Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders (original) (raw)
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Immunology and Cell Biology, 1995
Tcell proliferative responses to rye and Bermuda grass pollen allergens have been studied in a series of 51 atopic and 18 non-atopic subjects. Mean T cell responses were higher in the atopie group than in the non-atopic group (P < 0.001). and there was a strong correlation between the magnitude of reaction in the T cell assay and in the skin test (rye P<0.0\, Bermuda P < 0.05). A similar association was shown between T cell reactivity and serum levels of allergen-specific IgE (rye P < 0.05. Bermuda P < 0.05), but no relationship was found between serum allergen-specifie IgG levels and any other parameter studied, T cell reactivity was not found in three cord blood samples tested. Discordance between positivity for T cell responses and skin test reactions in some cases might reflect reactivity by T cell subsets that promote IgG antibody or cell-mediated responses without IgE antibody production. A precise knowledge of T cell recognition of grass pollen allergens will provide exciting new prospects for more effective and safer immunotherapy strategies for allergic diseases including asthma.
Thorax, 1996
Background -Bronchial challenge with allergen causes a specific form of airways inflammation consisting of an influx of neutrophils, eosinophils, and T cells. Because the relevance of the challenge model to clinical asthma is uncertain, the cellular changes that occur in the lungs of asthmatic subjects during natural seasonal allergen exposure were investigated. Methods -Seventeen grass pollen sensitive asthmatic subjects with previously reported seasonal exacerbations of asthma kept records of symptoms and underwent fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial biopsy before and during the peak of the grass pollen season. The BAL cells were analysed for differential cell counts and by flow cytometry for T cell subsets and surface activation markers. The biopsy samples were processed into glycol methacrylate resin and immunohistochemical analysis was performed for mast cells, activated eosinophils, T cells and interleukin 4 (IL-4), a cytokine with a pivotal role in allergen-induced inflammation. Results -In the pollen season there was an increase in T lymphocyte activation in the BAL fluid as identified by increased expression of interleukin 2 receptor (IL-2R). In the submucosa these changes were paralleled by an increase in CD4 + T cells. By contrast, the numbers of metachromatic cells in BAL fluid staining with toluidine blue were reduced, possibly because of degranulation following allergen stimulation. In keeping with mast cell activation, the number of mucosal mast cells staining for secreted IL-4 increased during the season. In comparison with the period shortly before the onset of the season, all but two subjects experienced an asthma exacerbation which followed the rise in pollen counts but, compared with the period preceding the first bronchoscopic examination, asthma symptoms were not increased during the pollen season. Conclusions -The data suggest that natural allergen exposure, leading to a clinical exacerbation of asthma, may induce an inflammatory response involving T cells, mast cells and eosinophils. The relationship between allergen exposure, cellular infiltration and activation, and clinical symptoms appears to be complex, with factors other than allergen also contributing to asthmatic activity. (Thorax 1996;51:575-581)
Immunology, 2002
Grass pollen immunotherapy is the only treatment for hayfever that is both effective and confers long-term bene®t. Immunotherapy may act by altering the local nasal mucosal T helper type 2 (Th2) to type 1 (Th1) cytokine balance either by down-regulation and/or immune deviation of T-lymphocyte responses. There is controversy as to whether these changes are detectable in peripheral blood. We therefore examined both local nasal and peripheral T-cell responses to allergen exposure in the same subjects before and after immunotherapy. In a double-blind trial of grass pollen immunotherapy, nasal biopsies were obtained at baseline and during the peak pollen season following 2 years of immunotherapy. Placebo-treated patients showed a seasonal increase in CD3 + T cells (P=0. 02) and in interleukin-5 (IL-5) mRNA + cells (P=0. 03) and no change in interferon-c (IFN-c) mRNA + cells (P=0. 2) in the nasal mucosa. In contrast, in the immunotherapy-treated group, there were no changes in the number of CD3 + T cells (P=0. 3) and IL-5 mRNA + cells (P=0. 2) but a signi®cant increase in the number of IFN-c mRNA + cells (P=0. 03). Furthermore, clinical improvement in the immunotherapy-treated group was accompanied by a seasonal increase in the ratio of IFN-c to IL-5 mRNA + cells in the nasal mucosa (P=0. 03). In contrast, there were no signi®cant changes in peripheral T-cell proliferative responses or cytokine production for IFN-c or IL-5 in response to grass pollen either within or between the two treatment groups. We conclude that successful grass pollen immunotherapy was associated with an increase in the ratio of IFN-c to IL-5 mRNA + cells in the nasal mucosa, whereas these changes were not re¯ected by alterations in peripheral blood T-cell proliferative responses or cytokine production before/after treatment.
Journal of Clinical Investigation, 1993
We have studied the influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. In a doubleblind, placebo-controlled trial of immunotherapy in 40 adult hay fever sufferers, clinical improvement was accompanied by a decrease in the size of the late-phase skin response. When the immunotherapy-treated group was compared with the placebo group, analysis of skin biopsies obtained 24 h after intradermal allergen revealed a significant reduction in the number of infiltrating CD3+ (P = 0.04) and CD4+ (P = 0.009) cells and a trend for a decrease in EG2+ eosinophils (P = 0.08). Treatment did not influence allergen-induced recruitment of CD8+ cells, neutrophils, or macrophages. Unexpected increases in expression of CD25 (P = 0.006) and HLA-DR (P = 0.007) were observed in the actively treated group. In situ hybridization using a panel of riboprobes demonstrated "TH2-type" (IL-4, IL-5) cytokine mRNA responses in both groups of patients. In contrast, significant hybridization for IL-2 (8/16 patients, P = 0.02) and for interferon-gamma (6/16 patients, P = 0.04) was observed only in the actively treated group. These findings indicate that immunotherapy is associated with suppression of allergen-induced CD4+ T lymphocyte infiltration, but among the cells that are recruited, there is upregulation of CD25 and HLA-DR. At least in this model, immunotherapy does not appear to affect expression of TH2-pattern cytokines in response to allergen exposure, but expression of mRNA for Thl-type cytokines was enhanced in half of the patients. The results support the view that immunotherapy may possibly be working through induction of T cell tolerance.
Clinical & Experimental Allergy, 2014
Background-Conceptually, allergic responses may involve cross-reactivity by antibodies or Tcells. While IgE cross-reactivity amongst grass pollen allergens has been observed, crossreactivity at the allergen-specific T-cell level has been less documented. Identification of the patterns of cross-reactivity may improve our understanding, allowing optimization of better immunotherapy strategies. Objectives-We use Phleum pratense as model for the studying of cross-reactivity at the allergen-specific CD4 + T cell level amongst DR04:01 restricted Pooideae grass pollen T-cell epitopes. Methods-After In vitro culture of blood mononucleated cells from Grass-pollen allergic subjects with specific Pooideae antigenic epitopes, dual tetramer staining with APC-labeled DR04:01/Phleum pratense tetramers and PE-labeled DR04:01/Pooideae grass homolog tetramers was assessed to identify cross-reactivity amongst allergen-specific DR04:01-restricted T-cells in 6 subjects. Direct ex vivo staining enabled the comparison of frequency and phenotype of different Pooideae grass pollen reactive T-cells. Intracellular cytokine staining (ICS) assays were also used to examine phenotypes of these T-cells. Results-T-cells with various degree of cross reactive profiles could be detected. Poa p 1 97-116 , Lol p 1 221-240, Lol p 5a 199-218, and Poa p 5a 199-218 were identified as minimally-crossreactive T-cell epitopes that do not show cross reactivity to Phl p 1 and Phl p 5a epitopes. Ex vivo tetramer staining assays demonstrated T-cells that recognized these minimally-cross reactive Tcell epitopes are present in Grass-pollen allergic subjects. Conclusions-Our results suggest that not all Pooideae grass epitopes with sequence homology are cross-reactive. Non-cross reactive T-cells with comparable frequency, phenotype and functionality to Phl p-specific T-cells, suggest that a multiple allergen system should be considered for immunotherapy instead of a mono allergen system.
Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy, 2004
Background T helper (Th)2 cells play an important role in the development of IgE-mediated diseases, with local overproduction of Th2 cytokines at the site of allergic inflammation. Furthermore, IL-10 has been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in human atopic diseases. Aim We studied whether circulating allergen-specific Th2 cells persist outside the season of exposure in patients mono-sensitized to birch pollen and whether healthy control individuals also have allergen-specific Th2 cells. We also studied whether IL-10-producing allergen-specific T cells can be found in circulation either in healthy controls or in allergic patients. Methods Blood was drawn outside the birch-pollen season from 15 birch-pollen-allergic patients, with seasonal respiratory symptoms and with (n 5 12) or without (n 5 3) oral allergy syndrome, and from 10 matched healthy controls. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with recombinant Bet v 1 allergen, control antigen tetanus toxoid (TT) and anti-CD3/CD80. In part of the cultures, rIL-4 was added in order to reinforce the allergen-specific Th2 cell responses.
Allergy, 2003
According to a hypothesis allergens induce Th2 responses in allergic patients, and microbes induce Th1 responses. We studied the kinetics of in vitro allergen-, tuberculin (PPD)- and tetanus toxin (TT)-induced IFN-gamma and IL-4 mRNA expression in peripheral blood mononuclear cell (PBMC) cultures of pollen-allergic patients and healthy controls. PBMC of 10 birch or timothy pollen-allergic patients and of 13 healthy controls were stimulated in vitro with allergen (birch or timothy), PPD or TT. Pellets and supernatants were collected at 24, 48, 72 and 96 h after stimulation. IFN-gamma and IL-4 production was measured by enzyme linked immunosorbent assay and mRNA expression using RT-PCR and time-resolved fluorometry. Allergen induced IFN-gamma production and mRNA expression in PBMC more in allergic patients than in healthy controls. Also allergen induced IL-4 mRNA expression more in allergic patients than in healthy controls. PPD induced IFN-gamma mRNA expression both in allergic patients and healthy controls, whereas IFN-gamma production was induced only in healthy controls and IL-4 was not induced at all. TT induced IFN-gamma mRNA expression in both groups, IFN-gamma production in allergic patients, and IL-4 mRNA expression in both allergic patients and healthy controls. In vitro stimulation with allergen induced both IFN-gamma and IL-4 mRNA expression of PBMC in allergic patients. These observations challenge the clearcut division of microbe-specific Th1 and allergen-specific Th2 responses in peripheral blood.
Journal of Allergy and Clinical Immunology, 1984
F(fteen grass pollen-sensitive asthmatic patiet, ts were selected from 200 patients with gr..~., pollenosis on the basis of positive SPTs and RASTs that were restricted to grass pollens (e.~cept Bermuda grass), no previous IT, and residence and occupation in an area monitored b~ vertal pollen counts. They underwent a double-blind trial of specific 17" with a m&ture of three gtas.~ pollen-aqueous extracts (velvet, sweet vernal, and timothy) or placebo. After 10 mo, the meatt maintenance dose of pollen extract (assayed bv RAST inhibition) in eight actively treated patients was 6000 PAST units (range 3000 to 8000) and the mean total dose was 18.700 RAST unit.~ (range 10,200 to 30,000). Results were assessment done by the fi~llowing clinical and immunological data. (l) during the pollen season, daily .symptom scores; r PD 20% FEV. IgE antibody to timothy 6y RAST in serum and in nasal secretions, .~erum IgG antibody to purified timothr allergen D by solid-phase radioimmunoassay, and the four IgG subclass antibodie.s t;x enzyme intmunoass~ O" were all measured before treatment and be]bre and after the pollen seasoll. Symptom scores of both tt'eated patients and controls correhated with pollen (ount.s (R = 0.88, p < 0.05 and R = 0.71, p < 0.05, respectively'). There was a significant differem c between the mean symptom score values of treated patients versus controls (Kruskal-Wallis w.~t. p < 0.001). No significant differences or changes either in the PD 20% FFV t or IgE antibod~ to timothy in seram and nasal secretions were found in the two groups &fore or after 17". Tom/ IgG tlnd all fimr lgG subclass antibodies to timothy atttigen D increased significantly in aepve/v treated patients (p < 0.00.5 for each). The increase in IgG4 subclass atttibodie.~ was greater than in that of the other three IgG subclasses (p < 0.05). We conclude that a shtgle):ear ~/ aqueous grass pollen IT is clinically effective in properly .selected patients without demonstr~ahtc decreases in serum or seeretot 3" IgE antibody and is associated with significant rises ill all lgt; subcla.ss atttibodies, especially lgG4.
Journal of Allergy and Clinical Immunology, 1996
Background: Grass pollen injection immunotherapy is effective in patients with summer hay fever, although efficacy must be balanced against possible side effects. The mechanism of immunotherapy is unknown but may be related to its ability to inhibit allergen-induced late responses, which are known to be characterized by infiltration of T lymphocytes, eosinophils, and cells with messenger RNA for so-called Tin-type cytokines . Objective: This study was designed to observe the effect of grass pollen immunotherapy on late nasal responses and associated cellular infiltration and cytokine mRNA expression. Methods: We performed local nasal provocation with grass pollen (and a control challenge) in 28 patients after a 12-month double-blind, placebo-controlled trial of immunotherapy. Nasal biopsy specimens were obtained at 24 hours and processed for immunohistology and in situ hybridization studies.