atopic subjects are influenced by regulatory cytokines produced in response to the important allergens. Differences in CD4⁺CD25⁺ T cell expression of chemokine receptors in allergic compared to non-atopic donors could suggest that the homing of CD4⁺CD25⁺ T cells is important for the regulation of allergen-specific responses.

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“…In general, allergens induce T cell proliferative responses in the majority of sensitized subjects; however, the magnitude of the responses varies considerably between different individuals. Furthermore, though the magnitude of T cell proliferative responses can be higher in sensitized compared with non-sensitized individuals, this is highly variable, particularly among patients with very high titers of circulating IgE ab such as subjects with atopic dermatitis [36][37][38][39][40][41][42][43]. It has been argued that T cell responses to ubiquitous allergens such as those derived from house dust mites are universal [43].…”

Section: Relevance Of the Th1/th2 Paradigm To Allergic Disease In Manmentioning

confidence: 99%

Cytokines as a Therapeutic Target for Allergic Diseases: A Complex Picture

Woodfolk

2006

CPD

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Production of IgE antibodies promotes the development of allergic disorders such as asthma, rhinitis and atopic eczema. Though Th2 cytokines play a pivotal role in the allergic inflammatory cascade, therapeutic strategies which target these factors have not been curative in clinical trials. In humans, the allergic phenotype encompasses a broad spectrum of diverse clinical entities, which are dictated by genetics as well as the nature of the allergen and the time in life at which allergen is encountered. The disparate findings in animal and human systems highlight the complexity of cytokine-mediated events in allergic responses in man. Different allergic phenotypes cannot be distinguished strictly on the basis of Th1 and Th2 cytokines. These observations coupled with an emerging role for regulatory T cells in modulation of the allergic response warrant re-examination of the cytokine network in allergic disease. This article highlights the challenges of dissecting the role of individual cytokines in the development of allergic responses and manifestation of allergic symptoms. Regulatory T cells have been implicated in modulation of the activity of allergen-specific Th1 and Th2 effector cells and immune outcome; however, the characteristics of these regulatory T cells remain largely undefined. The effects of existing and emerging therapies which target Th1, Th2 and regulatory cytokines on established allergic responses are examined in the context of this new paradigm. Taken together, existing data suggest that a multi-faceted approach, which is tailored to each patient, will be required in order to attain clinical benefit.

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Dissection of the grass allergen–specific immune response in patients with allergies and control subjects: T-cell proliferation in patients does not correlate with specific serum IgE and skin reactivity☆☆☆★

Cited by 32 publications

References 45 publications

Previously undescribed grass pollen antigens are the major inducers of T helper 2 cytokine-producing T cells in allergic individuals

Previously undescribed grass pollen antigens are the major inducers of T helper 2 cytokine-producing T cells in allergic individuals

The T Cell Response to Major Grass Allergens Is Regulated and Includes IL-10 Production in Atopic but Not in Non-Atopic Subjects

Cytokines as a Therapeutic Target for Allergic Diseases: A Complex Picture

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