Development and preliminary clinical evaluation of a peptide immunotherapy vaccine for cat allergy

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:127

Article

Worm, Margitta¹  Lee, Hae-Hyuk¹  Kleine-Tebbe, Joerg²  Hafner, Roderick P.³  Laidler, Paul³  Buhot, Cecile⁵  Maillere, Bernard⁵  Kay, A. Barry^4,6,7  Larche, Mark^6,7,8,9,10 

[1] Charite, Dept Dermatol Venerol & Allergol, D-13353 Berlin, Germany

[2] Allergy & Asthma Ctr Westend, Berlin, Germany

[3] Circassia Ltd, Magdalen Ctr, Oxford, England

[4] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Fac Med, Leukocyte Biol Sect, London, England

[5] CEA, Saclay, France

[6] MRC, London W1N 4AL, England

[7] Asthma UK Ctr Allerg Mech Asthma, London, England

[8] McMaster Univ, Firestone Inst Resp Hlth, Hamilton, ON, Canada

[9] McMaster Univ, Dept Med, Div Clin Immunol & Allergy, Hamilton, ON, Canada

[10] McMaster Univ, Dept Med, Div Respirol, Hamilton, ON, Canada

关键词: Immunotherapy;    allergy;    T cell;    epitope;    peptide;    MHC;    immune tolerance;    vaccine;   

DOI  :  10.1016/j.jaci.2010.11.029

来源: Elsevier

【 摘 要 】

Background: Allergic sensitization to cat allergens is common and represents a major risk factor for asthma. Specific immunotherapy (SIT) is effective but cumbersome and associated with IgE-dependent adverse events. Immunotherapy targeting allergen-specific T cells, with synthetic peptides representing T-cell epitopes, might improve safety and reduce the duration of treatment. Objective: We sought to define major T-cell epitopes of Fel d 1 for peptide immunotherapy, generate a peptide vaccine, and evaluate its safety and tolerability in subjects with cat allergy. Methods: We determined the binding affinities of Fel d 1 peptides for 10 commonly expressed HLA-DR molecules. Functionally immunodominant peptides were identified by means of proliferation and cytokine secretion. Histamine-releasing activity was assessed, and a peptide vaccine was formulated. Safety and tolerability were evaluated in a dose-ranging phase IIa clinical trial. Results: MHC-binding sequences were identified throughout Fel d 1. Some regions contained multiple overlapping T-cell epitopes that bound multiple MHC molecules. Immunodominant sequences were identified on the basis of proliferative and cytokine (IFN-gamma, IL-10, and IL-13) responses. Cat allergen extract, but not peptides, induced histamine release in blood basophils. A single administration of peptide vaccine was safe and well tolerated. The dose of vaccine resulting in the greatest inhibition of the late-phase skin response to intradermal whole allergen challenge was 3 nmol. Conclusions: Fel d 1 contains multiple overlapping MHC-binding motifs. A peptide vaccine comprising the immunodominant regions of the allergen was safe and well tolerated when given to subjects with cat allergy as a single dose. The dose of vaccine resulting in the greatest reduction in late-phase skin response was defined for future clinical development. (J Allergy Clin Immunol 2011;127:89-97.)

【 授权许可】

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