Scientific publications using Citeq products

Products of Citeq Biologics are used by scientists all over the world. Besides active collaborations with multiple research groups our products are cited in articles which will be listed here but can also be found on Google Scholar.

A T cell – myeloid IL-10 axis regulates pathogenic IFN-y dependent immunity in a mouse model of type 2-low asthma 

Published: August 22, 2019
Research group of Clare M. Lloyd
Institution: Imperial College London

Background
Although originally defined as a type 2 (T2) immune-mediated condition, non-T2 cytokines, such as IFN-γ and IL-17A, have been implicated in asthma pathogenesis, particularly in patients with severe disease. IL-10 regulates TH cell phenotypes and can dampen T2 immunity to allergens, but its functions in controlling non-T2 cytokine responses in asthmatic patients are unclear.

Objective
We sought to determine how IL-10 regulates the balance of TH cell responses to inhaled allergen.

Methods
Allergic airway disease was induced in wild-type, IL-10 reporter, and conditional IL-10 or IL-10 receptor α (IL-10Rα) knockout mice by means of repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-γ signaling were disrupted by using blocking antibodies.

Results
Repeated HDM inhalation induced a mixed IL-13/IL-17A response and accumulation of IL-10–producing forkhead box P3–negative effector CD4+ T cells in the lungs. Ablation of T cell–derived IL-10 increased the IFN-γ and IL-17A response to HDM, reducing IL-13 levels and airway eosinophilia without affecting IgE levels or airway hyperresponsiveness. The increased IFN-γ response could be recapitulated by IL-10Rα deletion in CD11c+ myeloid cells or local IL-10Rα blockade. Disruption of the T cell–myeloid IL-10 axis resulted in increased pulmonary monocyte–derived dendritic cell numbers and increased IFN-γ–dependent expression of CXCR3 ligands by airway macrophages, which is suggestive of a feedforward loop of TH1 cell recruitment. Augmented IFN-γ responses in the HDM allergic airway disease model were accompanied by increased disruption of airway epithelium, which was reversed by therapeutic blockade of IFN-γ.

Conclusions
IL-10 from effector T cells signals to CD11c+ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.

Key words:
Severe asthma, type 2–low asthma, IL-10, immune regulation, T cell, macrophage, dendritic cell, IFN-γ

Visual abstract:

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Published: July 19, 2019
Research group of Arno C. Gutleb
Institution: Luxembourg Institute of Science and Technology

The aim of the study was to develop an in vitro model that mimics the alveolar-capillary barrier and that allows assessment of the respiratory sensitizing potential of substances. The 3D in vitro model cultured at the air liquid interface consists of alveolar type II epithelial cells (A549), endothelial cells (EA.hy926), macrophage-like cells (PMA-differentiated THP-1), and dendritic-like cells (non-differentiated THP-1). This alveolar model was exposed apically to nebulized chemical respiratory sensitizers (phthalic anhydride (PA) and trimellitic anhydride (TMA)) or to irritants (methyl salicylate (MeSa) and acrolein (Acr)) at concentrations inducing 25% cytotoxicity. The exposure to respiratory sensitizers induced den­dritic-like cell activation and a specific cytokine release pattern, while exposure to irritants did not. In addition, the cell surface marker OX40L was found to identify dendritic-like cell activation by high molecular weight allergens. With this in vitro model we can postulate a set of promising markers that allow the discrimination of chemical respiratory sensitizers from irritants.

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PAG1 limits allergen-induced type 2 inflammation in the murine lung 

Published: July 18, 2019
Research group of Simon Phipps
Institution: Imperial College London

Background
Phosphoprotein associated with glycosphingolipid‐enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome‐wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)‐induced allergic sensitization and allergic airway inflammation.

Methods
Pag1‐deficient (Pag1−/−) and wild‐type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti‐CD4 antibody) and adoptive transfer studies.

Results
Type 2 inflammation (eosinophilia, eotaxin‐2 expression, IL‐4/IL‐5/IL‐13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1−/− mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high‐mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte‐derived dendritic cell numbers in the mediastinal lymph nodes, and increased T‐helper type 2 (TH2)‐cell differentiation. CD4+ T‐cell depletion studies or the adoptive transfer of WT OVA‐specific CD4+ T cells to WT or Pag1−/− recipients demonstrated that the heightened propensity for TH2‐cell differentiation was both T cell intrinsic and extrinsic.

Conclusion
PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

Key words:
HMGB1; PAG1; TH2 cells; house dust mite; type 2 inflammation

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