by B Bonnet · 2018 · Cited by 39 — Ten cat allergens have been identified. The major allergen responsible for symptoms is Fel d 1, a secretoglobin and not a lipocalin, making the cat a special case
9 pages

142 KB – 9 Pages

PAGE – 1 ============
Bonnet et al. Allergy Asthma Clin Immunol (2018) 14:14 https://doi.org/10.1186/s13223-018-0239-8 REVIEW An update on molecular cat allergens: Fel d 1 and what else? Chapter 1: Fel d 1, the major cat allergen B. Bonnet 1,2ƒ , K. Messaoudi 3ƒ , F. Jacomet 4 , E. Michaud 5 , J. L. Fauquert 5 , D. Caillaud 6 and B. Evrard 1,2* Abstract Background: Cats are the major source of indoor inhalant allergens after house dust mites. The global incidence of cat allergies is rising sharply, posing a major public health problem. Ten cat allergens have been identi˜ed. The major allergen responsible for symptoms is Fel d 1, a secretoglobin and not a lipocalin, making the cat a special case among mammals. Main body: Given its clinical predominance, it is essential to have a good knowledge of this allergenic fraction, including its basic structure, to understand the new exciting diagnostic and therapeutic applications currently in development. The recent arrival of the component-resolved diagnosis, which uses molecular allergens, represents a unique opportunity to improve our understanding of the disease. Recombinant Fel d 1 is now available for in vitro diagnosis by the anti-Fel d 1 speci˜c IgE assay. The ˜rst part of the review will seek to describe the recent advances related to Fel d 1 in terms of positive diagnosis and assessment of disease severity. In daily practice, anti-Fel d 1 IgE tend to replace those directed against the overall extract but is this attitude justi˜ed? We will look at the most recent arguments to try to answer this question. In parallel, a second revolution is taking place thanks to molecular engi- neering, which has allowed the development of various forms of recombinant Fel d 1 and which seeks to modify the immunomodulatory properties of the molecule and thus the clinical history of the disease via various modalities of anti-Fel d 1-speci˜c immunotherapy. We will endeavor to give a clear and practical overview of all these trends. Keywords: Cat allergy, Fel d 1, CRD, Immunotherapy © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/ publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated. Background Worldwide, the domestic cat, Felis domesticus , is one of the most frequently encountered pets. It is a major source of allergens in the indoor environment and is placed in second position after dust mites for its involvement in the incidence of allergic respiratory diseases. In Western countries, the prevalence of sensitization to allergens of cat has increased dramatically to 10Œ30% in the general population [ 1 ]. A signi˜cant proportion of atopic sub – jects (about 20Œ40%) are sensitized to cat allergens [ 2 , 3 ]. ˚e severity of induced symptoms varies widely and cat allergy is thus a main risk factor of both rhinitis and asthma, including severe asthma, which can develop into a life-threatening condition. Cat allergens have signi˜cant allergenicity. ˚ey are also numerous and cat allergen extracts are therefore a multi-allergenic source. Historically, 10 allergens recog – nized by speci˜c IgE have been identi˜ed in studies of extracts from fur, saliva, serum and urine [ 4 , 5 ]. Eight cat allergens have been registered to date in the WHO/IUIS allergen nomenclature (Fel d 1 to Feld d 8). ˚e develop – ment of the component-resolved diagnosis (CRD), which uses molecular allergens produced by genetic engineer – ing, o˛ers new possibilities to improve the diagnosis and understanding of cat allergies [ 6 ]. ˚e most important cat allergen in disease pathogenesis is, unlike in other mam – mals, a secretoglobin, called Fel d 1, and not a lipocalin Open Access Allergy, Asthma & Clinical Immunolog y *Correspondence: bevrard@chu – clermontferrand.fr ƒ B. Bonnet and K. Messaoudi contributed equally to this work 1 Laboratoire d™Immunologie, ECREIN, UMR1019 Unité de Nutrition Humaine, Université Clermont Auvergne, 63000 Clermont – Ferrand, France Full list of author information is available at the end of the article

PAGE – 2 ============
Page 2 of 9 Bonnet et al. Allergy Asthma Clin Immunol (2018) 14:14 [7]. Its predominance, shown by inhibition studies, is such that it is classically recognized as the major cat aller -gen, the only one whose clinical impact is essential [ 8].˚e aim of this ˜rst chapter is to review the basic knowledge of Fel d 1 and to give an update on new clini -cal data, particularly the most recent clinical studies on the Fel d 1-based CRD of cat allergy and the various modalities of Fel d 1-speci˜c immunotherapy. Main text Fel d 1, an uteroglobin-like protein Molecular characteristics Fel d 1 is a glycoprotein of about 35Œ38˝kDa [ 9, 10]. It consists of two identical heterodimers, each of 18Œ19˝kDa, linked noncovalently and eventually form -ing a tetramer [ 10]. Each dimer consists of two poly -peptide chains, chain 1 and chain 2, covalently linked by three disul˜de bridges and encoded by two di˛erent genes [ 11, 12]. Chain 1 (or ˙) consists of 70 amino acids and has a molecular weight of 8˝kDa. ˚is polypeptide has a marked structural identity with the rabbit lipophi -lin/secretoglobin (Ory c 3) and sequence homology with another member of the uteroglobin family, a protein of the human bronchial epithelial cells called Clara cell 10-kDa protein [ 11, 13]. Chain 2 (or ˆ) is a glycoprotein of 10˝kDa with N-oligosaccharides. It consists of 85, 90 or 92 amino acids [ 9]. Fel d 1 in its natural form is thought to be a mix of full and truncated forms of chain 2 [ 14]. ˚e three-dimensional structure of Fel d 1 was determined, it is more complex than that of other allergens, with an internal cavity which could accommodate an endogenous ligand and two calcium external binding sites [ 9, 15, 16] (Fig.˝ 1). Hence, the expression of recombinant Fel d 1 was more diˇcult to obtain than for other allergens. Each chain was ˜rst produced separately in simple systems using Escherichia coli (E. coli ). However, to produce the full molecule rFel d 1, it was necessary to use a Baculo -virus [ 14]. ˚e advantage is that rFel d 1 is glycosylated (unlike products obtained via recombinant E. coli ) and has a similar structure to that of the natural cat allergen nFel d 1 [ 14]. ˚e epitopes of Fel d 1 are partially confor -mational because the amount of IgE reactivity directed against each of the two chains of Fel d 1 separately is far less than that of total IgE reactivity against the natural heterodimer [ 17, 18].Biological function, family Fel d 1 belongs to the family of secretoglobins or secre -tory globins [ 15]. ˚e biological function of Fel d 1 is still unknown. It has been suggested that its role is to protect the skin, by homology with the uteroglobin whose func -tion is to protect mucosa [ 19]. Other authors believe that Fel d 1 would rather have a role in the transport of lipid molecules, especially steroids, hormones or pheromones [20].Epidemiology Fel d 1 is a thermostable protein found in the saliva, anal glands, sebaceous glands, skin and fur of cats [ 11, 21, 22]. It is now recognized that the sebaceous glands, and not saliva, are the main production site [ 21Œ23].All cats produce Fel d 1, but hormonal status modi˜es its production. For example, it has been shown that males produce more Fel d 1 than females [ 24]. In addition, cas -trated male cats produce less Fel d 1 than non-castrated males [ 25]. Not all cats shed Fel d 1 in the air at the same rate [ 26]. Production of Fel d 1 on the skin varies accord -ing to anatomical site and, for example, is much greater on the head than on the chest. ˚e same distribution of Fel d 1 is found in the fur. ˚e length of hair does not seem to a˛ect the production of Fel d 1. Washing cats reduces the amount of Fel d 1 on the skin and fur but the e˛ect does not last long as the amount of Fel d 1 returns to its original level in just 2˝days [ 27, 28]. Similarly, the amount of Fel d 1 in ambient air is restored within 24˝h [29]. Washing the cat is thus of little bene˜t. In two large national surveys in the United States, Fel d 1 was detected, respectively, in 99.9 and 99.7% of Ameri -can homes [ 30, 31]. Fel d 1 was found in the dust of sofas, carpets and beds in homes with cats, but also in homes without a cat [ 30]. High levels of Fel d 1 were also found in the classroom, in cars, the oˇces of allergists, and shopping centers [ 32Œ34]. Fel d 1 allergen is ubiquitous. It is likely that it spreads from the clothes of cat owners and may also spread from their hair. 60% of airborne Fel d 1 is carried by small particles, of which 75% are more than 5 microns in diameter and 25% less than 2.5 microns [ 35]. ˚e immediate bronchial Fig. 1 Fel d 1 crystallographic structure highlighting the location of the calcium ions. From Ligabue-Braun et al. [ 16] reprints in open access

PAGE – 3 ============
Page 3 of 9 Bonnet et al. Allergy Asthma Clin Immunol (2018) 14:14 response to Fel d 1 appears to be located in the proximal airways. ˚e concentration of Fel d 1 required to induce a positive bronchial response in subjects with intermittent asthma was 20 times less when the allergen was carried by large particles (10.3˝˘m) than when Fel d 1 was carried by small particles (1.4˝˘m) [ 36]. However, a more recent article suggests that exposure under natural conditions to cat allergens (and not just to Fel d 1) induces a more peripheral airway obstruction [ 37].Fel d 1 is easily airborne and remains in the indoor environment but the relationship between antigenic load and onset of symptoms is not as clear as with mite- borne antigens [ 38]. ˚ere is still considerable di˛erence of opinion on this subject. Several studies have reported a paradoxical e˛ect of the presence of animals at home. While the presence of a cat in childhood seems to be a risk factor for sensitization and for developing asthma, children heavily exposed to a cat probably have a lower risk of developing a cat allergy [ 39Œ41]. Another large prospective study showed that living with a cat during childhood, especially during the ˜rst year of a child™s life, could be protective against allergic diseases [ 42]. Recent studies con˜rm these data, reporting that cat ownership during pregnancy and childhood in a large birth cohort (Avon Longitudinal Study of Parents and Children or ALSPAC) was consistently associated with a reduced risk of aeroallergen sensitization, wheezing and atopic asthma at the age of 7, but tended to be associated with an increased risk of non-atopic asthma [ 43, 44]. In another study, Carlsen™s team showed that the acquisition of a pet in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6Œ10˝years [ 45]. Conversely, a recent French study (named PARIS) of 1860 infants reported that a cat enter -ing the baby™s room in early life was strongly associated with aeroallergen sensitization (ORa 3.21, 95% CI 1.29Œ 8.01), particularly against Fe l d 1 [ 46]. An interesting explanation of these contradictory results could be found in the impact of pet allergen exposure during the neona -tal period or early childhood on IgE trajectory develop -ment, which can be modi˜ed by concomitant changes in microbial exposure (because of cesarean birth, for exam -ple) [ 47]. ˚us, changes in the environment, via modi˜ca -tions induced in the gut microbiota (because of di˛erent diets, for example), could have a signi˜cant impact on the protective e˛ect or not of early exposure to pets and thus explain the disparities found in the di˛erent studies. It is interesting to note that these studies were not carried out in the same countries: for example, the studies of Collin et˝al. [ 43, 44] and Gabet et˝al. [ 46], which yielded contra -dictory results, were respectively performed on children in the UK and in France, two countries with di˛erent eat -ing habits. ˚e role of these multiple interactions, such as exposure to allergens, intestinal microbiota and diet, need to be better understood and characterized. CRD-based clinical aspects Allergenicity Fel d 1 is the major allergen of domestic cats [ 7, 48, 49]. Anti-Fel d 1 speci˜c IgE is found in the serum of more than 80Œ95% of patients allergic to cats [ 4, 5, 50, 51]. Crossed immunoelectrophoresis tests showed that most IgE antibodies to cat allergens in the serum of aller -gic patients are directed against Fel d 1, and account for 60Œ90% of overall allergenic activity [ 4, 5, 11, 50, 52]. In˝vivo, the allergenicity of Fel d 1 is determined by its recognition by the mannose receptor on mucosal antigen-presenting cells, such as dendritic cells or mac -rophages [ 53]. Several studies have shown that T cell response against Fel d 1 is polarized toward the ˚2 path -way [ 54Œ56].Positive diagnostic value ˚e ˜rst clinical question regarding Fel d 1 is its place in the diagnostic strategy of cat allergy. Speci˜cally, some authors question its ability to replace the overall extract in daily diagnostic practice, because theoretically, using anti-Fel d 1 speci˜c IgE alone can lead to potential false negative results owing to the atypical pro˜les of sensitiza -tion with IgE directed only against other cat allergens. A very recent study tried to provide an answer to this key point. Smoldovskaya et˝al. [ 57] compared in 139 patient serum samples the results of sensitization of the whole allergen extracts in relation to the recombinant pro -tein in biochip-based immunoassay (EIMB RAS). ˚ey reported that values for diagnostic accuracy for the cat dander extract and its major recombinant component Fel d 1 were comparable, with similar ROC curves [ 57]. ˚is suggests that the global extract could be replaced by the major allergen component Fel d 1 for diagnostic pur -poses. Moreover, Asarnoj et˝al. [ 58], in the large BAMSE/ MeDALL study, showed that testing Fel d 1 sensitiza -tion (analyzed with a chip based on ISAC ˚ermo Fis -cher technology˝ ˜˝Mechanisms for the Development of Allergy chip) was as good as testing for IgE to cat allergen extract (ImmunoCAP) and was more predictive of cat allergy at 16˝years of age (Fig.˝ 2).Conversely, two new studies analyzing the usefulness of CRD analysis of cat allergy in routine clinical practice drew the exactly opposite conclusion [ 59, 60]. In the ˜rst, native cat extract serology testing was 100% successful in detecting patients who were allergic to cats but rFel d 1 testing only 91% [ 59]. ˚us, 9% of cat allergic patients would have not been detected with CRD testing alone. In the second, a substantial proportion (56/117; 48%) of subjects tested IgE positive for cat extracts (ImmunoCAP

PAGE – 4 ============
Page 4 of 9 Bonnet et al. Allergy Asthma Clin Immunol (2018) 14:14 IgE) were negative for all the corresponding cat compo -nents (ImmunoCAP ISAC) including Fel d 1. However, as cat allergen components were not measured by unitary ImmunoCAP IgE, these results rct probably more the lack of sensitivity of ISAC technology than of cat allergen components [ 60].In another very recent study, of 70 pet allergic patients 69 had positive cat skin prick tests and 65 were sensi -tized to at least one feline component (Fel d 1, Fel d 2 and Fel d 4). However, the IgE against cat global extract was not tested. Of the latter 65 patients, 61 were sensi -tized against Fel d 1 (87.1% of the overall study group or 93.8% of patients having positive component-speci˜c IgE), of whom 30 (46.2%) were monosensitized. Of the 65 patients, 4 were sensitized only against Fel d 2 and/or Fel d 4 (6.1%) [61].Finally, a synthesis of the recent literature on the bio -logical diagnosis of cat allergy shows that the data from the studies are not always consistent. ˚e analytical per -formances of the anti-Fel d 1 speci˜c IgE assay are close to those of the speci˜c IgE assay directed against the overall extract. However, for a small number of cases with non-typical sensitization pro˜les (about 5Œ10%), the latter could have higher sensitivity. In our center, there -fore, we consider that in the current state of knowledge an anti-overall extract speci˜c IgE assay still has its place in daily practice in the positive diagnosis of cat allergy. Assessment of the disease severity ˚e correlation between the level of Fel d 1-speci˜c IgE and the severity of symptoms was assessed in a caseŒcon -trol study by ImmunoCap in 140 cat-allergic children and adults from Sweden and Austria su˛ering from asthma and/or rhinoconjunctivitis [ 48]. Positive IgE response to rFel d 1 was observed in 95.6% of cat-allergic children and in 94.4% of cat-allergic adults. ˚e IgE levels in rFel d 1 among children with asthma were signi˜cantly higher than in children with rhinoconjunctivitis and adults with asthma. Increased Fel d 1-speci˜c IgE levels could thus be a potential risk factor for allergic asthma in chil -dren. In another recent study, IgE antibodies to Fel d 1 were also associated with current asthma and showed a strong degree of correlation (r˝ ˜˝0.94) with cat dander titers, which were strongly associated with the preva -lence, severity, and persistence of asthma in a 19-year-old population (ImmunoCAP 250) [ 62]. In the study of Pat -elis, subjects sensitized to both cat extract and compo -nents had higher FeNO (P˝ ˜˝0.008) and more bronchial responsiveness (P˝ ˜˝0.002) than subjects sensitized only to the extract [ 60]. Subjects sensitized to cat compo -nents were more likely to develop asthma (P˝ ˜˝0.005) and rhinitis (P˝ ˜˝0.007) than subjects sensitized only to cat extract, which indicates the interest of CRD in cat allergy analysis, and in particular its value in testing the severity of the disease. An interesting study, comparing children with severe asthma (n˝ ˜˝37, age 13˝years) and controlled asthmatics (n˝ ˜˝28, age 14˝years) demonstrated that chil -dren with severe asthma had higher levels of IgE antibod -ies towards cat or Fel d 1 [ 63] (Fig.˝ 3).In addition, it has been shown that multi-sensitization towards more than three components including animal- derived lipocalin, kallikrein and Fel d 1 was associated with cases of severe asthma and among which occurred increased bronchiammation and a trend towards more courses of oral corticosteroid treatment [ 64]. Another study involving 696 Swedish children reported that current asthma and asthma symptoms following contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4 (tested with ImmunoCAP ISAC). Asthma was associated with higher levels of component sensitization (Fel d 1˝ ˚˝15 ISU), and sensitization to more than one component from the same animal conferred the greatest risk [ 65].˚us, when all these data are compiled, it is clear that measuring anti-Fel d 1 speci˜c IgE levels makes it pos -sible to better evaluate the prognosis of cat allergy. ˚e quantitative aspect of the assay is important since the highest levels will be correlated with the most severe forms of the disease. In daily practice in our hospital, we therefore perform anti-Feld 1 speci˜c IgE assay as soon as it is necessary to evaluate the severity of cat allergy. Use in speci˜c immunotherapy Allergen speci˜c immunotherapy (AIT), consisting in progressive administration of increasing doses of Fig. 2 Speci˜c IgE levels ( ˚ 0.3 ISU-E) to cat allergens in children with (white box plots) or without (gray box plots) symptoms to cat at 4, 8, and 16 years of age. From Asarnoj et al. [ 58] reprinted with permission from the publisher

PAGE – 5 ============
Page 5 of 9 Bonnet et al. Allergy Asthma Clin Immunol (2018) 14:14 allergens by di˛erent delivery routes (mainly subcutane -ous, sublingual or oral), results in long-term allergenic desensitization [ 66, 67]. Designed to modify the nature of the immune response against allergens and thus the history of the disease, it is currently the only treatment whose aim is not only symptomatic but also etiological [50].In cat allergy, AIT was initially tested with cat dander extract, which was e˛ective in the treatment of cat allergy symptoms, particularly respiratory symptoms. For exam -ple, Alvarez-Cuesta et˝al. [ 68], tested sublingual immu -notherapy with an aqueous standardized semi-puri˜ed cat dander extract in a double blind placebo-controlled study. ˚e results obtained showed that in the active group there was a signi˜cant reduction in symptoms dur -ing the natural exposure challenge test. In addition, skin test reactivity to a standardized cat extract was better than in the placebo group [ 68]. However, the use of cat dander extract is constrained by di˛erent problems such as standardization, compliance and severe side e˛ects [69].For these reasons, and owing to its clinical predomi -nance mentioned above, most studies now favor the use of Fel d 1 rather than global extract for cat allergy speci˜c immunotherapy. Several molecular approaches using standardized preparations of Fel d 1 have been developed since the recombinant forms of this allergen have become available. Hypoallergenic Fel d 1 To reduce the allergenicity of Fel d 1, and thus increase the security of AIT, various structural changes were made to Fel d 1. First, in order to modify the B cell epitopes, the disul˜de bonds linking the Fel d 1 chains together were disrupted [ 70]. ˚is leads to a decreased aˇnity of speci˜c Fel d 1 IgE bound to the surface of mast cells and basophils on the Fc RI receptor for Fel d 1. Seven candidates were thus generated and so designated hypoallergenic Fel d 1, owing to their ability to dimin -ish IgE-binding and basophil activation [ 70]. In parallel, duplication of T-cell epitopes were added. Activation of T cells by these hypoallergenic Fel d 1 were thus not a˛ected, or even increased, by this change in the struc -ture [ 70]. More recently, seven recombinant mosaic pro -teins were generated by reassembly of non-IgE-reactive peptides of Fel d 1 which contained the sequence ele -ments for induction of allergen-speci˜c blocking IgG antibodies and T cell epitopes [ 71]. Immunization of rab -bits has showed that three constructs may be useful for vaccination and induction of blocking IgG antibodies and for tolerance induction. T cell epitope-containing peptides In another approach based on the pivotal role of T cells in polarizing immune responsiveness to allergen, a team selected two peptides containing multiple T-cell epitopes from the sequence of Fel d 1. Unlike Fel d 1, these two peptides caused histamine release from basophils in˝<˝1% of cat allergic patients and are unable to crosslink aller -gen-speci˜c IgE molecules on basophils in˝vitro [ 72]. ˚ese peptides were then produced to obtain a peptide vaccine named Allervax CAT ®, which has been tested in clinical trials. Norman et˝al. [ 72] conducted a study comparing a placebo group with three groups receiv -ing Allervax CAT ® (7.5, 75 and 750˝µg per dose) admin -istered as a subcutaneous injection for 4˝weeks. A high dose of Allervax CAT ® improved allergy symptoms after 6˝weeks of treatment [ 72]. However, the treatment was accompanied by side e˛ects within minutes or hours after administration [ 73]. ˚ereafter, new Fel d 1 vaccines Fig. 3 Di˚erence in bronchial responsiveness (lower values show more responsiveness, a) and % di˚erence of fraction of exhaled nitric oxide (FeNO) ( b) between subjects sensitized to cat extract or both extract and components vs. subjects not sensitized to cat. Results are from a multiple linear regression model and adjusted for age, BMI, sex, smoking at baseline. Reference group are the subjects negative to both extract and any cat component. From Patelis et al. [ 60] reprinted with permission from the publisher PAGE - 6 ============ Page 6 of 9 Bonnet et al. Allergy Asthma Clin Immunol (2018) 14:14 were generated, in particular one using 12 shorter syn -thetic peptides, which reduced late-phase cutane -ous reaction in a randomized double-blind controlled trial and late asthmatic reaction in another trial after 3Œ4˝months of treatment [ 55, 74]. From a mechanistic point of view, evidence has been provided that treatment with selected epitopes from Fel d 1 resulted in suppres -sion of both human and murine responses unrestricted to these epitopes (namely associated with suppression of responses to other epitopes within the same molecule, called linked epitope suppression), together with sub -stantial induction of IL-10 in murine T cells that was not limited to cells speci˜c for the treatment peptide [ 75].Another product for cat peptide immunotherapy was then developed and tested in allergic rhinoconjunctivi -tis. ˚is product, called Cat-PAD (Cat-peptide antigen desensitization), was the ˜rst in a new class of synthetic peptide immuno-regulatory epitopes (SPIREs). It consists of a mixture of seven small peptides derived from Fel d 1 [76]. ˚ese peptides were selected to provide a similar T cell response to that generated by cat dander in ex˝vivo PBMC derived from cat-allergic patients [ 76]. Owing to their small size (13Œ17 amino acids), the peptides con -stituting CAT-PAD cannot achieve cross-linking of IgE present on the surface of mast cells and basophils [ 76]. Clinical data from a series of randomized double-blind placebo-controlled studies con˜rm that Cat-PAD sig -ni˜cantly reduced allergic rhinoconjunctivitis symptoms. ˚e e˛ects lasted for 2˝years after the initiation of treat -ment [ 77, 78].Recombinant fusion proteins A third interesting approach consists in linking to Fel d 1 another molecule that may have various immunological properties in order to target both e˛ectors of innate or adaptive immunity. For example, the fusion protein H22- Fel d 1, composed of rFel d 1 associated with a fragment of a humanized anti-CD64 antibody, has a high aˇnity for FI, the high aˇnity IgG receptor, which is present on the surface of dendritic cells. In a monocyte-derived dendritic cell model, this resulted in increased uptake of Fel d 1. H22-Fel d 1 induced a semi-maturation of den -dritic cells and led to a state of tolerance by promoting the secretion of cytokines such as IL-10 and IL-5 [ 79]. Another strategy was based on covalent linkage of Fel d 1 to carbohydrate-based particles (CBP), i.e. agarose par -ticles [ 80]. ˚e objective was to enhance the amount of Fel d 1 at the particle surface to improve phagocytosis by antigen presenting cells to subsequently induce an immu -nomodulatory e˛ect on allergen-speci˜c T cells. CBP-Fel d 1 was tested on a mouse model with cat allergy and the results obtained showed a reduction of airwaam -mation and decreased levels of Fel d 1-speci˜c IgE [ 81]. Zhu et˝al. [ 82] designed and tested a chimeric human-cat fusion protein composed of Funcated human IgG, and Fel d 1, in a new approach to allergy immunotherapy targeting FIIb, the inhibitory receptor present on the surface of mast cells and basophils. ˚is F-Fel d 1 pro -tein induced as expected an allergen-speci˜c inhibition of the degranulation of both types of cell [ 82]. Luzar et˝al. [83], developed a new hypoallergenic vaccine against cat Fig. 4 Possible mechanism of immune modulation in intralymphatic immunotherapy. From Kim et al. [ 87] reprints in open access PAGE - 8 ============ Page 8 of 9 Bonnet et al. Allergy Asthma Clin Immunol (2018) 14:14 8. Konradsen JR, Fujisawa T, van Hage M, Hedlin G, Hilger C, Kleine-Tebbe J, et al. Allergy to furry animals: new insights, diagnostic approaches, and challenges. J Allergy Clin Immunol. 2015;135:616Œ25. 9. Kaiser L, Velickovic TC, Badia-Martinez D, Adedoyin J, Thunberg S, Hallén D, et al. Structural characterization of the tetrameric form of the major cat allergen Fel d 1. J Mol Biol. 2007;370:714Œ27. 10. Du˚ort O, Carreira J, Lombardero M. Monoclonal antibodies against Fel d I and other clinically relevant cat allergens. Immunol Lett. 1988;17:71Œ7. 11. Morgenstern JP, Gri˛th IJ, Brauer AW, Rogers BL, Bond JF, Chapman MD, et al. Amino acid sequence of Fel dI, the major allergen of the domestic cat: protein sequence analysis and cDNA cloning. Proc Natl Acad Sci USA. 1991;88:9690Œ4. 12. Gri˛th IJ, Craig S, Pollock J, Yu XB, Morgenstern JP, Rogers BL. Expression and genomic structure of the genes encoding FdI, the major allergen from the domestic cat. Gene. 1992;113:263Œ8. 13. Hilger C, Kler S, Arumugam K, Revets D, Muller CP, Charpentier C, et al. Identi˜cation and isolation of a Fel d 1-like molecule as a major rabbit allergen. J Allergy Clin Immunol. 2014;133:759Œ66. 14. Seppälä U, Hägglund P, Wurtzen PA, Ipsen H, Thorsted P, Lenhard T, et al. Molecular characterization of major cat allergen Fel d 1: expression of heterodimer by use of a baculovirus expression system. J Biol Chem. 2005;280:3208Œ16. 15. Kaiser L, Grönlund H, Sandalova T, Ljunggren H-G, van Hage-Hamsten M, Achour A, et al. The crystal structure of the major cat allergen Fel d 1, a member of the secretoglobin family. J Biol Chem. 2003;278:37730Œ5. 16. Ligabue-Braun R, Sachett LG, Pol-Fachin L, Verli H. The calcium goes meow: e˚ects of ions and glycosylation on Fel d 1, the major cat allergen. PLoS ONE. 2015;10:e0132311. 17. Vailes LD, Li Y, Bao Y, DeGroot H, Aalberse RC, Chapman MD. Fine speci˜c - ity of B-cell epitopes on Felis domesticus allergen I (Fel d I): e˚ect of reduction and alkylation or deglycosylation on Fel d I structure and antibody binding. J Allergy Clin Immunol. 1994;93:22Œ33. 18. Bond JF, Brauer AW, Segal DB, Nault AK, Rogers BL, Kuo MC. Native and recombinant Fel dI as probes into the relationship of allergen structure to human IgE immunoreactivity. Mol Immunol. 1993;30:1529Œ41. 19. Karn RC. The mouse salivary androgen-binding protein (ABP) alpha subu - nit closely resembles chain 1 of the cat allergen Fel dI. Biochem Genet. 1994;32:271Œ7. 20. Vervloet D, Birnbaum J. Origine des allergènes du chat. Rev Fr Allergol. 1995;35:533Œ8. 21. Charpin C, Mata P, Charpin D, Lavaut MN, Allasia C, Vervloet D. Fel d I allergen distribution in cat fur and skin. J Allergy Clin Immunol. 1991;88:77Œ82. 22. Bartholomé K, Kissler W, Baer H, Kopietz-Schulte E, Wahn U. Where does cat allergen 1 come from? J Allergy Clin Immunol. 1985;76:503Œ6. 23. Mata P, Charpin D, Charpin C, Lucciani P, Vervloet D. Fel d I allergen: skin and or saliva? Ann Allergy. 1992;69:321Œ2. 24. Jalil-Colome J, de Andrade AD, Birnbaum J, Casanova D, Mège JL, Lanteaume A, et al. Sex di˚erence in Fel d 1 allergen production. J Allergy Clin Immunol. 1996;98:165Œ8. 25. de Blay F, Krieger P. Les allergies aux principaux mammifères domestiques et leur traitement. Rev Fr Allergol. 1997;37:56Œ64. 26. Wentz PE, Swanson MC, Reed CE. Variability of cat-allergen shedding. J Allergy Clin Immunol. 1990;85:94Œ8. 27. Carayol N, Birnbaum J, Magnan A, Ramadour M, Lanteaume A, Vervloet D, et al. Fel d 1 production in the cat skin varies according to anatomical sites. Allergy. 2000;55:570Œ3. 28. Avner DB, Perzanowski MS, Platts-Mills TA, Woodfolk JA. Evaluation of di˚erent techniques for washing cats: quantitation of allergen removed from the cat and the e˚ect on airborne Fel d 1. J Allergy Clin Immunol. 1997;100:307Œ12. 29. Nageotte C, Park M, Havstad S, Zoratti E, Ownby D. Duration of airborne Fel d 1 reduction after cat washing. J Allergy Clin Immunol. 2006;118:521Œ2. 30. Arbes SJ, Cohn RD, Yin M, Muilenberg ML, Friedman W, Zeldin DC. Dog allergen (Can f 1) and cat allergen (Fel d 1) in US homes: results from the National Survey of Lead and Allergens in Housing. J Allergy Clin Immunol. 2004;114:111Œ7. 31. Salo PM, Arbes SJ, Crockett PW, Thorne PS, Cohn RD, Zeldin DC. Exposure to multiple indoor allergens in US homes and its relationship to asthma. J Allergy Clin Immunol. 2008;121:678Œ84.e2. 32. Munir A. Allergens in school dust. I. The amount of the major cat (Fel d I) and dog (Can f I) allergens in dust from Swedish schools is high enough to probably cause perennial symptoms in most children with asthma who are sensitized to cat and dog. J Allergy Clin Immunol. 1993;91:1067Œ74. 33. Justino CM, Segundo GRS, Pereira FL, Silva DAO, Sopelete MC, Sung SSJ, et al. Mite and pet allergen exposure in Brazilian private cars. Ann Allergy Asthma Immunol. 2005;94:658Œ61. 34. Enberg RN, Shamie SM, McCullough J, Ownby DR. Ubiquitous presence of cat allergen in cat-free buildings: probable dispersal from human clothing. Ann Allergy. 1993;70:471Œ4. 35. Luczynska C. Airborne concentrations and particle size distribution of allergen derived from domestic cats (Felis domesticus). Measurements using cascade impactor, liquid impinger, and a two-site monclonal antibody assay for Fel d I. Am Rev Respir Dis. 1990;141:361Œ7. 36. Lieutier-Colas F. Bronchial challenge tests in patients with asthma sensitized to cats: the importance of large particles in the immediate response. Am J Respir Crit Care Med. 2003;167:1077Œ82. 37. Zeidler MR, Goldin JG, Kleerup EC, Kim HJ, Truong DA, Gjertson DW, et al. Small airways response to naturalistic cat allergen exposure in subjects with asthma. J Allergy Clin Immunol. 2006;118:1075Œ81. 38. Erwin EA, Woodfolk JA, Custis N, Platts-Mills TAE. Animal danders. Immu - nol Allergy Clin North Am. 2003;23:469Œ81. 39. Platts-Mills TAE. Paradoxical e˚ect of domestic animals on asthma and allergic sensitization. JAMA J Am Med Assoc. 2002;288:1012Œ4. 40. Lau S, Illi S, Platts-Mills TAE, Riposo D, Nickel R, Grüber C, et al. Longitu - dinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-speci˜c IgG and development of asthma in childhoodŠreport of the German Multicentre Allergy Study (MAS 90). Allergy. 2005;60:766Œ73. 41. Hesselmar B, Aberg N, Aberg B, Eriksson B, Björkstén B. Does early expo -sure to cat or dog protect against later allergy development? Clin Exp Allergy. 1999;29:611Œ7. 42. Dharmage SC, Lodge CL, Matheson MC, Campbell B, Lowe AJ. Exposure to cats: update on risks for sensitization and allergic diseases. Curr Allergy Asthma Rep. 2012;12:413Œ23. 43. Collin SM, Granell R, Westgarth C, Murray J, Paul ES, Sterne JAC, et al. Asso -ciations of pet ownership with wheezing and lung function in childhood: ˜ndings from a UK birth cohort. PLoS ONE. 2015;10:e0127756. 44. Collin SM, Granell R, Westgarth C, Murray J, Paul E, Sterne JAC, et al. Pet ownership is associated with increased risk of non-atopic asthma and reduced risk of atopy in childhood: ˜ndings from a UK birth cohort. Clin Exp Allergy. 2015;45:200Œ10. 45. Lødrup Carlsen KC, Roll S, Carlsen K-H, Mowinckel P, Wijga AH, Brunekreef B, et al. Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts. PLoS ONE. 2012;7:e43214. 46. Gabet S, Just J, Couderc R, Seta N, Momas I. Allergic sensitisation in early childhood: patterns and related factors in PARIS birth cohort. Int J Hyg Environ Health. 2016;219:792Œ800. 47. Johnson CC, Ownby DR. Allergies and asthma: do atopic disorders result from inadequate immune homeostasis arising from infant gut dysbiosis? Expert Rev Clin Immunol. 2016;12:379Œ88. 48. Grönlund H, Adédoyin J, Reininger R, Varga EM, Zach M, Fredriksson M, et al. Higher immunoglobulin E antibody levels to recombinant Fel d 1 in cat-allergic children with asthma compared with rhinoconjunctivitis. Clin Exp Allergy. 2008;38:1275Œ81. 49. Kleine-Tebbe J, Kleine-Tebbe A, Jeep S, Schou C, Løwenstein H, Kunkel G. Role of the major allergen (Fel d I) in patients sensitized to cat allergens. Int Arch Allergy Immunol. 1993;100:256Œ62. 50. Grönlund H, Saarne T, Gafvelin G, van Hage M. The major cat allergen, Fel d 1, in diagnosis and therapy. Int Arch Allergy Immunol. 2010;151:265Œ74. 51. Ohman JL, Lowell FC. IgE antibody to cat allergens in an allergic popula - tion. J Allergy Clin Immunol. 1977;60:317Œ23. 52. de Groot H, Goei KG, van Swieten P, Aalberse RC. A˛nity puri˜cation of a major and a minor allergen from dog extract: serologic activity of a˛nity- puri˜ed Can f I and of Can f I-depleted extract. J Allergy Clin Immunol. 1991;87:1056Œ65. 53. Emara M, Royer P-J, Abbas Z, Sewell HF, Mohamed GG, Singh S, et al. Recognition of the major cat allergen Fel d 1 through the cysteine-rich 142 KB – 9 Pages