The Notch pathway inhibitor stapled α-helical peptide derived from mastermind-like 1 (SAHM1) abrogates the hallmarks of allergic asthma

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:142

Article

KleinJan, Alex¹  Tindemans, Irma¹  Montgomery, Jeffrey E.^2,3  Lukkes, Melanie¹  de Bruijn, Marjolein J. W.¹  van Nimwegen, Menno¹  Bergen, Ingrid¹  Moellering, Raymond E.^2,3  Hoogsteden, Henk C.¹  Boon, Louis⁴  Amsen, Derk⁵  Hendriks, R. W.¹ 

[1] Erasmus MC, Dept Pulm Med, Rm Ee2251,POB 2040, NL-3000 CA Rotterdam, Netherlands

[2] Univ Chicago, Dept Chem, 5735 S Ellis Ave, Chicago, IL 60637 USA

[3] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA

[4] Epirus Biopharmaceut Netherlands, Utrecht, Netherlands

[5] Sanquin, Amsterdam, Netherlands

关键词: Allergic asthma;    Notch signaling;    Gata3;    T(H)2 immunity;    house dust mite;    recombination signal-binding protein for IgJ kappa region;    stapled alpha-helical peptide derived from mastermind-like 1;   

DOI  :  10.1016/j.jaci.2017.08.042

来源: Elsevier

【 摘 要 】

Background: The Notch signaling pathway has been implicated in the pathogenesis of allergic airway inflammation. Targeting the active Notch transactivation complex by using the cell-permeable, hydrocarbon-stapled synthetic peptide stapled alpha-helical peptide derived from mastermind-like 1 (SAHM1) resulted in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, the efficacy of SAHM1 in allergic asthma models has remained unexplored. Objective: We aimed to investigate the therapeutic efficacy of SAHM1 in a house dust mite (HDM)-driven asthma model. Methods: Topical therapeutic intervention with SAHM1 or a control peptide was performed during sensitization, challenge, or both with HDM in mice. Airway inflammation was assessed by using multicolor flow cytometry, and bronchial hyperreactivity was studied. Additionally, SAHM1 therapy was investigated in mice with established allergic airway inflammation and in a model in which we neutralized IFN-gamma during HDM challenge to support the T(H)2 response and exacerbate asthma. Results: SAHM1 treatment during the challenge phase led to a marked reduction of eosinophil and T cell numbers in bronchoalveolar lavage fluid compared with those in diluenttreated or control peptide-treated mice. Likewise, T-cell cytokine content and bronchial hyperreactivity were reduced. SAHM1 treatment dampened T(H)2 inflammation during ongoing HDM challenge and enhanced recovery after established asthma. Additionally, in the presence of anti-IFN-gamma antibodies, SAHM1 downregulated expression of the key T(H)2 transcription factor GATA3 and intracellular IL-4 in bronchoalveolar lavage fluid T cells, but expression of the T(H)17 transcription factor retinoic acid-related orphan receptor gamma t or intracellular IL-17 was not affected. SAHM1 therapy also reduced serum IgE levels. Conclusions: Therapeutic intervention of Notch signaling by SAHM1 inhibits allergic airway inflammation in mice and is therefore an interesting new topical treatment opportunity in asthmatic patients.

【 授权许可】

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