Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma

• Published in: Journal of allergy and clinical immunology Vol. 132; no. 2; pp. 455 - 462
• Main Authors: Cheng, Donavan T., PhD, Ma, Cynthia, MD, Niewoehner, Jens, PhD, Dahl, Martin, PhD, Tsai, Angela, BA, Zhang, Jun, MSc, Gonsiorek, Waldemar, MSc, Apparsundaram, Subbu, PhD, Pashine, Achal, PhD, Ravindran, Palanikumar, PhD, Jung, Jimmy, BS, Hang, Julie, MS, Allard, John, PhD, Bitter, Hans, PhD, Tribouley, Catherine, PhD, Narula, Satwant, PhD, Wilson, Stephen, BA, Fuentes, Maria E., PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.08.2013; Elsevier; Elsevier Limited
• Subjects: allergen challenge; Allergies; Allergy and Immunology; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Asthma; Asthma - immunology; Asthma - therapy; Biological and medical sciences; Cricetinae; Cynomolgus; cynomolgus monkey; Cytokines - immunology; Cytokines - metabolism; dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Disease Models, Animal; eosinophilia; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; gene expression profiling; Humans; Hypersensitivity - immunology; Hypersensitivity - therapy; Hypotheses; Inflammation - immunology; Inflammation - therapy; Ligands; Macaca fascicularis - immunology; Medical sciences; Receptors, Cytokine - antagonists & inhibitors; Receptors, Cytokine - immunology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Smooth muscle; Th2 Cells - immunology; Th2 Cells - metabolism; TH2 inflammation; Thymic stromal lymphopoietin; Dendritic cell; Inhibitory concentration of 50; IC 50; T H2 inflammation; Anti–thymic stromal lymphopoietin receptor antibody; TSLP; TSLPR; AHR; Thymic stromal lymphopoietin receptor; allergen challenge; BAL; mDC; Airway hyperresponsiveness; Thymic stromal lymphopoietin; dendritic cells; cynomolgus monkey; Bronchoalveolar lavage; eosinophilia; Myeloid dendritic cell; TSLPR mAb; gene expression profiling; DC; TH2 inflammation; IC50; Allergy; Monkey; Hemopathy; Immunology; T; Antigen presenting cell; T-Lymphocyte; Primates; Bronchus disease; Th2 lymphocyte; Obstructive pulmonary disease; Biological receptor; Lung disease; Immunopathology; Respiratory disease; Inflammation; Eosinophilia; Asthma; Gene expression profile; 2 inflammation; Vertebrata; Mammalia; Animal; Models; Provocation test; T(H)2 inflammation; IC
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.05.011

Background Thymic stromal lymphopoietin (TSLP) pathway blockade is a potential strategy for asthma treatment because the main activities of TSLP are activation of myeloid dendritic cells (mDCs) and modulation of cytokine production by mast cells. TSLP-activated mDCs prime the differentiation of naive T cells into inflammatory TH 2 cells. Objective We sought to investigate mechanisms underlying the development of allergic lung inflammation in cynomolgus monkeys using gene expression profiling and to assess the effect of thymic stromal lymphopoietin receptor (TSLPR) blockade in this model. Methods An mAb against human TSLPR was generated and confirmed to be cross-reactive to cynomolgus monkey. Animals were dosed weekly with either vehicle or anti–TSLPR mAb for 6 weeks, and their responses to allergen challenge at baseline, week 2, and week 6 were assessed. Results After 6 weeks of treatment, anti-TSLPR mAb–treated animals showed reduced bronchoalveolar lavage (BAL) fluid eosinophil counts, reduced airway resistance in response to allergen challenge, and reduced IL-13 cytokine levels in BAL fluid compared with values seen in vehicle-treated animals. Expression profiling of BAL fluid cells collected before and after challenge showed a group of genes upregulated by allergen challenge that strongly overlapped with 11 genes upregulated in dendritic cells (DCs) when in vitro stimulated by TSLP (TSLP-DC gene signature). The number of genes differentially expressed in response to challenge was reduced in antibody-treated animals after 6 weeks relative to vehicle-treated animals. Expression of the TSLP-DC gene signature was also significantly reduced in antibody-treated animals. Conclusion These results demonstrate promising efficacy for TSLPR blockade in an allergic lung inflammation model in which TSLP activation of mDCs might play a key role.