Late-phase Skin Reactions Research Articles

Coronavirus disease 2019 and allergen immunotherapy: Theoretical benefits invite to adjustments in practice recommendations

Coronavirus disease 2019 and allergen immunotherapy: Theoretical benefits invite to adjustments in practice recommendations

The anti-inflammatory effect of topical tofacitinib on immediate and late-phase cutaneous allergic reactions in dogs: a placebo-controlled pilot study.

Topical Janus kinase (JAK) inhibition is a promising therapeutic target for several inflammatory skin diseases of humans. To evaluate the anti-inflammatory effect of tofacitinib, a JAK 1/3 inhibitor, on immediate and late-phase skin reactions in dogs. Five healthy laboratory beagle dogs. Topical tofacitinib (total daily dosage: 0.5 mg/cm2 ) or its gel vehicle were applied on either the left or right lateral thorax of each dog for eight days. Three days before application and after eight days of topical treatment, intradermal injections of histamine and anticanine-IgE antibodies were performed on both sides; they were evaluated by an investigator blinded to the interventions. The tofacitinib gel was well-tolerated; one dog developed mild erythema at Day 5 that resolved by the next application. Treatment with tofacitinib reduced histamine and anticanine-IgE global wheal scores (one-way ANOVA, P ≤ 0.005 for both) compared to baseline; there was no significant difference for the vehicle placebo (histamine; P = 0.163; IgE, P = 0.223). Late-phase reactions (LPRs) were markedly, but not significantly reduced after tofacitinib treatment (P = 0.071). A blinded histological evaluation of 6 h-anti-IgE-associated LPRs revealed a significant reduction in the total leucocyte superficial dermal cellularity (P = 0.022), as well as eosinophil (P = 0.022) and mast cell (P = 0.022) counts at tofacitinib-treated sides compared with pretreatment values. Post-treatment complete blood counts and serum chemistry profiles did not show relevant tofacitinib-induced changes. Our observations suggest that topical tofacitinib exerts an inhibitory effect on activated canine skin-emigrating immune cells; this drug should be investigated further as a topical immunosuppressive drug in dogs.

Calcitonin gene‐related peptide and vascular endothelial growth factor are expressed in lesional but not uninvolved skin in chronic spontaneous urticaria

The mechanisms for producing weals in chronic spontaneous (idiopathic) urticaria (CSU) are incompletely understood. Leucocyte infiltration with vascular leakage and expression of the potent vasoactive agents' calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) are features of late-phase allergic skin reactions, previously proposed as a model of CSU. To measure CGRP and VEGF expression in lesional and non-lesional skin from CSU patients and to compare results with a control group. Eight paired biopsies (one from 4-8 h spontaneous weals and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects and studied by immunohistochemistry and confocal microscopy. Lesional skin in CSU contained significantly more CGRP+ and VEGF+ cells than non-lesional skin. No significant differences were observed in CGRP and VEGF expression between non-lesional skin and controls. In lesional skin, VEGF and CGRP co-localised to UEA-1+ blood vessels. CGRP was also expressed by neutrophils and eosinophils and to a lesser extent by CD90(+) fibroblasts, mast cells, CD3(+) and CD68(+) cells. CGRP and VEGF expression was not related to the duration of disease. Increased expression of CGRP and VEGF in lesional, but not uninvolved, skin indicates that these potent vasoactive agents may play a role in wealing and tissue oedema in CSU so representing novel targets in therapy.

Impact of Schizophyllum sensitization on decline of lung function in asthma

Objective: There is increasing interest in the association between the severity of asthma and fungal sensitization, and lung function decline in relation to mold and dampness in the home has recently been reported. This study was performed to determine the correlation between sensitization to Schizophyllum commune and decline of lung function, and to elucidate the outcomes and risk factors, especially from Schizophyllum allergy. Methods: The medical records of 50 patients with asthma who satisfied the following inclusion criteria were collected and reviewed retrospectively: (1) at least 5 years of follow-up with five evaluations; (2) intradermal skin tests including S. commune performed at the initial assessment; and (3) severity ranging from mild-to-moderate. Lung function decline (evaluated as adjusted delta FEV1/year) was compared in a cross-sectional manner with regard to gender, age, BMI, smoking habit, allergological characteristics and exacerbation frequency. Results and Conclusions: There were significant differences in lung function decline between females and males (p < 0.05), positive and negative results of late-phase skin reaction to S. commune (p < 0.001), and positive and negative late-phase skin reaction to Aspergillus (p < 0.05). Lung function decline was correlated with exacerbation frequency (r = 0.428, p = 0.002). On multiple regression analysis, the probability of lung function decline in asthma was found to be significantly associated with female gender and positive late-phase skin reaction against S. commune. Our results suggested that sensitization to S. commune may be one of the risk factors involved in lung function decline in asthmatic patients.

D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells

BackgroundDopamine transduces signals via five subtypes of G protein-coupled receptors. Among these subtypes, the D1 and D5 receptors belong to the D1-like group. Although dopamine is known to mediate immune responses, its involvement in cutaneous immunity remains unclear. ObjectiveThe aim of this study is to determine the role of dopamine and its D1-like receptors in cutaneous immune responses. MethodsBy using the D1-like receptor antagonist SCH 23390, we examined the role of D1-like receptors in murine models of Th1-type contact hypersensitivity and Th2-type atopic dermatitis in vivo, and in mast cells and Th2 cell differentiation in vitro. ResultsAdministration of SCH 23390 did not affect Th1-type contact hypersensitivity but suppressed the immediate-type reaction (ITR) and the late phase reaction (LPR) in the atopic dermatitis model. In addition, SCH 23390-treated mice showed higher IFN-γ and lower IL-4 mRNA levels in the ear skin of challenged mice than did non-treated mice as analyzed by real-time RT PCR. Consistently, the passive cutaneous anaphylaxis reaction was significantly reduced in SCH 23390-treated mice. Moreover, dopamine enhanced mast cell degranulation and Th2 cell differentiation, and both activities were abrogated by SCH 23390. ConclusionThese findings suggest that the D1-like receptors mediate immediate and late phase skin reactions by promoting Th2 induction and mast cell degranulation.

The Influence of Schizophyllum commune on Asthma Severity

The sensitization and exposure to fungal allergens have been reported to be associated with asthma. The aim of this study was to clarify the impact of sensitization to Schizophyllum commune (S. commune) on the severity and exacerbations of asthma. Ninety-two patients with asthma of various levels of severity [mild (n=18), moderate (28), and severe (46)] and exacerbation severity [moderate (n=43) and severe (6)] were retrospectively examined with regard to fungal sensitization such as specific IgE or intradermal skin reactions against S. commune and other common allergens. We also classified the patients into three groups: (1) three or more asthma attacks during the past year (F-BA) (n=29),(2) one or two asthma attacks (NF-BA) (n=20), and (3) no asthma attack (C-BA) (n=43). The positive rate of late cutaneous reactions to S. commune was higher in patients with severe asthma (41.2%) than with moderate (26.1%) or mild asthma (6.7%), and was significantly different among the three groups (P<0.05). Although the ratio did not show a significant difference between the patients with severe (83.3%) or moderate (36.1%) exacerbation, it was higher in F-BA (60.9%) than in NF-BA (21.1%) and C-BA patients (10.0%), and it was significantly different among the three groups (P=0.0002). Multivariate analysis identified positive results for late-phase skin reactions to S. commune and the age of the patients as an independent determinant of asthma severity, and the skin results and %FVC an independent determinant of exacerbation frequency. This study demonstrated that S. commune is an environmental fungus that appears to enhance both the severity of asthma and the exacerbation frequency.

Calcitonin gene-related peptide– and vascular endothelial growth factor–positive inflammatory cells in late-phase allergic skin reactions in atopic subjects

Allergen-induced late-phase skin reactions are characterized by erythema and edema, but the vasoactive mediators involved remain unclear. Limited evidence from human studies suggests that calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF), potent vasodilator and permeability factors, respectively, are expressed by infiltrating inflammatory cells in certain allergic tissue reactions. We sought to determine whether tissue swelling in allergen-challenged skin sites in atopic subjects is associated with the infiltration of CGRP(+) and VEGF(+) inflammatory cells. Skin biopsy specimens were obtained from atopic subjects at various times after cutaneous allergen challenge and studied by means of single and double immunohistochemistry and in situ hybridization. CGRP-immunoreactive and CGRP mRNA-positive cell numbers were increased in biopsy specimens from sites of late-phase skin reactions compared with those at the control site (P = .03 and P = .03, respectively). Their numbers paralleled the development and resolution of the edematous late-phase skin reaction, both peaking at 6 hours after allergen challenge. The majority of CGRP-immunoreactive cells were neutrophils and CD3(+) cells, whereas eosinophils were CGRP negative. VEGF-immunopositive cell numbers were also increased in 6-hour biopsy specimens from late-phase skin reactions compared with those seen at control sites (P = .001) with a lesser but significant response (P = .008) at 24 hours. VEGF(+) cells were largely eosinophils, neutrophils, and CD68(+) macrophages. Late-phase skin reactions in atopic subjects were associated with the infiltration of inflammatory cells expressing CGRP and VEGF, suggesting that these vasoactive factors might play a role in the erythema and edema characteristic of allergic inflammation. They could also be considered targets in attempts to control allergic inflammation.

FTY720 Regulates Bone Marrow Egress of Eosinophils and Modulates Late-Phase Skin Reaction in Mice

Eosinophilia in the blood and skin is frequently observed in patients with certain inflammatory skin diseases, such as atopic dermatitis. However, the mechanism underlying eosinophil circulation and the role of eosinophils in cutaneous immune responses remain unclear. In repeated hapten application-induced cutaneous responses in BALB/c mice, the administration of FTY720 before the last challenge decreased the number of skin-infiltrating eosinophils and reduced the late-phase reaction. A similar reduction of the late-phase reaction was observed by a sphingosine-1-phosphate G protein-coupled receptor (S1P1)-selective agonist, SEW2871. We monitored numerous alterations of eosinophils in the blood, spleen, bone marrow, and lymph nodes of interleukin-5 transgenic mice, used as an eosinophilia model, following FTY720 administration. The number of circulating eosinophils was significantly decreased after treatment with FTY720, and eosinophils accumulated in the bone marrow. In addition, eosinophils expressed S1P1, S1P3, and S1P4 mRNAs, and their chemotactic response to S1P was abolished by FTY720 as well as by SEW2871. These findings suggest that FTY720 affects the number of eosinophils in both the blood and skin by inhibiting the egress of eosinophils from the bone marrow and thus downmodulating the late-phase reaction.

SQ-standardized house dust mite immunotherapy as an immunomodulatory treatment in patients with asthma.

BackgroundSpecific immunotherapy is the only treatment with the potential to prevent progression of the allergic disease and the potential to cure patients. The immunomodulatory ability of SQ-standardized house dust mite (HDM) subcutaneous immunotherapy (SCIT) was investigated in patients with allergic asthma.MethodsFifty-four adults with HDM-allergic asthma were randomized 1 : 1 to receive SQ-standardized HDM SCIT (ALK) or placebo for 3 years. At baseline, and after 1, 2 and 3 years of treatment, the lowest possible inhaled corticosteroid dose required to maintain asthma control was determined, followed by determinations of nonspecific and HDM-allergen-specific bronchial hyperresponsiveness, late asthmatic reaction (LAR), immediate and late-phase skin reactions, and immunological response.ResultsSQ-standardized HDM SCIT provided a statistically significantly higher HDM-allergen tolerance (P < 0.05 vs placebo) in terms of a 1.6-fold increase in PD20 (HDM-allergen inhalation challenge), a 60-fold increase in skin test histamine equivalent HDM-allergen concentrations, reduced immediate- and reduced or abolished late-phase skin reactions, as well as fewer patients with LAR. PD20 (methacholine inhalation challenge) increased initially and was similar between groups. House dust mite SCIT induced an initial increase in serum HDM-allergen-specific IgE (P = 0.028 vs placebo), which then declined to baseline value. House dust mite SCIT induced an increase in components blocking IgE binding to allergen [ΔIgE-blocking factor: 0.31; 95% CI of (0.26; 0.37)] after 1 year that remained constant after 2 and 3 years (P < 0.0001 vs placebo).ConclusionSQ-standardized HDM SCIT induced a consistent immunomodulatory effect in adults with HDM-allergic asthma; the humoral immune response was changed and the HDM-allergen tolerance in lung and skin increased.

Effect of a novel topical diester glucocorticoid spray on immediate- and late-phase cutaneous allergic reactions in Maltese-beagle atopic dogs: a placebo-controlled study

The inhibitory effect of 0.0584% hydrocortisone aceponate spray on immediate- and late-phase skin reactions and the duration of inhibition after medication withdrawal were studied in 10 Maltese-beagle atopic dogs. All subjects were sprayed on axillary and inguinal regions and on one randomly chosen side of the thorax once daily for 14 (phase 1) or 7 days (phase 2). Intradermal injections (IDT) of histamine and anticanine IgE antiserum were performed bilaterally on the thorax before, 7 and 14 days after treatment. During phase 2, IDT was performed once weekly for 5 weeks. Each IDT was evaluated by an investigator blinded to the site of active treatment. Skin biopsies of 24-h anti-IgE-associated late-phase reactions were collected from both thoracic sides before and 14 days after treatment to determine the number of inflammatory cells and dermal thickness. Phase 1: Histamine and anti-IgE-induced global wheal scores at treated sites were significantly lower after 7 and 14 days with negative reactions present in >90% of dogs. Late-phase reactions at both sides were also significantly decreased compared with that at baseline, and this was associated with reduced inflammatory cell influx. Moreover, a significant decrease in dermal thickness was recorded at treated sides after 14 days. Phase 2: Histamine reactions became positive at untreated sides in all dogs 2 weeks after treatment. In conclusion, the 0.0584% hydrocortisone aceponate spray significantly decreased immediate- and late-phase IDT reactions, and prolonged application caused skin atrophy at treated sites. A 2-week withdrawal period prior to IDT is proposed.

T helper 2 biased de novo immune response to Keyhole Limpet Hemocyanin in humans

Allergen-specific T helper 2 (Th2) cells play an important role in the pathogenesis of atopic disorders. To date, no model system exists in humans that would allow the monitoring of a developing de novo Th2 immune response in vivo. The aim of the experiment was to establish an immunization protocol inducing a de novo Th2 response in humans using Keyhole Limpet Hemocyanin (KLH) as neo-antigen. The double-blind placebo-controlled, parallel-group study was conducted in two groups of subjects (16 healthy volunteers and 16 patients with allergic rhinitis). Subjects received three i.m. injections of 100 microg KLH adsorbed to aluminium hydroxide or matching placebo (alum alone) in intervals of 2 weeks. On day 43, KLH alone (10 microg) was given intra-dermally (i.d.) to all subjects to assess immediate and late-phase skin responses. The immunization protocol was well tolerated, highly specific and efficient. Antigen-specific production of Th2-cytokines (mainly IL-5 and IL-13) by PBMCs suggested a Th2 pattern, as did the presence of KLH-specific IgG4 in sera. Intra-dermal KLH challenge induced an immediate-type of response predominantly in atopic subjects followed by a late-phase skin reaction. The latter was accompanied by the presence of IgE(+) cells, eosinophils and a strong up-regulation of IL-4 and IL-13 along with the absence of Th1 transcripts in biopsies taken from the site of antigen challenge. IL-17 and IL-22 transcripts were detected only in healthy subjects skin following KLH challenge, while IL-1beta and IL-33 expression did not differ between the healthy and the atopics. The immunization protocol resulted in the elicitation of a local and peripheral Th2 immune response in both healthy and atopic individuals. This may permit the investigation and monitoring of novel immunomodulatory strategies aiming to interfere with Th2 responses in man. The relevance of lack of Th17 cells in atopic skin in this model remains to be determined.

Atopic dermatitis: Therapeutic concepts evolving from new pathophysiologic insights

Recent insights into the relevance of the epidermal barrier function and its interaction with components of the innate and adaptive immune responses in patients with atopic dermatitis (AD) give rise to a number of novel potential treatment options. In particular, the identification of loss-of-function mutations in the barrier protein filaggrin and of a diminished expression of certain antimicrobial peptides in AD skin stimulates new concepts to think beyond the T(H)1/T(H)2 paradigm. This review will focus on these most recent discoveries and will discuss new and corresponding proof-of-concept trials in patients with AD. It will further speculate on novel ways to restore the homeostasis among the 3 major components in AD skin suspected to be clinically relevant.

Imaging of Effector Memory T Cells during a Delayed-Type Hypersensitivity Reaction and Suppression by Kv1.3 Channel Block

Effector memory T (Tem) cells are essential mediators of autoimmune disease and delayed-type hypersensitivity (DTH), a convenient model for two-photon imaging of Tem cell participation in an inflammatory response. Shortly (3 hr) after entry into antigen-primed ear tissue, Tem cells stably attached to antigen-bearing antigen-presenting cells (APCs). After 24 hr, enlarged Tem cells were highly motile along collagen fibers and continued to migrate rapidly for 18 hr. Tem cells rely on voltage-gated Kv1.3 potassium channels to regulate calcium signaling. ShK-186, a specific Kv1.3 blocker, inhibited DTH and suppressed Tem cell enlargement and motility in inflamed tissue but had no effect on homing to or motility in lymph nodes of naive and central memory T (Tcm) cells. ShK-186 effectively treated disease in a rat model of multiple sclerosis. These results demonstrate a requirement for Kv1.3 channels in Tem cells during an inflammatory immune response in peripheral tissues. Targeting Kv1.3 allows for effector memory responses to be suppressed while central memory responses remain intact.

Failure Co detect deposition of complement and immunoglobulin in allergen-induced late-phase skin reaction in atopic subjects

There still remains some controversy regarding the possible role of immune complexes in the pathogenesis of the late-phase skin reaction (LPSR). To assess this, skin biopsies were obtained from LPSR induced in atopic human subjects 6, 24 and 48 h after allergen challenge. Cryostat sections were stained by direct immunofluorescence for the presence of fibrinogen, immunoglobulin classes IgM and IgG and for the complement components C1q and C3c. Complement components were observed in only two of the 29 biopsies studied. In both instances, only C3c was detected. One of these subjects also had unequivocal IgG staining at 6 h. IgM staining was detected in two out of 10 subjects at 6 h but no significant deposition of immunoglobulins could be found at 24 or 48 h. Fibrinogen deposition was observed in about half of the biopsies at each time-point. This study suggests that substantial complement and immunoglobulin deposition are not overt features of the allergen-induced LPSR, although the presence of small amounts of immune complexes, below the sensitivity of the method employed cannot be excluded. Fibrin deposition occurs in the LPSR but does not appear to be a prerequisite for LPSR development.

UCHL1+ (CD45RO+)‘memory’T cells predominate in the CD4+ cellular infiltrate associated with allergen-induced late-phase skin reactions in atopic subjects

We have previously shown that CD4+ T lymphocytes accumulated at the site of allergen induced late-phase reactions (LPR) in the skin of atopic subjects. In order to determine whether these were predominantly 'memory' or 'naive' cells, monoclonal antibodies recognizing isoforms of the CD45 common leucocyte antigen and immunocytochemical methods were used to study the composition of the T cell infiltrate. Allergen-induced late-phase skin reactions were biopsied 6, 24 or 48 h after allergen challenge. Memory (CD45RO+/UCHL1+) T cells predominated and few naive (CD45RA+/Leu18+) cells were identified. Double immunofluorescence was used to confirm that the UCHL1+ and Leu 18+ cells were CD4+ T lymphocytes. The selective recruitment of memory T cells to LPR sites is consistent with the active involvement of T lymphocytes in atopic allergic inflammation. A possible alternative explanation for apparently selective recruitment is the differential expression of endothelial adhesion molecules on memory and naive T lymphocytes.

Allergen‐induced in vitro expression of IL‐18, SLAM and GATA‐3 mRNA in PBMC during sublingual immunotherapy

Signalling lymphocytic activation molecule (SLAM) and interleukin (IL)-18 induce interferon (IFN)-gamma production from Th1 cells. The allergen-induced SLAM and IL-18 mRNA expressions are increased during subcutaneous immunotherapy (SCIT), but nothing is known about their role during sublingual immunotherapy (SLIT). Transcription factor GATA-3 is associated with Th2 cells but its role in SCIT and SLIT is yet unexplored. This study was undertaken to analyse the allergen induced in vitro mRNA expression of IL-18, SLAM and GATA-3 in peripheral blood mononuclear cells (PBMC) of children with allergic rhinitis (AR) during SLIT. Ten patients with AR undergoing pollen SLIT with a weekly dose of 200,000 SQ-U, 10 with 24,000 SQ-U of mixture of Betula verrucosa, Corylus avellana and Alnus glutinosa and 10 with placebo were included. Peripheral blood mononuclear cell were stimulated with birch extract prior to, after 1 and 2 years of the treatment. The mRNA expression was assessed using kinetic real-time RT-PCR (TaqMan); Applied Biosystems, Foster City, CA, USA). The expression of IL-18 mRNA was increased in the high-dose group in comparison to the placebo group after 1 year of therapy (P = 0.028) and had an inverse correlation with the late phase skin reaction after the second study year (r = -0.41, P = 0.041). SLAM mRNA expression increased in the high-dose group from baseline to 1 year (P = 0.028) and correlated with IL-10 (r = 0.96, P < 0.0001) and transforming growth factor-beta (r = 0.80, P = 0.0037) mRNA expression. No significant changes were seen in GATA-3 mRNA expression. During SLIT, IL-18 and SLAM are upregulated, suggesting that the Th2 type inflammatory response is downregulated during SLIT by increased Th1 type response.

Cooking birch pollen–related food: Divergent consequences for IgE- and T cell–mediated reactivity in vitro and in vivo

The major birch pollen allergen Bet v 1 cross-reacts with homologous food allergens, resulting in IgE-mediated oral allergy syndromes (OASs). To avoid this food, allergy allergologists and guidebooks advise patients to consume birch pollen-related foods after heating. We sought to evaluate whether cooked Bet v 1-related food allergens induce IgE- and T cell-mediated reactions in vitro and in vivo. Recombinant Bet v 1, Mal d 1 (apple), Api g 1 (celery), and Dau c 1 (carrot) were incubated at increasing temperatures. Protein structures were determined by means of circular dichroism. Mediator release was tested in basophil activation assays. PBMCs and Bet v 1-specific T-cell lines with known epitope specificity were stimulated with native and cooked food allergens. Patients with birch pollen allergy who experienced OAS and the exacerbation of atopic dermatitis (AD) on ingestion of fresh apple, celery, or carrot were retested in double-blind, placebo-controlled food challenges with the respective foods in cooked form. In vitro, cooked food allergens lost the capacity to bind IgE and to induce mediator release but had the same potency to activate Bet v 1-specific T cells as native proteins. In vivo, ingestion of cooked birch pollen-related foods did not induce OAS but caused atopic eczema to worsen. T-cell cross-reactivity between Bet v 1 and related food allergens occurs independently of IgE cross-reactivity in vitro and in vivo. In patients with AD, the resulting immune reaction can even manifest as late eczematous skin reactions. Therefore the view that cooked pollen-related foods can be consumed without allergologic consequences should be reconsidered. Symptom-free consumed pollen-related food allergens might cause T cell-mediated late-phase skin reactions in patients with pollen allergy and AD.

In vitro and in vivo characterization of a novel CCR3 antagonist, YM-344031

Eosinophils play a prominent proinflammatory role in a broad range of diseases, including atopic dermatitis and asthma. Eotaxin-1 and its receptor CCR3 are implicated in the recruitment of eosinophils from blood into inflammatory tissues, therefore inhibition of Eotaxin-1/CCR3 interaction may have therapeutic potential for allergic inflammation with eosinophil infiltration. YM-344031, a novel and selective small molecule CCR3 antagonist, potently inhibited ligand binding (IC 50 = 3.0 nM), ligand-induced Ca 2+ flux (IC 50 = 5.4 nM), and the chemotaxis of human CCR3-expressing cells (IC 50 = 19.9 nM). YM-344031 (1–10 mg/kg) orally administered to cynomolgus monkeys significantly inhibited Eotaxin-1-induced eosinophil shape change in whole blood. Additionally, orally administered YM-344031 (100 mg/kg) prevented both immediate- and late-phase allergic skin reactions in a mouse allergy model. YM-344031 therefore has potential as a novel and orally available compound for the treatment of allergic inflammation, such as atopic dermatitis and asthma.

The effect of Fel d 1‐derived T‐cell peptides on upper and lower airway outcome measurements in cat‐allergic subjects

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.

Anti-IgE (omalizumab) inhibits late-phase reactions and inflammatory cells after repeat skin allergen challenge

Anti-IgE (omalizumab) inhibited early and late asthmatic reactions and infiltration of inflammatory cells in asthmatic bronchial biopsies at baseline. The effect of chronic allergen exposure on these outcomes is unknown. Repeat allergen challenge in human skin represents a suitable model to address this question. To study the effect of anti-IgE (omalizumab) on early-phase (EPR) and late-phase (LPR) skin reactions and cellular infiltration by using a repeat skin allergen challenge designed to imitate chronic allergen exposure. Twenty-four atopic allergic volunteers received omalizumab or placebo for 12 weeks. Paired intradermal challenges of allergen (30 biological units) and diluent control were administered on 9 occasions at 2-week intervals. Early-phase and late-phase skin reactions and cellular infiltration in skin biopsies (using immunohistochemistry and in situ hybridization) were measured at intervals. Compared with placebo, omalizumab-treated patients had a progressive reduction in the LPR that was significantly greater than its effect on the EPR (median, --63% vs--24% respectively; P=.009). In addition, significant reduction of the LPR was reached within 2 weeks of commencing treatment, compared with 8 weeks for the EPR. There was a priming effect of repeated allergen challenge on infiltration of eosinophil, neutrophil, T(H)2 (CD3(+)/IL-4(+)), and total FcepsilonRI(+) cells in patients on placebo that was abrogated in those receiving omalizumab. The more marked effect of omalizumab on the LPR and prevention of the repeat-dose priming effect on several inflammatory cell types support a role for anti-IgE treatment in conditions associated with chronic allergic inflammation.