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Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma.
J Allergy Clin Immunol 2013; 132(2):455-62JA

Abstract

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 TH2 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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23810153

Citation

Cheng, Donavan T., et al. "Thymic Stromal Lymphopoietin Receptor Blockade Reduces Allergic Inflammation in a Cynomolgus Monkey Model of Asthma." The Journal of Allergy and Clinical Immunology, vol. 132, no. 2, 2013, pp. 455-62.
Cheng DT, Ma C, Niewoehner J, et al. Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma. J Allergy Clin Immunol. 2013;132(2):455-62.
Cheng, D. T., Ma, C., Niewoehner, J., Dahl, M., Tsai, A., Zhang, J., ... Fuentes, M. E. (2013). Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma. The Journal of Allergy and Clinical Immunology, 132(2), pp. 455-62. doi:10.1016/j.jaci.2013.05.011.
Cheng DT, et al. Thymic Stromal Lymphopoietin Receptor Blockade Reduces Allergic Inflammation in a Cynomolgus Monkey Model of Asthma. J Allergy Clin Immunol. 2013;132(2):455-62. PubMed PMID: 23810153.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma. AU - Cheng,Donavan T, AU - Ma,Cynthia, AU - Niewoehner,Jens, AU - Dahl,Martin, AU - Tsai,Angela, AU - Zhang,Jun, AU - Gonsiorek,Waldemar, AU - Apparsundaram,Subbu, AU - Pashine,Achal, AU - Ravindran,Palanikumar, AU - Jung,Jimmy, AU - Hang,Julie, AU - Allard,John, AU - Bitter,Hans, AU - Tribouley,Catherine, AU - Narula,Satwant, AU - Wilson,Stephen, AU - Fuentes,Maria E, Y1 - 2013/06/26/ PY - 2012/11/09/received PY - 2013/04/05/revised PY - 2013/05/01/accepted PY - 2013/7/2/entrez PY - 2013/7/3/pubmed PY - 2013/10/19/medline KW - AHR KW - Airway hyperresponsiveness KW - Anti–thymic stromal lymphopoietin receptor antibody KW - BAL KW - Bronchoalveolar lavage KW - DC KW - Dendritic cell KW - IC(50) KW - Inhibitory concentration of 50% KW - Myeloid dendritic cell KW - T(H)2 inflammation KW - TSLP KW - TSLPR KW - TSLPR mAb KW - Thymic stromal lymphopoietin KW - Thymic stromal lymphopoietin receptor KW - allergen challenge KW - cynomolgus monkey KW - dendritic cells KW - eosinophilia KW - gene expression profiling KW - mDC SP - 455 EP - 62 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 132 IS - 2 N2 - 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 TH2 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. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/23810153/Thymic_stromal_lymphopoietin_receptor_blockade_reduces_allergic_inflammation_in_a_cynomolgus_monkey_model_of_asthma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(13)00828-2 DB - PRIME DP - Unbound Medicine ER -