Tags

Type your tag names separated by a space and hit enter

Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation.
Allergy 2009; 64(7):995-1002A

Abstract

BACKGROUND

As Th2 type lymphocytes orchestrate the cardinal features of allergic asthma, inhibiting their recruitment to the lungs could be of therapeutic benefit. Although human Th2 cells express the CCR4 chemokine receptor and increased production of CCR4 ligands has been found in asthmatic airways, studies in animals have reached contradictory conclusions on whether blocking this pathway would be beneficial.

OBJECTIVE

As a lack of efficacy might be due to differences between mouse and man, we readdressed this question using a humanized severe combined immunodeficiency model of asthma.

METHODS

Mice received peripheral blood mononuclear cells from house dust mite (HDM) allergic asthmatic patients and then underwent bronchial challenge with HDM.

RESULTS

This resulted in marked allergic inflammation and bronchial hyper-reactivity. Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyper-reactivity. In this chimeric system, human CD11c+ dendritic cells (DCs) were the predominant source of CCR4 ligands, suggesting that DC-derived chemokines attract Th2 cells. In separate experiments using human DCs, in vitro exposure to HDM of DCs from HDM allergic patients but not healthy controls caused CCL17 and CCL22 release that resulted in chemoattraction of polarized human Th2 cells in a CCR4-dependent way.

CONCLUSIONS

Taken together, our data provide proof of concept that CCR4 blockade inhibits the salient features of asthma and justify further clinical development of CCR4 antagonists for this disease.

Authors+Show Affiliations

Laboratory of Immunoregulation, University Hospital of Ghent, De Pintelaan 185, Ghent, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19630858

Citation

Perros, F, et al. "Blockade of CCR4 in a Humanized Model of Asthma Reveals a Critical Role for DC-derived CCL17 and CCL22 in Attracting Th2 Cells and Inducing Airway Inflammation." Allergy, vol. 64, no. 7, 2009, pp. 995-1002.
Perros F, Hoogsteden HC, Coyle AJ, et al. Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy. 2009;64(7):995-1002.
Perros, F., Hoogsteden, H. C., Coyle, A. J., Lambrecht, B. N., & Hammad, H. (2009). Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy, 64(7), pp. 995-1002. doi:10.1111/j.1398-9995.2009.02095.x.
Perros F, et al. Blockade of CCR4 in a Humanized Model of Asthma Reveals a Critical Role for DC-derived CCL17 and CCL22 in Attracting Th2 Cells and Inducing Airway Inflammation. Allergy. 2009;64(7):995-1002. PubMed PMID: 19630858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. AU - Perros,F, AU - Hoogsteden,H C, AU - Coyle,A J, AU - Lambrecht,B N, AU - Hammad,H, PY - 2009/7/28/entrez PY - 2009/7/28/pubmed PY - 2009/12/16/medline SP - 995 EP - 1002 JF - Allergy JO - Allergy VL - 64 IS - 7 N2 - BACKGROUND: As Th2 type lymphocytes orchestrate the cardinal features of allergic asthma, inhibiting their recruitment to the lungs could be of therapeutic benefit. Although human Th2 cells express the CCR4 chemokine receptor and increased production of CCR4 ligands has been found in asthmatic airways, studies in animals have reached contradictory conclusions on whether blocking this pathway would be beneficial. OBJECTIVE: As a lack of efficacy might be due to differences between mouse and man, we readdressed this question using a humanized severe combined immunodeficiency model of asthma. METHODS: Mice received peripheral blood mononuclear cells from house dust mite (HDM) allergic asthmatic patients and then underwent bronchial challenge with HDM. RESULTS: This resulted in marked allergic inflammation and bronchial hyper-reactivity. Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyper-reactivity. In this chimeric system, human CD11c+ dendritic cells (DCs) were the predominant source of CCR4 ligands, suggesting that DC-derived chemokines attract Th2 cells. In separate experiments using human DCs, in vitro exposure to HDM of DCs from HDM allergic patients but not healthy controls caused CCL17 and CCL22 release that resulted in chemoattraction of polarized human Th2 cells in a CCR4-dependent way. CONCLUSIONS: Taken together, our data provide proof of concept that CCR4 blockade inhibits the salient features of asthma and justify further clinical development of CCR4 antagonists for this disease. SN - 1398-9995 UR - https://www.unboundmedicine.com/medline/citation/19630858/Blockade_of_CCR4_in_a_humanized_model_of_asthma_reveals_a_critical_role_for_DC_derived_CCL17_and_CCL22_in_attracting_Th2_cells_and_inducing_airway_inflammation_ L2 - https://doi.org/10.1111/j.1398-9995.2009.02095.x DB - PRIME DP - Unbound Medicine ER -