-
M H Shamji,
C Ljørring,
J N Francis,
M A Calderon, M Larché,
I Kimber,
A J Frew,
H Ipsen,
K Lund,
P A Würtzen,
S R Durham
[show abstract]
[hide abstract]
ABSTRACT: Induction of allergen-specific IgG(4) antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG(4) antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG(4) titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG-associated inhibitory activity such as inhibition of IgE-allergen interactions (IgE-blocking factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response.
In an 8-month dose-response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100,000 SQ-U, 10,000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG(4) titres and IgG-associated inhibitory activity were evaluated.
A time- and dose-dependent increase in serum inhibitory activity for both the IgE-blocking factor and IgE-FAB was observed, which paralleled increases in grass pollen-specific IgG(4) antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom-rescue medication scores (IgE-FAB: r = -0.25, P = 0.0002; IgE-blocking factor: r = -0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG(4) levels (r = -0.11, P = 0.12).
Functional assays of inhibitory IgG(4) and IgE-blocking factor may be more useful surrogates of clinical response than IgG(4). Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation.
Allergy 11/2011; 67(2):217-26. · 6.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The mechanisms of late asthmatic reactions provoked in atopic asthmatics by allergen-derived T-cell peptide epitopes remain unclear. Previous studies showed no changes in airway eosinophils or mast cell products after peptide challenge. In the present study our aim was to measure calcitonin gene-related peptide (CGRP), neurokinin (NK)-A, and substance P (SP) in bronchoalveolar lavage fluid and bronchial biopsies (BB) after inhalation of allergen-derived T-cell peptide epitopes since these neuropeptides (NP) had not previously been evaluated in this chronic asthma model.
Bronchoscopy, with BB and bronchoalveolar lavage (BAL), was performed in 24 cat-allergic subjects 6 h after inhalation of Fel d 1-derived peptides. Neuropeptides were measured in BAL by enzyme-linked immunosorbent assay and CGRP expression in the airways was assessed by immunohistochemistry and confocal microscopy.
Twelve subjects (termed 'responders') developed isolated late reactions. Calcitonin gene-related peptide, but not NK-A or SP, was significantly elevated in BAL in responders only. Biopsy studies showed that in virtually all responders peptide challenge induced marked increases in CGRP immunoreactivity in bronchial epithelial cells, infiltrating submucosal cells and in association with airway smooth muscle. Double immunostaining indicated that CGRP colocalized predominantly to CD3+/CD4+ and CD68+ submucosal inflammatory cells.
Calcitonin gene-related peptide, a potent vasodilator, is markedly up-regulated in the airways of atopic asthmatics during late-phase reactions provoked by inhalation of allergen-derived T-cell peptides.
Allergy 06/2007; 62(5):495-503. · 6.27 Impact Factor
-
M Larché
[show abstract]
[hide abstract]
ABSTRACT: Specific allergen immunotherapy has been widely practised for almost 100 years. Whilst this approach is disease-modifying and efficacious, the use of whole allergen preparations is associated with an unacceptably high prevalence of allergic adverse events during treatment. Many approaches to reduce the allergenicity of immunotherapy preparations whilst maintaining immunogenicity are under development. One such approach is the use of short synthetic peptides which represent major T-cell epitopes of the allergen. Major potential advantages of this approach include markedly reduced capacity to cross-link immunoglobulin-E and activate mast cells and basophils, and ease of manufacture and standardization. Promising results in preclinical studies have led to the translation of this approach to clinical studies in humans. Peptide immunotherapy is currently under development for allergic and autoimmune diseases.
Allergy 04/2007; 62(3):325-31. · 6.27 Impact Factor
-
M Larché
European annals of allergy and clinical immunology 10/2006; 38(7):240-3.
-
[show abstract]
[hide abstract]
ABSTRACT: Allergen-derived (T cell epitope) peptides may be safer for immunotherapy than native allergen, as they do not cross-link immunoglobulin (Ig)E. However, HLA polymorphism results in multiple potential epitopes. Synthetic peptides of phospholipase (PL) A(2) were selected for a peptide vaccine, on the basis of binding affinity for commonly expressed HLA-DR molecules.
To evaluate treatment with an HLA-DR-based PLA(2) peptide vaccine in subjects with mild honeybee allergy in an open, controlled study.
Twelve volunteers with allergy to bee venom received nine intradermal injections of PLA(2) peptides, with six untreated subjects serving as controls. Outcome was assessed by the size of the late-phase cutaneous reaction to allergen, peripheral blood mononuclear cell (PBMC) proliferation, cytokine release, and expression of genes associated with immune regulation.
Subjects receiving peptides showed a decrease in the magnitude of the late-phase cutaneous reaction to bee venom compared with controls (P=0.03). The proliferation of venom-stimulated PBMCs decreased in treated subjects compared with controls (P=0.01). Peptide treatment reduced the production of IL-13 by PLA(2)-stimulated PBMCs (P<0.01) and IFN-gamma (P<0.01), and increased the production of IL-10 (P=0.02). Transcription of the suppressor of cytokine signalling (Socs)3 gene was significantly increased following therapy. A transient, but modest, increase in allergen-specific IgG was also observed.
HLA-DR-based T cell epitopes modify surrogate markers associated with successful immunotherapy and induction of immune regulation, supporting the concept that this form of treatment may be efficacious in human allergic disease.
Clinical & Experimental Allergy 04/2006; 36(4):465-74. · 5.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We previously showed that overlapping Fel d 1-derived T-cell peptides inhibited surrogate markers of allergy (i.e. early and late-phase skin reactions and T-cell function) in cat allergic subjects. The present pilot study was designed to determine whether this treatment affected clinically relevant outcome measurements such as the allergen-induced nasal and bronchial reactions, and asthma/rhinitis quality of life (QOL).
Sixteen cat-allergic asthmatic subjects who gave a dual (early and late) asthmatic response (DAR) to inhaled cat allergen were randomly assigned to receive either Fel d 1 peptides (approximately 300 mug in increasing, divided doses) or placebo (8 active : 8 placebo). Twelve single early responders (SER) were also studied in an open fashion design. Allergen-induced bronchial and nasal measurements as well as the QOL was measured at baseline, 4-8 weeks (follow-up 1 (FU1)) and 3-4 months (FU2).
In the active, but not placebo, group there were significant decreases in the late asthmatic reaction (LAR) to whole cat dander (P = 0.03) at FU2 but with no between group difference. There were also significant improvements in asthma quality of life (QOL) scores [asthma-activity limitation (P = 0.014); rhinitis-sleep (P = 0.024), non-nose/non-eye symptoms (P = 0.031), nasal problems (P = 0.015)]. In the open study Fel d 1 peptide treatment resulted in significant decreases in number of sneezes (P = 0.05), weight of nasal secretions (P = 0.04) and nasal blockage (P = 0.01) following allergen challenge.
Multiple, short, overlapping Fel d 1 T-cell peptides have potential for inhibiting upper and lower airway outcome measurements in cat allergic patients. Larger, dose-ranging, studies are required before firm conclusions on clinical efficacy of peptide allergen therapy can be made.
Allergy 11/2005; 60(10):1269-74. · 6.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Specific immunotherapy with whole allergen extracts is associated with local accumulation of IFN-gamma+ and CD25+ cells indicating recruitment of activated T-helper type 1 (Th1) and/or T regulatory cells. We have studied allergen-induced, late-phase skin biopsies before and after T cell peptide therapy for evidence of alterations in the pattern of local recruitment of Th1, T-helper type 2 (Th2) and T regulatory cells.
To evaluate the effect of T cell peptide therapy on the allergen-induced cutaneous late-phase reaction.
Increasing doses of synthetic Fel d 1-derived peptides were administered (by intradermal injection) to eight cat-allergic asthmatics at 14-day intervals. Twenty-four-hour skin biopsies were taken from whole cat allergen- and diluent-injected sites, before and after treatment and studied by immunohistochemistry and in situ hybridization.
Fel-d 1 peptides decreased airway hyper-responsiveness (P = 0.02) and inhibited the late-phase cutaneous reaction (LPCR) to whole cat allergen (P = 0.03). This was associated with significant increases (post- vs. pre-treatment) in the number of cutaneous CD4+/IFN-gamma+ (P = 0.03) and CD4+/CD25+ cells (P = 0.04), but not in CD4+/IL-10+ or CD4+/CTLA-4+ cells.
Treatment with allergen-derived T cell peptides results in allergen-dependent recruitment to the skin of Th1, rather than T regulatory cells, to cutaneous late-phase reaction sites.
Clinical & Experimental Allergy 02/2005; 35(1):52-8. · 5.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have previously described both modification of allergen immunotherapy using peptide fragments, and reduced regulation of allergen stimulated T cells by CD4(+) CD25(+) T cells from allergic donors when compared with nonallergic controls. It has been suggested that allergen immunotherapy induces regulatory T cell activity: we hypothesized that allergen peptide immunotherapy might increase suppressive activity of CD4(+) CD25(+) T cells.
To examine cat allergen-stimulated CD4 T cell responses and their suppression by CD4(+) CD25(+) T cells before and after cat allergen peptide immunotherapy in a double-blind placebo-controlled study.
Peripheral blood was obtained and stored before and after peptide immunotherapy or placebo treatment. CD4(+) and CD4(+) CD25(+) were then isolated by immunomagnetic beads and cultured with allergen in vitro.
Comparing cells from blood taken before with that after peptide immunotherapy there was a significant reduction in both proliferation and IL-13 production by allergen-stimulated CD4+ T cells, whereas no change was seen after placebo. CD4(+) CD25(+) T cells suppressed both proliferation and IL-13 production by CD4(+) CD25(-) T cells before and after therapy but peptide therapy was not associated with any change in suppressive activity of these cells.
Allergen peptide immunotherapy alters T cell response to allergen through mechanisms other than changes in CD4(+) CD25(+) T cell suppression.
Allergy 11/2004; 59(10):1097-101. · 6.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Some patients with asthma who are allergic to cats and are injected intradermally with short, overlapping, T-cell peptides derived from Fel d 1 develop late asthmatic reactions to the peptides, which are associated with a reduction in late-phase skin reactions induced by whole allergens and bronchial hyporesponsiveness to the peptides on the second injection. We aimed to ascertain the effect of multiple injections on the magnitude of the early and late phase skin reactions to intact allergens.
After a 9-week run-in period, we randomly assigned patients with asthma and allergies to cats to receive either Fel d 1 peptides (90 microg in increasing divided doses) or placebo. The primary outcome was late-phase cutaneous reactions to whole cat dander. Outcomes were measured at baseline, 4-8 weeks, and 3-9 months. Analysis was by intention to treat.
16 patients were randomly assigned to the peptides, and eight to placebo. All patients completed the course of injections. Four of the 16 patients on Fel d 1 peptides had initial late asthmatic reactions, but could be desensitised to the higher dose of peptide. Patients in the peptide group but not the placebo group had a significant reduction in the size of their late reaction to whole cat dander between baseline and both follow-ups, but the difference between groups was not significant (first follow-up, difference -422.8 mm(2) [95% CI -1115.0 to 269.4], p=0.43; second follow-up -1180.8 mm(2) [-2216.8 to -144.8], p=0.058). The size of the late reaction to Fel d 1 significantly differed between treatment groups at both follow-ups. At second follow-up, the size of the early reaction to Fel D 1, but not to whole cat dander was significantly reduced in those on peptides compared with those on placebo. The concentration of interferon gamma and of interleukin 4 and 13, and the amount of proliferation, significantly decreased between baseline and second follow-up, and the concentration of interleukin 10 was significantly higher in patients on peptides, however, none of these values differed significantly between groups. Patients on peptides had a significantly greater decrease in the concentration of interferon gamma and interleukin 13, and in the amount of proliferation between baseline and first follow-up than did those on placebo.
Several, short, overlapping Fel d 1 T-cell peptides have potential in treatment of cat allergy.
The Lancet 08/2002; 360(9326):47-53. · 38.28 Impact Factor
-
M Larché
[show abstract]
[hide abstract]
ABSTRACT: Specific allergen immunotherapy (SIT) has been shown to be effective in modulating allergic responses in diseases such as rhinitis and asthma. However, the ability of whole allergen to cross link mast cell bound IgE, resulting in release of mediators such as histamine, has limited the application of this therapy to carefully selected patients who have failed conventional pharmacotherapy. The use of peptide sequences corresponding to T cell epitopes of the allergen has been postulated as an alternative to SIT in which high molar doses of T cell epitope can be delivered over a shorter time period and with improved safety. Using peptides from the sequence of the major cat allergen, Fel d 1, we have demonstrated the ability to induce transient T cell activation, resulting in isolated late asthmatic reactions, which are followed by prolonged periods of allergen-specific hyporesponsiveness, both to peptide re-challenge and to cutaneous challenge with whole allergen. Thus, peptide therapy may prove safe and efficacious in the treatment of allergic diseases.
Allergy 02/2002; 57 Suppl 72:20-3. · 6.27 Impact Factor
-
M Larché
Immunology 01/2002; 104(4):377-82. · 3.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In general, T cells from normal, nonatopic individuals respond to aeroallergens with synthesis and release of IFN-gamma. In contrast, release of T(H)2-type cytokines by activated lymphocytes is a feature of allergic rhinitis and atopic asthma.
The purpose of this study was to determine differences in T-cell recognition of epitopes within allergenic sequences, in terms of proliferation and cytokine production, in subjects with atopic asthma compared with subjects with allergic rhinitis and normal controls.
Proliferative responses and IL-5/IFN-gamma release patterns from PBMCs from cat-allergic asthmatic, cat-allergic rhinitic, and non-cat-allergic asthmatic subjects and nonatopic normal controls were determined in primary cultures. Cells were challenged with 7 overlapping peptides spanning chain 1 of the major cat allergen, Fel d 1.
The 4 groups did not differ with respect to the ability to mount proliferative responses to Fel d 1 peptides. In all groups, the IFN-gamma responses were predominantly to the amino terminus peptides. Cat-allergic and non-cat-allergic asthmatic subjects (and not cat-allergic rhinitic subjects and normal controls) made IL-5 responses to most of the Fel d 1 peptides, the result being a mixed (T(H)0) cytokine response at the N-terminus and a restricted (T(H)2) response at the C-terminus.
Proliferative and IL-5/IFN-gamma responses of T cells from asthmatic and atopic rhinitic subjects and normal controls to allergen peptides can be dissociated. Furthermore, differing cytokine responses to peptides derived from a single antigen suggest that certain domains of the molecule might preferentially induce IL-5 rather than IFN-gamma and as a result could be more important in disease pathogenesis.
Journal of Allergy and Clinical Immunology 10/2001; 108(3):349-56. · 11.00 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Allergen-derived peptides can induce T cell tolerance in naive and Ag-primed mice. This is preceded by transient T cell activation. In humans, intradermal administration of short allergen-derived T cell peptide epitopes provokes IgE-independent isolated late asthmatic reactions (LARs) in sensitized subjects. In this study, we determine whether, as in mouse models, such peptides produce hyporesponsiveness to rechallenge with peptides, or whole allergen, either clinically or in terms of in vitro T cell responses. We found that a second injection of cat allergen (Fel d 1)-derived T cell peptides was associated with a marked reduction, or absence, of the LAR, and that up to 40 wk was required for return to baseline values. The cutaneous late-phase reaction to whole cat dander was also inhibited, even in subjects who did not experience an initial LAR. These observations were associated with a significant decrease in peptide- and whole allergen-induced proliferation of PBMCs and the production of IL-4, IL-13, and IFN-gamma in cultures. Thus, allergen-derived peptides induce tolerance to subsequent peptide injection in the target organ (the lung), reduce late-phase cutaneous responsiveness to whole allergen, and alter in vitro T cell reactivity.
The Journal of Immunology 09/2001; 167(3):1734-9. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Isolated late asthmatic reactions can be provoked by intradermal challenge of allergen-derived T-cell peptide epitopes.
The purpose of this study was to determine whether the isolated LAR is associated with the local accumulation of inflammatory cells, the expression of T(H)2 cytokines, and the production of pharmacologic mediators.
A randomized, placebo-controlled, crossover study design was used. The investigation involved bronchial and skin biopsies and bronchoalveolar lavage (BAL) fluids from 8 cat-allergic subjects who developed significant late asthmatic reactions 6 hours after intradermal injection of Fel d 1 chain 1-derived peptides (FC1Ps).
Immunostaining of bronchial biopsy specimens showed no changes in the numbers of eosinophils, neutrophils, basophils, mast cells, CD3(+), CD4(+) or CD8(+) T cells, CD25(+) cells or macrophages, or cells mRNA(+) for IL-4, IL-5, or IL-13 when the FC1P day was compared with the diluent control day. There were also no significant differences in eosinophil numbers, either in BAL fluids or in peripheral blood after FC1P challenge. Furthermore, there were no significant alterations in the concentrations of histamine, histamine-releasing factors, or eicosanoids (LTC(4)/D(4)/E(4), PGD(2), PGE(2), TXB(2), PGF(2alpha)) in BAL fluids. FC1Ps induced a significant (P <.05) elevation in CD8(+) cells in the skin and an unexpected decrease in IL-5 in BAL fluids (P =.043).
Part of the asthma process might involve T cell-dependent airway narrowing with no requirement for IgE, mast cells, or infiltrating inflammatory cells.
Journal of Allergy and Clinical Immunology 09/2001; 108(3):394-401. · 11.00 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: CD4+ T-cells are likely to be involved as a source of pro-inflammatory cytokines in asthma. This study assessed the effects of an infusion of keliximab (IDEC CE9.1), an anti-CD4+ monoclonal antibody, on peripheral blood CD4+ T-cells in corticosteroid-dependent asthmatics. Three cohorts of patients (termed C0.5: n=6, C1.5: n=5, and C3.0: n=5) received a single infusion of 0.5, 1.5 or 3.0 mg x kg(-1), respectively, with a fourth receiving placebo (Cpl: n=6), and were followed-up for 4 weeks. By flow cytometry in peripheral blood, pre- and postinfusion assessment was made of: a) CD4 and CD8 counts and mean fluorescence; b) CD25, human leukocyte antigen-DR (HLA-DR), CD45RO and CD45RA expression on CD4+ T-cells; and c) interferon (IFN)-gamma, interleukin (IL)-4 and IL-5 expression in CD4+ T-cells. Keliximab's in vitro effects on allergen-specific peripheral blood mononuclear cells (PBMC) proliferation in atopic asthmatics were also evaluated. There was a significant increase in lung function (peak expiratory flow rate) in the C3.0 group. Following infusion in C0.5, C1.5 and C3.0 but not Cpl: 1) the CD4, but not CD8 count was significantly decreased; 2) there was total loss of Leu3a staining; 3) there were significant reductions in the mean fluorescence of OKT4 binding; and 4) there were significant reductions in the numbers of CD25, HLA-DR, CD45RO and CD45RA/CD4+ cells. There were no changes in CD4+ cell expression of IFN-gamma, IL-4 or IL-5. Keliximab caused a significant reduction in T-cell proliferation as compared to a control monoclonal antibody. Keliximab, as an anti-CD4 monoclonal antibody, leads to a transient reduction in the number of CD4+ T-cells and modulation of CD4+ receptor expression in severe asthmatics. The effects of keliximab may be mediated through a decrease in CD4+ surface expression and T-lymphocyte numbers, in addition to a reduction in allergen-induced proliferation.
European Respiratory Journal 08/2001; 18(1):45-52. · 5.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Conventional immunotherapy using whole allergen extracts has been shown to be an effective, disease-modifying treatment in carefully selected patients with allergic conjunctivo-rhinitis, asthma and bee and wasp venom hypersensitivity. However, this form of therapy is associated with the risk of systemic anaphylaxis, which, when severe, can be life threatening. A potentially significant reduction in the incidence of IgE-mediated events during immunotherapy may be achieved by the use of short peptides corresponding to T cell epitopes which, by virtue of their size, are incapable of cross-linking allergen-specific IgE bound to the surface of mast cells and basophils. Initial clinical studies have demonstrated degrees of efficacy which have, in some cases, been associated with adverse events occurring immediately or several hours after peptide administration. Preliminary data from studies employing shorter peptides (20 amino acids or less) suggest that improved efficacy may be achieved by using peptides of defined major histocompatibility complex-binding specificity administered in an incremental dose fashion comparable to conventional immunotherapy. This review will discuss the concept of peptide immunotherapy and the implications of recent studies.
International Archives of Allergy and Immunology 09/2000; 122(4):229-37. · 2.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Background: Blood eosinophils from hypereosinophilic donors were previously reported to possess the functional high-affinity IgE receptor (Fc epsilon RI), so providing a potential mechanism to account for eosinophil degranulation in atopic allergic disease. Furthermore, tissue eosinophils from allergic tissue reactions were shown to be mRNA(+) for the alpha, beta, and gamma subunits of Fc epsilon RI and gave positive immunostaining with an anti-Fc epsilon RI-alpha antibody. Recent studies, however, revealed negative surface staining on peripheral blood eosinophils, but intracellular Fc epsilon RI-alpha protein was identified by Western blot analysis.
Our purpose was to examine on peripheral blood eosinophils from atopic subjects (1) surface expression and mRNA for Fc epsilon RI-alpha, (2) up-regulation of Fc epsilon RI-alpha by allergy-associated tissue factors, and (3) Fc epsilon RI-alpha-dependent release of eosinophil peroxidase (EPO).
We measured (1) Fc epsilon RI mRNA expression by in situ hybridization, (2) Fc epsilon RI-alpha by flow cytometry and immunocytochemistry (with use of nonpermeabilized and permeabilized cells), and (3) Fc epsilon RI-alpha-dependent release of EPO.
Eosinophils from atopic donors had negligible surface expression of Fc epsilon RI-alpha, which was not enhanced by culture with IgE, IL-3, IL-4, IL-5, GM-CSF, or fibronectin or coculture with fibroblasts. Permeabilization, however, revealed appreciable intracellular staining for Fc epsilon RI-alpha. The majority of eosinophils were mRNA(+) for the alpha, beta, and gamma subunits of Fc epsilon RI. Small but significant (P =.03) increases in alpha chain mRNA expression were observed after coculture of eosinophils with fibroblasts but not with IgE, IL-4, or fibronectin. Cross-linking of Fc epsilon RI on the surface of eosinophils from atopic donors did not lead to detectable EPO release.
Human blood eosinophils express negligible, nonfunctional membrane Fc epsilon RI-alpha but have intracellular Fc epsilon RI-alpha protein and mRNA expression for the alpha, beta, and gamma subunits.
Journal of Allergy and Clinical Immunology 03/2000; 105(2 Pt 1):309-17. · 11.00 Impact Factor
-
M Larché
Chemical immunology 02/2000; 78:30-8.
-
M Larché
[show abstract]
[hide abstract]
ABSTRACT: Together with B-lymphocytes, T-lymphocytes (or T-cells) comprise the antigen (Ag)-specific arm of the immune response. The Ag receptors of both cell types are generated by recombination of multiple gene segments (1), giving rise to a large repertoire of receptors of differing specificity. When a lymphocyte encounters Ag, cellular activation occurs via aggregation of cell surface Ag receptors (2). The consequences of activation are numerous, but, in the case of the T-cell, include clonal expansion, via proliferation, and also secretion of soluble mediators and growth factors, such as interleukin-2 (for a review of the role of the T-lymphocyte in allergic disease, see ref. 3).
Methods in molecular medicine 01/2000; 44:121-32.
-
[show abstract]
[hide abstract]
ABSTRACT: Intradermal administration of short overlapping peptides derived from chain 1 of the cat allergen Fel d 1 (FC1P) that did not cross-link IgE, elicited isolated late asthmatic reactions with no visible early or late cutaneous response in 9/40 cat-allergic asthmatics. Four of the nine were human histocompatibility leukocyte antigen DR13-positive, as compared with only 1/31 nonreactors. The other five reactors expressed either DR1 or DR4. To confirm major histocompatibility complex restriction, fibroblast cell lines transfected with HLA-DR molecules were used to present FC1Ps to cat allergen-specific T cell lines derived from subjects before peptide injection. FC1P3 (peptide 28-44 of Fel d 1 chain 1) was recognized in the context of DR13 alleles (DRB1*1301, 1302) and induced specific T cell proliferation and IL-5 production. T cells from a DR1(+) responder proliferated and produced IL-5 in the presence of FC1P3 and DR1 (DRB1*0101) fibroblast cell lines, whereas T cells from a DR4(+) subject recognized FC1P2 (peptide 22-37) when presented by DRB1*0405. We conclude that short, allergen-derived peptides can directly initiate a major histocompatibility complex-restricted, T cell-dependent late asthmatic reaction, without the requirement for an early IgE/mast cell-dependent response, in sensitized asthmatic subjects.
Journal of Experimental Medicine 07/1999; 189(12):1885-94. · 13.85 Impact Factor
