Cat-allergic Subjects Research Articles

Sensitization patterns to cat molecular allergens in subjects with allergic sensitization to cat dander.

The use of molecular allergology has increasingly become common in the diagnosis and management of allergic diseases. However, there is still a lack of data on cat molecular allergens in adults. Therefore, we aimed to uncover the sensitization patterns to cat molecular allergens. Participants were recruited from the West Asthma Sweden Study, a population-based study enriched with asthma subjects aged 16-75years. Of 1872, 361 individuals were positive for cat dander immunoglobulin E and were further analysed for cat molecular allergens (Fel d 1/2/4/7). Sensitization patterns were classified as monosensitization, polysensitization, and concomitant sensitization, and were related to demographic and clinical measurements. Among cat-sensitized subjects, 84.2% were sensitized to secretoglobin, while 42.4% were sensitized to lipocalins. Nearly half of the subjects were monosensitized to Fel d 1. Polysensitization was observed in 20.2%, and concomitant sensitization to protein families was seen in 7.2%. Asthma prevalence, cat exposure, and rural living were associated with poly- and concomitant sensitization to protein families. Concomitant sensitization to single allergens was more common in those with asthma than in those without, while concomitant sensitization to both Fel d 1 and Fel d 4 was the most common pattern in individuals with asthma. Sensitization patterns also differed according to cat ownership and the degree of urbanization. Sensitization to molecular allergens was observed in 90.9% of cat-sensitized subjects and showed variations across participants' background characteristics and the presence of asthma. Identification of sensitization patterns to cat allergens might provide better characterization of cat-allergic subjects.

Molecular Allergen-Specific IgE Recognition Profiles and Cumulative Specific IgE Levels Associated with Phenotypes of Cat Allergy.

Cat allergy is a major trigger factor for respiratory reactions (asthma and rhinitis) in patients with immunoglobulin E (IgE) sensitization. In this study, we used a comprehensive panel of purified cat allergen molecules (rFel d 1, nFel d 2, rFel d 3, rFel d 4, rFel d 7, and rFel d 8) that were obtained by recombinant expression in Escherichia coli or by purification as natural proteins to study possible associations with different phenotypes of cat allergy (i.e., rhinitis, conjunctivitis, asthma, and dermatitis) by analyzing molecular IgE recognition profiles in a representative cohort of clinically well-characterized adult cat allergic subjects (n = 84). IgE levels specific to each of the allergen molecules and to natural cat allergen extract were quantified by ImmunoCAP measurements. Cumulative IgE levels specific to the cat allergen molecules correlated significantly with IgE levels specific to the cat allergen extract, indicating that the panel of allergen molecules resembled IgE epitopes of the natural allergen source. rFel d 1 represented the major cat allergen, which was recognized by 97.2% of cat allergic patients; however, rFel d 3, rFel d 4, and rFel d 7 each showed IgE reactivity in more than 50% of cat allergic patients, indicating the importance of additional allergens in cat allergy. Patients with cat-related skin symptoms showed a trend toward higher IgE levels and/or frequencies of sensitization to each of the tested allergen molecules compared with patients suffering only from rhinitis or asthma, while there were no such differences between patients with rhinitis and asthma. The IgE levels specific to allergen molecules, the IgE levels specific to cat allergen extract, and the IgE levels specific to rFel d 1 were significantly higher in patients with four different symptoms compared with patients with 1–2 symptoms. This difference was more pronounced for the sum of IgE levels specific to the allergen molecules and to cat extract than for IgE levels specific for rFel d 1 alone. Our study indicates that, in addition to rFel d 1, rFel d 3, rFel d 4, and rFel d 7 must be considered as important cat allergens. Furthermore, the cumulative sum of IgE levels specific to cat allergen molecules seems to be a biomarker for identifying patients with complex phenotypes of cat allergy. These findings are important for the diagnosis of IgE sensitization to cats and for the design of allergen-specific immunotherapies for the treatment and prevention of cat allergy.

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Clinical & Experimental AllergyVolume 52, Issue 2 p. i-i FEATURED COVERFree Access Featured Cover First published: 28 January 2022 https://doi.org/10.1111/cea.14097AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract The cover image is based on the Research Article Cat allergen exposure in a naturalistic exposure chamber: A prospective observational study in cat-allergic subjects by Meagan O’Brien et al., https://doi.org/10.1111/cea.14087. Volume52, Issue2February 2022Pages i-i RelatedInformation

Clinical and immunological evaluation of cat-allergic asthmatics living with or without a cat.

BackgroundCharacterising the clinical and immunological impact of daily cat exposure in cat‐allergic subjects with asthma who live with cats (WC) and those who do not (WoC) may provide understanding of the drivers of the allergic response.MethodsClinical and immunological characteristics (skin prick test, spirometry, symptom assessments, immunological markers) were compared between asthmatic subjects WC (n = 10) and WoC (n = 9).ResultsWC subjects had greater use of long‐acting beta agonists (p < .05) and high‐potency corticosteroids. No differences were observed in lung function, nasal and ocular symptoms, or asthma control between the groups. Cat dander‐ and Fel d 1‐specific IgG4 concentrations were higher in WC than WoC subjects (both p < .05). Total IgE and cat dander‐, Fel d 1‐ and Fel d 7‐specific IgE concentrations were similar, but Fel d 4‐sIgE was higher in WC subjects (p < .05) versus WoC. Basophil sensitivity to cat dander extract and Fel d 1 was lower in WC versus WoC subjects (p < .05) and correlated with higher IgG4 concentrations (r = 0.63; p = .009). Fel d 1‐specific CD4+ T‐cell responses polarised toward Th2A responses in WC versus WoC subjects; Fel d 1‐specific IgE correlated with surface expression of CRTH2 and CD200R (both p ≤ .05).ConclusionImmunological differences observed in WC versus WoC did not reflect clinical tolerance with natural cat exposure. The ability to live with a cat despite allergy could be driven by higher preventative medication use. This study may support design of novel therapeutics for allergy management.

A Single-Dose of REGN1908-1909 Reduced Bronchoconstriction in Cat-Allergic Subjects with Mild Asthma for up to 3 months following a controlled cat allergen challenge: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study

To evaluate the efficacy of a novel anti-Fel d 1 monoclonal antibody cocktail (REGN1908-1909) in reducing acute bronchoconstriction, defined as early asthmatic response (EAR), in cat-allergic subjects with mild asthma (NCT03838731).

The Major Cat Allergen, Fel d 1, Is a Viable Target for CRISPR Gene Editing.

Allergy to domestic cat (Felis domesticus) affects >10% of the population. Fel d 1, the major cat allergen, causes IgE sensitization in >90% of cat allergic subjects and accounts for 60-90% of anti-cat IgE. Our goal was to identify and target conserved regions of Fel d 1 using CRISPR gene editing, as an approach for ultimately generating allergen-free cats.

Immunization of Cats to Induce Neutralizing Antibodies Against Fel D 1, the Major Feline Allergen in Human Subjects

F Thoms, GT Jennings, M Maudrich. J Allergy Clin Immunol . 2019;144(1):193–203 Cats are found in 25% of US households, and 10% of humans are allergic to them. Most cat-allergic subjects make IgE antibody to the major cat allergen Fel d 1. If environmental control measures and medication fail to provide sufficient control of allergic symptoms, allergen immunotherapy can be beneficial. What about immunizing the cat instead? Domestic cats. The cats received a series of 3 intramuscular injections at 3-week intervals of a conjugate vaccine consisting …

Sensitization to minor cat allergen components is associated with type‐2 biomarkers in young asthmatics

Cat allergy is a major trigger of asthma world-wide. Molecular patterns of cat sensitization vary between individuals, but their relationship to inflammation in asthmatics has not been extensively studied. To investigate the prevalence and levels of IgE antibodies against different cat allergen components and their relationship to type-2 inflammation and total IgE among young asthmatic subjects sensitized to furry animals. Patients with asthma (age 10-35 years; n = 266) and IgE sensitization to cat, dog or horse extract (ImmunoCAP), were analysed for IgE to the cat allergen components Fel d 1 (secretoglobin), Fel d 2 (serum albumin), Fel d 4 and Fel d 7 (lipocalins). Independent associations between IgE-antibody concentrations, and fraction of exhaled nitric oxide (FeNO), blood eosinophil (B-Eos) count, and total IgE were analysed by multiple linear regression after adjustment for possible confounders. The level of IgE against Fel d 2 was independently related to FeNO (P = .012) and total IgE (P < .001), and IgE against Fel d 4 associated with Β-Eos count (P = .009) and total IgE (P < .001). IgE antibodies against Fel d 1 or cat extract did not independently relate to these inflammatory markers (P = .23-.51). Levels of IgE to lipocalin (Fel d 4) and serum albumin (Fel d 2), but not to secretoglobin (Fel d 1) or cat extract, were independently associated with type-2 biomarkers and total IgE in young asthmatics. We suggest that measurement of IgE to minor cat allergen components may be useful when investigating asthma morbidity in cat allergic subjects.

Quantification of Fel d 1 in house dust samples of cat allergic patients by using monoclonal antibody specific to a novel IgE-binding epitope.

Avoidance of allergen exposure is an effective measure for preventing naÏve and allergic individuals from sensitization (primary intervention) and disease aggravation (secondary intervention), respectively. Regular monitoring of the allergens in the environment is required for the effective intervention. Thus, there is a need for cost-effective test kits for environmental allergen quantifications. To invent a test kit for quantification of cat major allergen, Fel d 1. A mouse monoclonal antibody (MAb) specific to the newly identified IgE-binding conformational epitope of the cat major allergen (Fel d 1) and rabbit polyclonal IgG to recombinant Fel d 1 were used as allergen capture and detection reagents, respectively. Native Fel d 1 was used in constructing a standard curve. Sixteen of 36 dust samples collected from houses of cat allergic subjects in Bangkok contained Fel d 1 above 0.29 μg/gram of dust which is considered as a novel threshold level for causing cat allergy sensitization or symptoms. Among them, 7 samples contained the allergen exceeding 2.35 μg/gram of dust which is the level that would aggravate asthma. Results of the allergen quantification using the locally made test kit showed strong correlation (r = 0.923) with the allergen quantification using commercialized reagents. The assay using MAb to Fel d 1 IgE-binding epitope of this study has potential application as an economic and practical tool for cat allergy intervention measure especially in localities where health resources are relatively limited.

Fel d 1-derived synthetic peptide immuno-regulatory epitopes show a long-term treatment effect in cat allergic subjects.

Cat-PAD, the first in a new class of synthetic peptide immuno-regulatory epitopes (SPIREs), was shown to significantly improve rhinoconjunctivitis symptoms in subjects with cat allergy up to 1 year after the start of a short course of treatment. To evaluate the long-term effects of Cat-PAD on rhinoconjunctivitis symptoms following standardized allergen challenge 2 years after treatment. In a randomized, double-blind, placebo-controlled, parallel group study, subjects were exposed to cat allergen in an environmental exposure chamber (EEC) before and after treatment with two regimens of Cat-PAD (either eight doses of 3 nmol or four doses of 6 nmol) given intradermally over a 3-month period. In this follow-up study, changes from baseline in rhinoconjunctivitis symptoms were reassessed 2 years after the start of treatment. The primary endpoint showed a mean reduction in total rhinoconjunctivitis symptom scores of 3.85 units in the 4 × 6 nmol Cat-PAD group compared to placebo 2 years after the start of treatment (P = 0.13), and this difference was statistically significant in the secondary endpoint at the end of day 4 when the cumulative allergen challenge was greatest (P = 0.02). Consistent reductions in nasal symptoms of between 2 and 3 units were observed for 4 × 6 nmol Cat-PAD compared to placebo between the 2 and 3 h time points on days 1-4 of EEC challenge at 2 years (P < 0.05). The 8 × 3 nmol dose did not show a meaningful effect in this study. A persistent, clinically meaningful reduction in rhinoconjunctivitis symptoms was observed on EEC challenge 2 years after the start of a short course of treatment with 4 × 6 nmol Cat-PAD. This study is the first to provide evidence of a long-term therapeutic effect with this new class of SPIREs.

Allergen challenge in allergic rhinitis rapidly induces increased peripheral blood type 2 innate lymphoid cells that express CD84

Type 2 innate lymphoid cells (ILC2) produce high levels of Th2 cytokines. Our study demonstrates that cat allergen challenge in allergic rhinitis subjects rapidly induces increased peripheral blood ILC2.

Immunotherapy – 2067. FEL d 1 peptide antigen desensitization safety and efficacy in a double-blind, placebo-controlled environmental exposure chamber study

Background Allergic rhinoconjunctivitis is an increasing problem worldwide with significant impact on quality of life and productivity. Sensitivity to cats accounts for 10-15% of the disease burden. Previous immunotherapy studies with two 27aa peptides were unsuccessful as a result of early and late phase responses. Cat Peptide Antigen Desensitisation (Cat-PAD) is a mixture of seven T-cell epitopes (13-17aa) derived from Fel d1. This study evaluated safety and relationship between dose, dosing regimen and symptom scores in cat allergic subjects with rhinoconjunctivitis 1721weeks(wk) after starting treatment using a standardized allergen challenge in an Environmental Exposure Chamber (EEC).

Immunotherapy – 2080. Fel d 1 derived peptide antigen desensitization results in a persistent treatment effect on symptoms of cat allergy 1 year after 4 doses

Background Previously, we identified a series of T-cell epitopes from the major cat allergen Fel d1 and showed these were safe and well-tolerated when administered to cat allergic subjects. In the current study, we evaluated persistence of the treatment effect (tolerance) one year after start of dosing for two treatment regimens with the same cumulative dose. Methods Subjects underwent Baseline Challenge in an Environmental Exposure Chamber (EEC) on 4 consecutive days, consisting of 3-hour allergen exposures (Fel d1 50.19±3.70 ng/m3). Subjects scored four nasal and four ocular symptoms every 30 minutes each on a scale of 0-3. 202 subjects were randomised to placebo, 8x3nmol Cat Peptide Antigen Desensitisation (Cat-PAD) 2weeks(wk) apart or 4x6nmol Cat-PAD 4wk apart. Subjects re-attended the EEC for 4 consecutive days, of 3-hours, 18-22wk after the start of treatment. 50-54wk after commencement of treatment subjects were invited to participate in a blinded follow-on study without further dosing. 89 subjects were enrolled and had a further 4 consecutive days, of 3-hours in the EEC.

IgE antibody-specific activity in human allergic disease

IgE antibody concentration, affinity, clonality and specific activity (also known as the allergen-specific IgE to total IgE ratio) influence the translation of IgE responses into clinically evident allergic symptoms following allergen exposure. Reported IgE-specific activity levels >3-4% place allergic individuals undergoing anti-IgE (Omalizumab((R))) therapy at a disadvantage for poor resolution of their allergy symptoms following manufacturer's recommended dosing schemes. We investigated the hypothesis that the specific activity of the IgE antibody response is highly variable with respect to age, allergen specificity and an individual's total serum IgE level. Second, we investigated whether the IgE-specific activity level influences the extent and rate of loss of effector cell mediator release. IgE-specific activity distributions were plotted against age, allergen specificity and total serum IgE using 18,950 paired total IgE and allergen-specific IgE antibody data obtained from the analysis of sera from 3,614 allergic subjects and covering 182 allergen specificities. The fraction of specific IgE antibody of the total serum IgE was dependent on age of the individual, epitope specificity (clonality) and total serum IgE. The youngest group of allergic individuals with the lowest total serum IgE levels tended to have the highest allergen-specific IgE to total IgE ratios. Hymenoptera venom (54%), peanut (33%) and milk (27%) were the three allergen specificities that elicited the highest frequency of IgE-specific activities >4% among sensitized individuals. A prospective double-blind, placebo-controlled clinical study involving anti-IgE treatment of cat-allergic subjects showed IgE-specific activity was remarkably constant over the 16-week course of treatment, despite the up to 8-fold rise in total serum IgE following repetitive Omalizumab administration. Changes in specific and total IgE levels paralleled each other in patients receiving anti-IgE therapy. The fastest rate of reduction in cat allergen-induced basophil histamine release following anti-IgE therapy was observed when the cat-specific IgE to total IgE ratio was <2.5%. This reflected the more rapid loss of surface cat-specific IgE antibody with anti-IgE therapy in allergic individuals who displayed a more diverse IgE antibody repertoire. We conclude that IgE-specific activity is an age-, IgE heterogeneity- and total serum IgE-dependent variable that influences the magnitude of effector cell mediator release, and by inference, ultimate allergic symptom induction.

IgG antibodies produced during subcutaneous allergen immunotherapy mediate inhibition of basophil activation via a mechanism involving both FcγRIIA and FcγRIIB

The majority of human subjects who receive subcutaneous allergen immunotherapy (IT) develop decreased sensitivity to their allergens. Multiple factors may explain the efficacy of IT, some evidence support a role for allergen specific IgG antibodies. There is controversy whether such antibodies act by blocking allergen binding to IgE or initiation of active inhibitory signaling through low affinity IgG receptors (FcγRIIB) on mast cells and basophils. In this study, we addressed this question using peripheral blood from cat non-allergic, cat allergic, and immunotherapy-treated cat allergic subjects. Blood from subjects who received IT contain IgG antibodies that mediate inhibition of basophil activation by a mechanism that is blocked by antibodies specific for the inhibitory IgG receptor FcγRIIB. Surprisingly, inhibition was also blocked by aglycosylated, putatively non-FcR binding, antibodies that are specific for the FcγRIIA, suggesting a contribution of this receptor to the observed effect. Consistent with a cooperative effect, ex vivo basophils were found to express both IgG receptors. In other studies we found that basophils from subjects who were both chronically exposed to allergen and were producing both cat allergen specific IgE and IgG, are hyporesponsive to allergen. These studies confirm that IgG antibodies produced during IT act primarily by stimulation of inhibitory signaling, and suggest that FcγRIIA and FcγRIIB function cooperatively in activation of inhibitory signaling circuit. We suggest that under normal physiologic conditions in which only a small proportion of FcɛRI are occupied by IgE of a single allergen specificity, FcγRIIA co-aggregation may, by providing activated Lyn, be required to fuel activation of inhibitory FcγRIIB function.

Comparison of In Vitro Basophil Response to Clinical Responses Among Cat Allergic Subjects

Comparison of In Vitro Basophil Response to Clinical Responses Among Cat Allergic Subjects

Thymic Stromal Lymphopoietin Potentiates the Immunomodulatory Effects of H22-Fel d 1 in Highly Atopic Subjects

RATIONALE: Targeting cat allergen to APCs via FcγRI using the variant H22-Fel d 1 selectively amplifies IL-4- and IL-10-expressing T cells in cultures from cat-allergic subjects. In order to further investigate its therapeutic potential, we examined whether protective T-cell elements induced by H22-Fel d 1 were maintained in a “pro-allergic” milieu using cells isolated from highly atopic subjects.

The Effect of Omalizumab on Basophil and Mast Cell Responses using an Intranasal Cat Allergen Challenge

RATIONALE: Omalizumab treatment suppresses basophil FcɛRI expression faster than skin mast cells. We utilized omalizumab to elucidate the relative contributions of basophil versus mast cell activation in a nasal allergen challenge (NAC) model. METHODS: Eleven cat-allergic subjects were enrolled in a 3.5-month, double-blinded, randomized (3.5:1), placebo-controlled trial of omalizumab using standard allergic asthma dosing. Cat allergen was used for all study procedures. At baseline, subjects underwent NAC-1 with lavage for PGD2 measurement, skin prick test titration (SPTT), and blood sampling for basophil histamine release (BHR) and basophil IgE/IgE-receptor measurements. Basophil studies were repeated at day 3 and then weekly until cat allergen-induced BHR was <20% of baseline or until day 45. Baseline visit procedures were repeated after the BHR reduction (NAC-2) and at the treatment period's completion (NAC-3). RESULTS: In subjects with a >80% reduction in their basophil IgE receptors by day 10 (n = 8), BHR to their optimal dose (0.1 or 1 BAU/mL) of cat allergen was significantly lower by NAC-2 compared to NAC-1 (71% decrease; p = 0.03). Compared to NAC-1, these subjects demonstrated significant decreases in total sneeze counts (59% decrease, p = 0.03) and combined nasal symptom scores (53% decrease, p = 0.02) by NAC-2. In contrast, no significant (p > 0.05) shifts in SPTT or nasal lavage PGD2 were seen until NAC-3. Subjects without a significant change in their basophil IgE receptors (n = 3) had no significant shifts in any outcome. CONCLUSIONS: Reduction in nasal symptom scores occurred when the basophil, but not mast cell, response was reduced. NAC responses appear partially basophil dependent.

Targeting Fel d 1 to FcγRI: Single Cell Analysis Reveals a Novel Variation of the Th2 Response in Cat-Allergic Subjects

Targeting Fel d 1 to FcγRI: Single Cell Analysis Reveals a Novel Variation of the Th2 Response in Cat-Allergic Subjects

Airway expression of calcitonin gene‐related peptide in T‐cell peptide‐induced late asthmatic reactions in atopics

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.