Airway responsiveness in CD38-deficient mice in allergic airway disease: studies with bone marrow chimeras

CD38 is a cell-surface protein involved in calcium signaling and contractility of airway smooth muscle. It has a role in normal airway responsiveness and in airway hyperresponsiveness (AHR) developed following airway exposure to IL-13 and TNF-α but appears not to be critical to airway inflammation in response to the cytokines. CD38 is also involved in T cell-mediated immune response to protein antigens. In this study, we assessed the contribution of CD38 to AHR and inflammation to two distinct allergens, ovalbumin and the epidemiologically relevant environmental fungus Alternaria. We also generated bone marrow chimeras to assess whether Cd38+/+inflammatory cells would restore AHR in the CD38-deficient ( Cd38−/−) hosts following ovalbumin challenge. Results show that wild-type (WT) mice develop greater AHR to inhaled methacholine than Cd38−/−mice following challenge with either allergen, with comparable airway inflammation. Reciprocal bone marrow transfers did not change the native airway phenotypic differences between WT and Cd38−/−mice, indicating that the lower airway reactivity of Cd38−/−mice stems from Cd38−/−lung parenchymal cells. Following bone marrow transfer from either source and ovalbumin challenge, the phenotype of Cd38−/−hosts was partially reversed, whereas the airway phenotype of the WT hosts was preserved. Airway inflammation was similar in Cd38−/−and WT chimeras. These results indicate that loss of CD38 on hematopoietic cells is not sufficient to prevent AHR and that the magnitude of airway inflammation is not the predominant underlying determinant of AHR in mice.

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Regulatory T cells mediated immunomodulation during asthma: a therapeutic standpoint

Journal of Translational Medicine ◽

10.1186/s12967-020-02632-1 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Mohammad Afzal Khan

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Airway Inflammation ◽

Therapeutic Potential ◽

Airway Remodeling ◽

Clinical Manifestations ◽

Inflammatory Cells ◽

Airway Disease ◽

Vital Role ◽

Allergic Airway Disease

AbstractAsthma is an inflammatory disease of the lung airway network, which is initiated and perpetuated by allergen-specific CD4+ T cells, IgE antibodies, and a massive release of Th2 cytokines. The most common clinical manifestations of asthma progression include airway inflammation, pathological airway tissue and microvascular remodeling, which leads to airway hyperresponsiveness (AHR), and reversible airway obstruction. In addition to inflammatory cells, a tiny population of Regulatory T cells (Tregs) control immune homeostasis, suppress allergic responses, and participate in the resolution of inflammation-associated tissue injuries. Preclinical and clinical studies have demonstrated a tremendous therapeutic potential of Tregs in allergic airway disease, which plays a crucial role in immunosuppression, and rejuvenation of inflamed airways. These findings supported to harness the immunotherapeutic potential of Tregs to suppress airway inflammation and airway microvascular reestablishment during the progression of the asthma disease. This review addresses the therapeutic impact of Tregs and how Treg mediated immunomodulation plays a vital role in subduing the development of airway inflammation, and associated airway remodeling during the onset of disease.

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Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma

Journal of Experimental Medicine ◽

10.1084/jem.20051680 ◽

2006 ◽

Vol 203 (5) ◽

pp. 1173-1184 ◽

Cited By ~ 44

Author(s):

Jiankun Tong ◽

Hozefa S. Bandulwala ◽

Bryan S. Clay ◽

Robert A. Anders ◽

Rebecca A. Shilling ◽

...

Keyword(s):

T Cells ◽

Airway Inflammation ◽

Inflammatory Cells ◽

Airway Disease ◽

Airway Hyperreactivity ◽

Allergic Airway Disease ◽

Mucus Production ◽

Human T Cells ◽

Highly Sensitive

Persistent airway inflammation, mucus production, and airway hyperreactivity are the major contributors to the frequency and severity of asthma. Why lung inflammation persists in asthmatics remains unclear. It has been proposed that Fas-mediated apoptosis of inflammatory cells is a fundamental mechanism involved in the resolution of eosinophilic airway inflammation. Because infiltrating eosinophils are highly sensitive to Fas-mediated apoptosis, it has been presumed that direct ligation of Fas on eosinophils is involved. Here, we utilize adoptive transfers of T cells to demonstrate that the delayed resolution of eosinophilia in Fas-deficient mice is a downstream effect of Fas deficiency on T cells, not eosinophils. Interestingly, the mice that received Fas-deficient T cells, but not the controls, developed a persistent phase of inflammation that failed to resolve even 6 wk after the last challenge. This persistent phase correlated with decreased interferon (IFN)γ production by Fas-deficient T cells and could be reproduced with adoptive transfer of IFNγ-deficient T cells. These data demonstrate that Fas deficiency on T cells is sufficient for the development of long-term allergic airway disease in mice and implies that deregulation of death receptors such as Fas on human T cells could be an important factor in the development and/or chronic nature of asthma.

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Responses of bone-marrow eosinophil/basophil progenitors in experimental mouse models of upper and/or lower airway inflammation

Journal of Allergy and Clinical Immunology ◽

10.1016/s0091-6749(03)81005-9 ◽

2003 ◽

Vol 111 (2) ◽

pp. S280

Author(s):

J. Li ◽

H. Saito ◽

L. Crawford ◽

J.A. Denburg

Keyword(s):

Bone Marrow ◽

Airway Inflammation ◽

Mouse Models ◽

Lower Airway ◽

Experimental Mouse

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Potential of Immunoglobulin A to Prevent Allergic Asthma

Clinical and Developmental Immunology ◽

10.1155/2013/542091 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 24

Author(s):

Anouk K. Gloudemans ◽

Bart N. Lambrecht ◽

Hermelijn H. Smits

Keyword(s):

Allergic Asthma ◽

Immunoglobulin A ◽

Bronchial Hyperresponsiveness ◽

Airway Disease ◽

Epidemiological Studies ◽

Allergic Airway Disease ◽

Secretory Iga ◽

Th2 Cells ◽

Lower Airway

Allergic asthma is characterized by bronchial hyperresponsiveness, a defective barrier function, and eosinophilic lower airway inflammation in response to allergens. The inflammation is dominated by Th2 cells and IgE molecules and supplemented with Th17 cells in severe asthma. In contrast, in healthy individuals, allergen-specific IgA and IgG4 molecules are found but no IgE, and their T cells fail to proliferate in response to allergens, probably because of the development of regulatory processes that actively suppress responses to allergens. The presence of allergen-specific secretory IgA has drawn little attention so far, although a few epidemiological studies point at a reverse association between IgA levels and the incidence of allergic airway disease. This review highlights the latest literature on the role of mucosal IgA in protection against allergic airway disease, the mechanisms described to induce secretory IgA, and the role of (mucosal) dendritic cells in this process. Finally, we discuss how this information can be used to translate into the development of new therapies for allergic diseases based on, or supplemented with, IgA boosting strategies.

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Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00056.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. L730-L739 ◽

Cited By ~ 22

Author(s):

Jill R. Johnson ◽

Filip K. Swirski ◽

Beata U. Gajewska ◽

Ryan E. Wiley ◽

Ramzi Fattouh ◽

...

Keyword(s):

Airway Inflammation ◽

Inflammatory Responses ◽

Airway Remodeling ◽

Bronchial Hyperresponsiveness ◽

Airway Disease ◽

Allergic Airway Disease ◽

Th Cell ◽

And Function ◽

Deficient Mice ◽

Chronic Airway

Asthma is a chronic airway inflammatory disease that encompasses three cardinal processes: T helper (Th) cell type 2 (Th2)-polarized inflammation, bronchial hyperreactivity, and airway wall remodeling. However, the link between the immune-inflammatory phenotype and the structural-functional phenotype remains to be fully defined. The objective of these studies was to evaluate the relationship between the immunologic nature of chronic airway inflammation and the development of abnormal airway structure and function in a mouse model of chronic asthma. Using IL-4-competent and IL-4-deficient mice, we created divergent immune-inflammatory responses to chronic aeroallergen challenge. Immune-inflammatory, structural, and physiological parameters of chronic allergic airway disease were evaluated in both strains of mice. Although both strains developed airway inflammation, the profiles of the immune-inflammatory responses were markedly different: IL-4-competent mice elicited a Th2-polarized response and IL-4-deficient mice developed a Th1-polarized response. Importantly, this chronic Th1-polarized immune response was not associated with airway remodeling or bronchial hyperresponsiveness. Transient reconstitution of IL-4 in IL-4-deficient mice via an airway gene transfer approach led to partial Th2 repolarization and increased bronchial hyperresponsiveness, along with full reconstitution of airway remodeling. These data show that distinct structural-functional phenotypes associated with chronic airway inflammation are strictly dependent on the nature of the immune-inflammatory response.

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Dilodendron bipinnatum Radlk. ameliorates airway inflammation through multiple targets in a murine model of ovalbumin-induced allergic airway disease

Journal of Ethnopharmacology ◽

10.1016/j.jep.2018.07.025 ◽

2018 ◽

Vol 226 ◽

pp. 17-25 ◽

Cited By ~ 2

Author(s):

Ruberlei Godinho de Oliveira ◽

Fábio Miyajima ◽

Geovane Roberto de Campos Castilho ◽

Amílcar Sabino Damazo ◽

Antonio Macho ◽

...

Keyword(s):

Airway Inflammation ◽

Murine Model ◽

Airway Disease ◽

Allergic Airway Disease ◽

Multiple Targets

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Bone marrow derived inflammatory cells traffic to airways in allergic airway inflammation

Journal of Allergy and Clinical Immunology ◽

10.1016/s0091-6749(03)80642-5 ◽

2003 ◽

Vol 111 (2) ◽

pp. S188

Author(s):

A.H. Johansson ◽

S. Sergejeva ◽

J.J. Lee ◽

J. Lotvall

Keyword(s):

Bone Marrow ◽

Airway Inflammation ◽

Allergic Airway Inflammation ◽

Inflammatory Cells

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Ultrafine Carbon Black Particles Cause Early Airway Inflammation and Have Adjuvant Activity in a Mouse Allergic Airway Disease Model

Toxicological Sciences ◽

10.1093/toxsci/kfi255 ◽

2005 ◽

Vol 87 (2) ◽

pp. 409-418 ◽

Cited By ~ 48

Author(s):

Colin de Haar ◽

Ine Hassing ◽

Marianne Bol ◽

Rob Bleumink ◽

Raymond Pieters

Keyword(s):

Carbon Black ◽

Airway Inflammation ◽

Disease Model ◽

Airway Disease ◽

Allergic Airway Disease ◽

Adjuvant Activity

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Airway exposure to staphylococcal enterotoxin A potentiates allergen-induced bone marrow eosinophilia and trafficking to peripheral blood and airways

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00025.2013 ◽

2013 ◽

Vol 304 (10) ◽

pp. L639-L645 ◽

Cited By ~ 2

Author(s):

Dalize M. Squebola-Cola ◽

Glaucia C. Mello ◽

Lorenzo Pissinatti ◽

André A. Schenka ◽

Gabriel F. Anhê ◽

...

Keyword(s):

Bone Marrow ◽

Cell Adhesion ◽

Peripheral Blood ◽

Airway Disease ◽

Peripheral Circulation ◽

Staphylococcal Enterotoxin ◽

Allergic Airway Disease ◽

Staphylococcal Enterotoxin A ◽

Gm Csf ◽

Macrophage Colony

Bone marrow (BM) eosinopoiesis is a common feature during allergen exposure in atopic individuals. Airway exposure to staphylococcal superantigens aggravates allergic airway disease and increases the output of BM eosinophils. However, the exact mechanisms regulating eosinophil mobilization and trafficking to the peripheral circulation and airways remain to be elucidated. Therefore, this study aimed to investigate the mechanisms determining the BM eosinopoiesis in allergic mice under exposure to staphylococcal enterotoxin A (SEA). Ovalbumin (OVA)-sensitized male BALB/C mice were intranasally exposed to SEA (1 μg), and at 4, 12, 24, and 48 h later animals were challenged with OVA (10 μg, twice a day). Measurement of IL-5, eotaxin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels, flow cytometry for CCR3+, VLA4+, and CCR3+VLA4+, as well as adhesion assays to VCAM-1 were performed in BM. Prior airway exposure to SEA time dependently increased the BM eosinophil number in OVA-challenged mice. Eosinophils gradually disappear from peripheral blood, being recruited over time to the airways, where they achieve a maximal infiltration at 24 h. SEA exposure increased the levels of IL-5 and eotaxin (but not GM-CSF) in BM of OVA-challenged mice. Marked increases in CCR3+and CCR3+VLA4+expressions in BM eosinophils of OVA-challenged mice were observed, an effect largely reduced by prior exposure to SEA. Adhesion of BM eosinophils to VCAM-1 was increased in OVA-challenged mice, but prior SEA exposure abrogated this enhanced cell adhesion. Accumulation of BM eosinophils by airway SEA exposure takes place through IL-5- and CCR3-dependent mechanisms, along with downregulation of CCR3/VL4 and impaired cell adhesion to VCAM-1.

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