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To investigate the cellular immune events contributing to airway hyperreactivity (AHR), we studied an in vivo mouse model induced by the hapten picryl (trinitrophenyl) chloride (PCl). Mice were immunized by cutaneous contact sensitization with PCl and airway challenged subsequently with picryl sulfonic acid (PSA) antigen (Ag). Increased airway resi...
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Hydrogen sulfide (H2S) has been shown to act as both anti-inflammatory and pro-inflammatory mediators. Application of H2S donors generally protects against inflammation; however, experimental results using mice lacking endogenous H2S-producing enzymes, such as cystathionine γ-lyase (CTH) and mercaptopyruvate sulfurtransferase (MPST), are often cont...
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... In addition, AHR did not occur after transfer of the Ag-specific IgE antibody. All of these findings suggest non-atopic mechanism of PCLinduced response (Geba et al., 1997). In another study, sensitization and challenge with PCL was described as a delayed-type hypersensitivity (DTH) reaction. ...
Asthma is a chronic inflammatory disorder of the respiratory tract that is characterized by reversible airflow obstruction and airway hyperresponsiveness. The non-atopic variant of asthma that appears later in life has no allergic background and is more severe and resistant to standard treatment. Hapten-induced asthma models can be utilized to investigate mechanisms behind the development of non-atopic and occupational asthma, in which non-allergic processes seems to play significant role. The development of adequate animal models of non-allergic asthma is a necessary prerequisite both for understanding the pathophysiology of non-allergic asthma and for the possibility of testing new therapies. Still, there is no ideal model that represents all the hallmarks of this complex disease. In this review, we examine the most popular hapten-induced murine models of occupational and non-atopic asthma. For this reason, we describe the most popular sensitizing haptens, sensitization and challenge protocols, symptoms produced by asthma, and advantages and disadvantages of the models.
... Very importantly, suppression was restored by coating of these non-suppressive exosomes from tolerized JH −/− mice with monoclonal Ab light chains [2]. Of related translational clinical significance, in our prior work on immediate hypersensitivity, on models of CHS [198] and asthma [199], induced by cutaneous sensitization with hapten or protein [200], the rapid activation of the small subpopulation of Ag-specific special B1a cells induced early after immunization was observed in all of these instances. Their activation resulted in production of Ag-specific IgM Ab and the Ag-specific Ab light chains that coat the Ts cellderived exosomes and that have the additional ability to sensitize cells; so far principally mast cells by surface coating for mediator release when Ag is added, in an analogous manner to IgE Ab [201]. ...
Extracellular vesicles, such as exosomes, are newly recognized intercellular conveyors of functional molecular mechanisms. Notably, they transfer RNAs and proteins between different cells that can then participate in the complex pathogenesis of allergic and related hypersensitivity responses and disease mechanisms, as described herein. This review highlights this important new appreciation of the in vivo participation of such extracellular vesicles in the interactions between allergy-mediating cells. We take into account paracrine epigenetic exchanges mediated by surrounding stromal cells and the endocrine receipt of exosomes from distant cells via the circulation. Exosomes are natural ancient nanoparticles of life. They are made by all cells and in some form by all species down to fungi and bacteria, and are present in all fluids. Besides a new focus on their role in the transmission of genetic regulation, exosome transfer of allergens was recently shown to induce allergic inflammation. Importantly, regulatory and tolerogenic exosomes can potently inhibit allergy and hypersensitivity responses, usually acting nonspecifically, but can also proceed in an antigen-specific manner due to the coating of the exosome surface with antibodies. Deep analysis of processes mediated by exosomes should result in the development of early diagnostic biomarkers, as well as allergen-specific, preventive and therapeutic strategies. These will likely significantly diminish the risks of current allergen-specific parenteral desensitization procedures, and of the use of systemic immunosuppressive drugs. Since extracellular vesicles are physiological, they can be fashioned for the specific delivery of therapeutic molecular instructions through easily tolerated, noninvasive routes, such as oral ingestion, nasal administration, and perhaps even inhalation.
... PCl-F is produced within hours of contact immunization by the activated B-1 B cells. Amongst other proteins, this PCL-F contained antigenspecific IgM [32][33][34][35][36][37][38][39][40][41]. In fact, monoclonal anti-TNP IgM myeloma proteins could substitute for PCl-F in reconstitution of CS in JH -/pan immunoglobulin deficient mice. ...
Mast cells are increasingly recognized as critical players in elicitation and maintenance of different inflammatory related disorders, like allergy, autoimmune diseases and cancer. Mast cells maturate within the tissue and are able to adapt to microenvironmental changes. Together with the ability to produce multiple pro- and anti-inflammatory mediators upon activation, mast cells are highly capable of exerting immunomodulatory functions. Cross-linking of receptor bound IgE is the best known mechanism of antigen-specific mast cell activation. In this review we focus on a different route of activation, via immunoglobulin free light chains (FLCs). Here, we describe current knowledge and concepts on FLCs based on preclinical models and data on human subjects, after briefly recapitulating early research findings on FLCs. Furthermore, because FLC research mainly focuses on mast cells, several mast cell mediated pathologies and mouse models for mast cell research will be discussed. Whether targeting of mast cells is beneficial for the treatment of specific disorders has to be addressed in future studies. Specific inhibition of FLC-mediated mast cell activation may be an interesting avenue to treat chronic inflammatory diseases.
... The features observed in these murine models resemble those found in non-atopic asthma and are hapten-induced acute bronchoconstriction, pulmonary edema, infiltration of neutrophils and mononuclear cells, in vitro tracheal hyperresponsiveness and in vivo airway hyperresponsiveness. Both the early (< 3 h) and the late (24 to 48 h) phases of the hapten-induced pulmonary reaction were found to depend on the presence of T lymphocytes, since in athymic mice airway hyperreactivity and cellular accumulation were suppressed (10,12,15). ...
Three models/protocols designed to mimic an inflammation process characteristic of a specific lung disease are described in this unit. Included are a single allergen inhalation in monkeys to model acute asthmatic episodes, repeated allergen inhalations in monkeys to model chronic asthma, and a lower-respiratory viral infection in mice to model acute and chronic viral alveolitis and bronchitis. In each case, alterations in lung functions believed to correlate with symptoms of the respective disease are measured along with pulmonary inflammation.
Stat3, Socs3 and cytokines play an integral role in the coordination and persistence of inflammation. However, a clear understanding of the role played by the Stat3/IL-6 and Socs3 pathway in airway inflammation is lacking. We report the alteration in the status of expression and activation of Stat3 by ovalbumin (OVA), and establish its relationship with Socs3 and IL-6 in the lungs of mice with eosinophilic pulmonary inflammation and airway hyperresponsiveness.
Alterations in the expression of Stat3, Socs3 and IL-6 were determined in a murine model of asthma, where Balb/c mice were sensitized and challenged with OVA (OVA/OVA) and compared with control mice sensitized and challenged with saline (SAL) (SAL/SAL) mice. The OVA/OVA mice were characterized by a moderate increase in methacholine-induced specific airway resistance, the presence of 150 microg/ml of OVA-specific IgG and 8.93 microg/ml OVA-specific IgE antibody and elevated levels of eosinophils and Th2 cytokines (IL-4 and IL-5) in the bronchoalveolar lavage fluid. In contrast SAL/SAL mice had low eosinophils, IL-4 and IL-5 and no OVA-specific IgG and IgE antibodies in the BALF. Stat3 and Socs3 expression profiles were monitored in OVA/OVA and Stat3- and Socs3-silenced OVA/OVA mice. Furthermore, expression of IL-6 in Stat3- and Socs3-silenced mice and the exogenous effect of IL-6 on Stat3 were studied.
The results show that expression and activation of Stat3 mRNA and proteins are significantly low in lung of OVA/OVA mice in comparison to SAL/SAL mice following OVA challenge. An increased pool of Socs3 mRNA is observed in OVA/OVA mice with or without OVA challenge and in SAL/SAL mice 24 h after OVA challenge. Transient in vivo blocking of Socs3 gene by Socs3 siRNA restores the expression of IL-6 mRNA and protein in OVA/OVA mice, and nasal administration of recombinant IL-6 to OVA/OVA mice enhanced Stat3 mRNA expression.
Our data suggest that airway inflammation is associated with low expression of Stat3 and IL-6 and overexpression of Socs3 genes in a mouse model of asthma. Furthermore, IL-6 is under the influence of the Socs3 gene and may contribute to the negative regulation of Stat3 via IL-6 following a challenge with an allergen during the development of asthma.
We have uncovered a role for B-1-B-cell-produced IgM antibody, in the initiation of contact sensitivity (CS) in mice. CS and delayed-type hypersensitivity (DTH) involve recruitment of T cells to the tissues, to be activated by antigen-presenting cells (APC), and then make cytokines. Little is known about low recruitment is initiated. In CS, soon after immunization, the unique B-1 cell subset, responsible for the formation of most IgM, is activated to produce antigen (Ag)-specific IgM for export to tissues. IgM forms complexes with challenge Ag, activating the classical complement (C) pathway, generating C5a, to activate endothelium directly, or indirectly via C5a receptors (R) on mast cells and platelets, that release vasoactive amines (serotonin) and cytokines (TNF-alpha). These act together to induce vasodilatation, vascular permeability and expression of endothelial adhesion molecules to promote optimal T cell recruitment.
New findings that established this pathway include: (1) absent CS response in C-deficient, or C-inhibited mice; (2) local generation of C5a in CS tissue extracts; (3) absent CS in C5aR-/- mice; (4) decreased CS in B cell and B-1-cell-deficient mice, and (5) reconstitution of CS by transfer of B-1 cells, or hapten-specific IgM.
These findings indicate that the B-1 subset producing Ag-specific IgM is required early in CS to activate C, to induce vasoactive mediators that initiate local T recruitment.
The mechanisms regulating airway function are complex and still poorly understood. In diseases such as asthma, involvement of immune-dependent mechanisms has been suggested in causing changes in airway responsiveness to bronchoconstrictors. We now demonstrate that gammadelta T cells can regulate airway function in an alphabeta T cell-independent manner, identifying them as important cells in pulmonary homeostasis. This function of gammadelta T cells differs from previously described immune-dependent mechanisms and may reflect their interaction with innate systems of host defense.
With over 50 potential asthma mediators, cytokines are the latest group of substances which have been investigated for their potential role in this disease. The use of murine models of allergic inflammation has facilitated the investigation of the role of individual cytokines in this response. The use of targeted gene disruption, overexpression of genes and monoclonal antibodies directed against cytokines have allowed a detailed examination of the role cytokines play in IgE production, eosinophil recruitment and bronchial hyperresponsiveness, which are the characteristic features of the asthma phenotype. Despite the introduction of this new methodology, conflicting reports relating to the role of cytokines in allergic inflammation, highlight the complexity of allergic inflammation and challenge the notion that a single cytokine can explain the asthma phenotype.
