Sensitization to cat is a common cause of allergic disease all over the world. Symptoms range from mild rhinoconjunctivitis to potentially life-threatening asthmatic exacerbations. In vivo and in vitro diagnostics of cat allergy is currently based on cat dander extract. As allergen extracts from natural sources are heterogeneous in composition, the allergen content may vary. With the introduction of allergens produced by recombinant techniques, a large panel of recombinant allergenic molecules including the major cat allergen, recombinant Fel d 1, has become available for immunological investigations, diagnosis and treatment. Studies have shown that this single allergen, which belongs to the uteroglobin protein family, is at least as good as cat dander extract in identifying cat-allergic patients. The introduction of recombinant Fel d 1-based tests into clinical practice will increase our knowledge of this single allergen molecule as a diagnostic tool and improve the selection for therapy of cat allergy. Several different modes for allergen-specific immunotherapy of cat allergy based on Fel d 1 have been developed. These include Fel d 1 hypoallergens and allergen constructs where Fel d 1 is coupled to immunomodulatory proteins or carriers. The approaches have been evaluated in experimental in vitro and in vivo model systems with promising results. In addition, immunotherapy with Fel d 1 peptides containing T-cell epitopes has been tested in clinical trials. After initial problems with adverse reactions, more recent data show that peptide immunotherapy modulates the immune response to Fel d 1 and reduces early- and late-phase effector reactions in cat-allergic patients.

1.
Ichikawa K, Iwasaki E, Baba M, Chapman MD: High prevalence of sensitization to cat allergen among Japanese children with asthma, living without cats. Clin Exp Allergy 1999;29:754–761.
2.
Lau S, Illi S, Sommerfeld C, Niggemann B, Bergmann R, von Mutius E, Wahn U: Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet 2000;356:1392–1397.
3.
Freidhoff LR, Meyers DA, Marsh DG: A genetic-epidemiologic study of human immune responsiveness to allergens in an industrial population. 2. The associations among skin sensitivity, total serum IgE, age, sex, and the reporting of allergies in a stratified random sample. J Allergy Clin Immunol 1984;73:490–499.
4.
Plaschke P, Janson C, Norrman E, Björnsson E, Lundbäck B, Lindholm N, Rosenhall L, Järvholm B, Boman G: Skin prick tests and specific IgE in adults from three different areas of Sweden. Allergy 1996;51:461–472.
5.
Roost HP, Kunzli N, Schindler C, Jarvis D, Chinn S, Perruchoud AP, Ackermann- Liebrich U, Burney P, Wuthrich B: Role of current and childhood exposure to cat and atopic sensitization. European Community Respiratory Health Survey. J Allergy Clin Immunol 1999;104:941–947.
6.
Almqvist C, Li Q, Britton WJ, Kemp AS, Xuan W, Tovey ER, Marks GB: Early predictors for developing allergic disease and asthma: examining separate steps in the ‘allergic march’. Clin Exp Allergy 2007;37:1296–1302.
7.
Schafer T, Ruhdorfer S, Weigl L, Wessner D, Heinrich J, Wichmann HE, Ring J: School education and allergic sensitization in adults. Allergy 2001;56:1206–1210.
8.
Perzanowski MS, Rönmark E, Platts-Mills TA, Lundbäck B: Effect of cat and dog ownership on sensitization and development of asthma among preteenage children. Am J Respir Crit Care Med 2002;166:696–702.
9.
Lau S, Illi S, Platts-Mills TA, Riposo D, Nickel R, Grüber C, Niggemann B, Wahn U, Multicentre Allergy Study Group: Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood – report of the German Multicentre Allergy Study (MAS 90). Allergy 2005;60:766–773.
10.
Anderson MC, Baer H, Ohman JL Jr: A comparative study of the allergens of cat urine, serum, saliva, and pelt. J Allergy Clin Immunol 1985;76:563–569.
11.
Løwenstein H, Lind P, Weeke B: Identification and clinical significance of allergenic molecules of cat origin. Part of the DAS 76 Study. Allergy 1985;40:430–441.
12.
IUIS/WHO Allergen Nomenclature Sub-Committee. www.allergen.org.
13.
Ohman JL Jr, Lowell FC, Bloch KJ: Allergens of mammalian origin. 3. Properties of a major feline allergen. J Immunol 1974;113:1668–1677.
14.
Ohman JL, Lowell FC, Bloch KJ: Allergens of mammalian origin: characterization of allergen extracted from cat pelts. J Allergy Clin Immunol 1973;52:231–241.
15.
Spitzauer S, Pandjaitan B, Soregi G, Muhl S, Ebner C, Kraft D, Valenta R, Rumpold H: IgE cross-reactivities against albumins in patients allergic to animals. J Allergy Clin Immunol 1995;96:951–959.
16.
Hilger C, Grigioni F, Hentges F: Sequence of the gene encoding cat (Felis domesticus) serum albumin. Gene 1996;169:295–296.
17.
van Ree R, van Leeuwen WA, Bulder I, Bond J, Aalberse RC: Purified natural and recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy. J Allergy Clin Immunol 1999;104:1223–1230.
18.
Ichikawa K, Vailes LD, Pomes A, Chapman MD: Molecular cloning, expression and modelling of cat allergen, cystatin (Fel d 3), a cysteine protease inhibitor. Clin Exp Allergy 2001;31:1279–1286.
19.
Smith W, Butler AJ, Hazell LA, Chapman MD, Pomes A, Nickels DG, Thomas WR: Fel d 4, a cat lipocalin allergen. Clin Exp Allergy 2004;34:1732–1738.
20.
Adedoyin J, Grönlund H, Oman H, Johansson SG, van Hage M: Cat IgA, representative of new carbohydrate cross-reactive allergens. J Allergy Clin Immunol 2007;119:640–645.
21.
Adedoyin J, Johansson SG, Grönlund H, van Hage M: Interference in immunoassays by human IgM with specificity for the carbohydrate moiety of animal proteins. J Immunol Methods 2006;310:117–125.
22.
Ohman JL Jr, Lowell FC: IgE antibody to cat allergens in an allergic population. J Allergy Clin Immunol 1977;60:317–323.
23.
Kleine-Tebbe J, Kleine-Tebbe A, Jeep S, Schou C, Lowenstein H, Kunkel G: Role of the major allergen (Fel d I) in patients sensitized to cat allergens. Int Arch Allergy Immunol 1993;100:256–262.
24.
Brown PR, Leitermann K, Ohman JL Jr: Distribution of cat allergen 1 in cat tissues and fluids. Int Arch Allergy Appl Immunol 1984;74:67–70.
25.
van Milligen FJ, Vroom TM, Aalberse RC: Presence of Felis domesticus allergen I in the cat’s salivary and lacrimal glands. Int Arch Allergy Appl Immunol 1990;92:375–378.
26.
de Groot H, van Swieten P, Aalberse RC: Evidence for a Fel d I-like molecule in the ‘big cats’ (Felidae species). J Allergy Clin Immunol 1990;86:107–116.
27.
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;88:77–82.
28.
Bartholome K, Kissler W, Baer H, Kopietz-Schulte E, Wahn U: Where does cat allergen 1 come from? J Allergy Clin Immunol 1985;76:503–506.
29.
Dabrowski AJ, Van der Brempt X, Soler M, Seguret N, Lucciani P, Charpin D, Vervloet D: Cat skin as an important source of Fel d I allergen. J Allergy Clin Immunol 1990;86:462–465.
30.
Grönlund H, Bergman T, Sandstrom K, Alvelius G, Reininger R, Verdino P, Hauswirth A, Liderot K, Valent P, Spitzauer S, Keller W, Valenta R, van Hage-Hamsten M: Formation of disulfide bonds and homodimers of the major cat allergen Fel d 1 equivalent to the natural allergen by expression in Escherichia coli. J Biol Chem 2003;278:40144–40151.
31.
Duffort OA, Carreira J, Nitti G, Polo F, Lombardero M: Studies on the biochemical structure of the major cat allergen Felis domesticus I. Mol Immunol 1991;28:301–309.
32.
Morgenstern JP, Griffith IJ, Brauer AW, Rogers BL, Bond JF, Chapman MD, Kuo MC: Amino acid sequence of Fel d I, the major allergen of the domestic cat: protein sequence analysis and cDNA cloning. Proc Natl Acad Sci USA 1991;88:9690–9694.
33.
Kaiser L, Grönlund H, Sandalova T, Ljunggren HG, van Hage-Hamsten M, Achour A, Schneider G: The crystal structure of the major cat allergen Fel d 1, a member of the secretoglobin family. J Biol Chem 2003;278:37730–37735.
34.
Kaiser L, Velickovic TC, Badia-Martinez D, Adedoyin J, Thunberg S, Hallen D, Berndt K, Grönlund H, Gafvelin G, van Hage M, Achour A: Structural characterization of the tetrameric form of the major cat allergen Fel d 1. J Mol Biol 2007;370:714–727.
35.
Kaiser L, Grönlund H, Sandalova T, Ljunggren HG, Achour A, Schneider G, van Hage-Hamsten M: Three-dimensional structure of Fel d 1, the major allergen in cat. Int Arch Allergy Immunol 2003;132:25–26.
36.
Keating KM, Segal DB, Craig SJ, Nault AK, Semensi V, Wasserman AS, Counsell CM, Bond JF: Enhanced immunoreactivity and preferential heterodimer formation of reassociated Fel d I recombinant chains. Mol Immunol 1995;32:287–293.
37.
van Neerven RJ, van de Pol MM, van Milligen FJ, Jansen HM, Aalberse RC, Kapsenberg ML: Characterization of cat dander-specific T lymphocytes from atopic patients. J Immunol 1994;152:4203–4210.
38.
Grönlund H, Adedoyin J, Reininger R, Varga EM, Zach M, Fredriksson M, Kronqvist M, Szepfalusi Z, Spitzauer S, Gronneberg R, Valenta R, Hedlin G, van Hage M: Higher immunoglobulin E antibody levels to recombinant Fel d 1 in cat-allergic children with asthma compared with rhinoconjunctivitis. Clin Exp Allergy 2008;38:1275–1281.
39.
de Groot H, van Swieten P, van Leeuwen J, Lind P, Aalberse RC: Monoclonal antibodies to the major feline allergen Fel d I. 1. Serologic and biologic activity of affinity-purified Fel d I and of Fel d I-depleted extract. J Allergy Clin Immunol 1988;82:778–786.
40.
Chapman MD, Aalberse RC, Brown MJ, Platts-Mills TA: Monoclonal antibodies to the major feline allergen Fel d I. 2. Single step affinity purification of Fel d I, N-terminal sequence analysis, and development of a sensitive two-site immunoassay to assess Fel d I exposure. J Immunol 1988;140:812–818.
41.
Batard T, Bukovec F, Berrouet C, Destombes V, Didierlaurent A, Andre C: Demonstration of a partially cryptic epitope of the major cat allergen Fel d 1: consequences for mAb-based standardization of cat extracts. J Allergy Clin Immunol 2000;106:669–676.
42.
Kristensen AK, Schou C, Roepstorff P: Determination of isoforms, N-linked glycan structure and disulfide bond linkages of the major cat allergen Fel d 1 by a mass spectrometric approach. Biol Chem 1997;378:899–908.
43.
Beato M: Binding of steroids to uteroglobin. J Steroid Biochem 1976;7:327–334.
44.
Griffith 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;113:263–268.
45.
Klug J, Beier HM, Bernard A, Chilton BS, Fleming TP, Lehrer RI, Miele L, Pattabiraman N, Singh G: Uteroglobin/Clara cell 10-kDa family of proteins: nomenclature committee report. Ann NY Acad Sci 2000;923:348–354.
46.
Gillner M, Lund J, Cambillau C, Alexan- dersson M, Hurtig U, Bergman A, Klasson-Wehler E, Gustafsson JA: The binding of methylsulfonyl-polychloro-biphenyls to ute-roglobin. J Steroid Biochem 1988;31:27–33.
47.
Hard T, Barnes HJ, Larsson C, Gustafsson JA, Lund J: Solution structure of a mammalian PCB-binding protein in complex with a PCB. Nat Struct Biol 1995;2:983–989.
48.
Emes RD, Riley MC, Laukaitis CM, Goodstadt L, Karn RC, Ponting CP: Comparative evolutionary genomics of androgen-binding protein genes. Genome Res 2004;14:1516–1529.
49.
van Milligen FJ, van ‘t Hof W, van den Berg M, Aalberse RC: IgE epitopes on the cat (Felis domesticus) major allergen Fel d I: a study with overlapping synthetic peptides. J Allergy Clin Immunol 1994;93:34–43.
50.
van ‘t Hof W, van Milligen FJ, van den Berg M, Lombardero M, Chapman MD, Aalberse RC: Epitope mapping of the cat (Felis domesticus) major allergen Fel d I by overlapping synthetic peptides and monoclonal antibodies against native and denatured Fel d I. Allergy 1993;48:255–263.
51.
Vailes LD, Li Y, Bao Y, DeGroot H, Aalberse RC, Chapman MD: Fine specificity of B-cell epitopes on Felis domesticus allergen I (Fel d I): effect of reduction and alkylation or deglycosylation on Fel d I structure and antibody binding. J Allergy Clin Immunol 1994;93:22–33.
52.
van Milligen FJ, van ‘t Hof W, Aalberse RC: IgE and IgG4 binding to synthetic peptides of the cat (Felis domesticus) major allergen Fel d I. Int Arch Allergy Immunol 1994;103:274–279.
53.
Bond JF, Brauer AW, Segal DB, Nault AK, Rogers BL, Kuo MC: Native and recombinant Fel d I as probes into the relationship of allergen structure to human IgE immunoreactivity. Mol Immunol 1993;30:1529–1541.
54.
Counsell CM, Bond JF, Ohman JL Jr, Greenstein JL, Garman RD: Definition of the human T-cell epitopes of Fel d 1, the major allergen of the domestic cat. J Allergy Clin Immunol 1996;98:884–894.
55.
Mark PG, Segal DB, Dallaire ML, Garman RD: Human T and B cell immune responses to Fel d 1 in cat-allergic and non-cat-allergic subjects. Clin Exp Allergy 1996;26:1316–1328.
56.
Bateman EAL, Ardern-Jones MR, Ogg GS: Identification of an immunodominant region of Fel d 1 and characterization of constituent epitopes. Clin Exp Allergy 2008;38:1760–1768.
57.
Haselden BM, Syrigou E, Jones M, Huston D, Ichikawa K, Chapman MD, Kay AB, Larche M: Proliferation and release of IL-5 and IFN-gamma by peripheral blood mononuclear cells from cat-allergic asthmatics and rhinitics, non-cat-allergic asthmatics, and normal controls to peptides derived from Fel d 1 chain 1. J Allergy Clin Immunol 2001;108:349–356.
58.
Reefer AJ, Carneiro RM, Custis NJ, Platts-Mills TA, Sung SS, Hammer J, Woodfolk JA: A role for IL-10-mediated HLA-DR7-restricted T cell-dependent events in development of the modified Th2 response to cat allergen. J Immunol 2004;172:2763–2772.
59.
Pandjaitan B, Swoboda I, Brandejsky-Pichler F, Rumpold H, Valenta R, Spitzauer S: Escherichia coli expression and purification of recombinant dog albumin, a cross-reactive animal allergen. J Allergy Clin Immunol 2000;105:279–285.
60.
Spitzauer S, Schweiger C, Sperr WR, Pandjaitan B, Valent P, Muhl S, Ebner C, Scheiner O, Kraft D, Rumpold H, et al: Molecular characterization of dog albumin as a cross-reactive allergen. J Allergy Clin Immunol 1994;93:614–627.
61.
Reininger R, Varga EM, Zach M, Balic N, Lindemeier AD, Swoboda I, Grönlund H, van Hage M, Rumpold H, Valenta R, Spitz-auer S: Detection of an allergen in dog dander that cross-reacts with the major cat allergen, Fel d 1. Clin Exp Allergy 2007;37:116–124.
62.
Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ: Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clin Exp Allergy 1997;27:860–867.
63.
Ewbank PA, Murray J, Sanders K, Curran-Everett D, Dreskin S, Nelson HS: A double-blind, placebo-controlled immunotherapy dose-response study with standardized cat extract. J Allergy Clin Immunol 2003;111:155–161.
64.
Nanda A, O’Connor M, Anand M, Dreskin SC, Zhang L, Hines B, Lane D, Wheat W, Routes JM, Sawyer R, Rosenwasser LJ, Nelson HS: Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract. J Allergy Clin Immunol 2004;114:1339–1344.
65.
Niederberger V, Valenta R: Molecular approaches for new vaccines against allergy. Expert Rev Vaccines 2006;5:103–110.
66.
Saarne T, Kaiser L, Grönlund H, Rasool O, Gafvelin G, van Hage-Hamsten M: Rational design of hypoallergens applied to the major cat allergen Fel d 1. Clin Exp Allergy 2005;35:657–663.
67.
Ali FR, Larche M: Peptide-based immunotherapy: a novel strategy for allergic disease. Expert Rev Vaccines 2005;4:881–889.
68.
Larche M: Peptide therapy for allergic diseases: basic mechanisms and new clinical approaches. Pharmacol Ther 2005;108:353–361.
69.
Van Metre TE Jr, Marsh DG, Adkinson NF Jr, Fish JE, Kagey-Sobotka A, Norman PS, Radden EB Jr, Rosenberg GL: Dose of cat (Felis domesticus) allergen 1 (Fel d 1) that induces asthma. J Allergy Clin Immunol 1986;78:62–75.
70.
Marcotte GV, Braun CM, Norman PS, Nicodemus CF, Kagey-Sobotka A, Lichtenstein LM, Essayan DM: Effects of peptide therapy on ex vivo T-cell responses. J Allergy Clin Immunol 1998;101:506–513.
71.
Pene J, Desroches A, Paradis L, Lebel B, Farce M, Nicodemus CF, Yssel H, Bousquet J: Immunotherapy with Fel d 1 peptides decreases IL-4 release by peripheral blood T cells of patients allergic to cats. J Allergy Clin Immunol 1998;102:571–578.
72.
Chan-Yeung M, Manfreda J, Dimich-Ward H, Lam J, Ferguson A, Warren P, Simons E, Broder I, Chapman M, Platts-Mills T, et al: Mite and cat allergen levels in homes and severity of asthma. Am J Respir Crit Care Med 1995;152:1805–1811.
73.
Burr ML, Limb ES, Maguire MJ, Amarah L, Eldridge BA, Layzell JC, Merrett TG: Infant feeding, wheezing, and allergy: a prospective study. Arch Dis Child 1993;68:724–728.
74.
Haselden BM, Kay AB, Larche M: Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med 1999;189:1885–1894.
75.
Oldfield WL, Kay AB, Larche M: Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects. J Immunol 2001;167:1734–1739.
76.
Oldfield WL, Larche M, Kay AB: Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial. Lancet 2002;360:47–53.
77.
Alexander C, Tarzi M, Larche M, Kay AB: The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects. Allergy 2005;60:1269–1274.
78.
Alexander C, Ying S, Kay AB, Larche M: Fel d 1-derived T cell peptide therapy induces recruitment of CD4+ CD25+; CD4+ interferon-gamma+ T helper type 1 cells to sites of allergen-induced late-phase skin reactions in cat-allergic subjects. Clin Exp Allergy 2005;35:52–58.
79.
Zhu D, Kepley CL, Zhang K, Terada T, Yamada T, Saxon A: A chimeric human-cat fusion protein blocks cat-induced allergy. Nat Med 2005;11:446–449.
80.
Terada T, Zhang K, Belperio J, Londhe V, Saxon A: A chimeric human-cat Fcgamma-Fel d 1 fusion protein inhibits systemic, pulmonary, and cutaneous allergic reactivity to intratracheal challenge in mice sensitized to Fel d 1, the major cat allergen. Clin Immunol 2006;120:45–56.
81.
Saxon A, Kepley C, Zhang K: ‘Accentuate the negative, eliminate the positive’: engineering allergy therapeutics to block allergic reactivity through negative signaling. J Allergy Clin Immunol 2008;121:320–325.
82.
Hulse KE, Reefer AJ, Engelhard VH, Satinover SM, Patrie JT, Chapman MD, Woodfolk JA: Targeting Fel d 1 to FcgammaRI induces a novel variation of the T(H)2 response in subjects with cat allergy. J Allergy Clin Immunol 2008;121:756–762.e4.
83.
Grönlund H, Vrtala S, Wiedermann U, Dekan G, Kraft D, Valenta R, Van Hage-Hamsten M: Carbohydrate-based particles: a new adjuvant for allergen-specific immunotherapy. Immunology 2002;107:523–529.
84.
Andersson TN, Ekman GJ, Grönlund H, Buentke E, Eriksson TL, Scheynius A, Van Hage-Hamsten M, Gafvelin G: A novel adjuvant-allergen complex, CBP-rFel d 1, induces up-regulation of CD86 expression and enhances cytokine release by human dendritic cells in vitro. Immunology 2004;113:253–259.
85.
Thunberg S, Neimert-Andersson T, Cheng Q, Wermeling F, Bergstrom U, Swedin L, Dahlen SE, Arner E, Scheynius A, Karlsson MC, Gafvelin G, van Hage M, Grönlund H: Prolonged antigen-exposure with carbohydrate particle based vaccination prevents allergic immune responses in sensitized mice. Allergy 2009;64:919–926.
86.
Neimert-Andersson T, Thunberg S, Swedin L, Wiedermann U, Jacobsson-Ekman G, Dahlen SE, Scheynius A, Grönlund H, van Hage M, Gafvelin G: Carbohydrate-based particles reduce allergic inflammation in a mouse model for cat allergy. Allergy 2008;63:518–526.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.