Resistance to antigen-induced airway hyperresponsiveness requires endogenous production of IL-12 (original) (raw)
Related papers
IL-12 Contributes to Allergen-Induced Airway Inflammation in Experimental Asthma
The Journal of Immunology, 2006
Lack of sufficient IL-12 production has been suggested to be one of the basic underlying mechanisms in atopy, but a potential role of IL-12 in established allergic airway disease remains unclear. We took advantage of a mouse model of experimental asthma to study the role of IL-12 during the development of bronchial inflammation. Administration of anti-IL-12p35 or anti-IL-12p40 mAb to previously OVA-sensitized BALB/c mice concomitantly with exposure to nebulized OVA, abolished both the development of bronchial hyperresponsiveness to metacholine as well as the eosinophilia in bronchoalveolar lavage fluid and peripheral blood. Anti-IL-12 treatment reduced CD4 ؉ T cell numbers and IL-4, IL-5, and IL-13 levels in the bronchoalveolar lavage fluid and the mRNA expression of IL-10, eotaxin, RANTES, MCP-1, and VCAM-1 in the lung. Anti-IL-12p35 treatment failed to show these effects in IFN-␥ knockout mice pointing to the essential role
Regulation of Allergic Mucosal Sensitization by Interleukin-12 Gene Transfer to the Airway
American Journal of Respiratory Cell and Molecular Biology, 1999
Expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in the airway allows allergic sensitization to ovalbumin (OVA) in an experimental protocol that others have shown to induce inhalation tolerance. The ensuing response is characterized by T helper (Th)2 cytokines, marked eosinophilia in the bronchoalveolar lavage fluid (BALF) and the tissue, and goblet-cell hyperplasia. These findings, which underscore the importance of the airway microenvironment in the development of immune responses to airborne antigens, prompted us to investigate whether a Type 1 polarized cytokine milieu in the airway would modulate the allergic sensitization. To this end, we concurrently expressed GM-CSF and interleukin (IL)-12 in the airway, using an adenovirus-mediated gene transfer approach. Coexpression of IL-12 did not prevent the development of an antigen-specific immune inflammatory response, but altered its phenotype. Whereas a similar total cell number was observed in the BALF, airway eosinophilia was abrogated. Histologic evaluation of the tissue corroborated the findings in the BALF and demonstrated that IL-12 coexpression prevented goblet-cell hyperplasia. Expression of IL-12 decreased IL-4 and IL-5 content in the BALF by about 80 and 95%, respectively, and IL-5 in the serum by approximately 80%. In contrast, interferon (IFN)-␥ was increased in both BALF and serum. Similarly, we observed a Th2/Th1 shift in OVA-specific cytokine production in vitro. Recall challenge with OVA in vivo after resolution of the initial inflammatory response demonstrated that the effect of IL-12 was persistent. IL-12-mediated inhibition of airway eosinophilia was mainly IFN-␥-independent, whereas inhibition of OVA-specific IgE synthesis was IFN-␥-dependent. Our data underscore the importance of the airway microenvironment in the elicitation of immune responses to environmental antigens.
Journal of Allergy and Clinical Immunology, 1998
Background: Systemic administration of IL-12 can prevent airway hyperresponsiveness (AHR) in mice after sensitization and repeated allergen challenge. However, systemic IL-12 has been associated with severe adverse effects. Objective: We determined whether IL-12 administration to the airways in a dose sufficiently low so as not to result in systemic effects can modify allergic inflammation and AHR after allergen challenge. Methods: Mice were sensitized to ovalbumin by intraperitoneal injection and challenged with ovalbumin aerosol on 3 consecutive days. During the period of challenge, IL-12 was administered intranasally following 2 regimens, designated high (500 ng) or low (50 ng). We monitored airway responsiveness to inhaled methacholine by barometric body plethysmography, lung inflammatory cells, local cytokine production, and, to assess systemic effects of IL-12 treatment, spleen weights and numbers of eosinophils in the bone marrow. Results: Allergen challenge resulted in increases in airway responsiveness and in numbers of lung eosinophils. These increases were prevented by both high-and low-dose IL-12. Additionally, IL-12 administration resulted in enhanced local interferon-γ production and prevented the increases in local IL-4 and IL-5 production after airway challenge. A high dose, but not a low dose, of IL-l2 resulted in increased spleen weights and prevented the increase in numbers of bone marrow eosinophils after allergen challenge. Conclusion: These data indicate that local administration of IL-12 can prevent AHR and reduce lung eosinophilia after allergen challenge in sensitized mice without eliciting systemic adverse effects. IL-12 exerts these effects by inducing local T H1 -type responses in the airways in a setting that is normally dominated by T H2 -type responses. (J Allergy Clin Immunol 1998;102:86-93.)
International Immunopharmacology, 2003
IL-12 modulates T cell responses between helper T cells Th2 and Th1; however, the therapeutic potential of IL-12 for allergic diseases either directly or as an adjuvant in allergen therapy has been controversial. The role of intranasal IL-12 as an adjuvant in modulating the grass pollen allergen (GAL) therapy-induced systemic immune response and lung-specific inflammation and airway reactivity was examined in this study using a mouse model of established allergic asthma. The effects of intranasal or nebulized IL-12 with or without intranasal anti-IFN-g antibody were examined in groups of control and allergen-sensitized or-challenged mice. T cell cytokine patterns, antibody response profiles, pulmonary inflammation and airway reactivity were examined. Intranasal IL-12 was found to be more effective in the Th2-Th1 shifting of immune response and anti-inflammatory activity in the lung compared to nebulized IL-12 at the given doses. Intranasal IL-12 significantly decreased production of IFN-g, eotaxin and LTC4/D4/E4 in the lung and decreased eosinophil infiltration, resulting in attenuated airway hyper-responsiveness in GAL-sensitized (GS) mice. In contrast, intranasal IL-12 significantly increased IFN-g production in the thoracic lymph node cultures and decreased the IL-5/IFN-g ratio, suggesting a Th2-Th1 shift. Also, intranasal IL-12 increased GAL-specific IgG2a antibody response, while the IgE response remained unaffected. The systemic effects of IL-12 were IFN-g dependent. IL-12 induces differential expression of its own receptor h1 and h2 subunits in the lung tissues to augment IL-12 responsiveness. Together, these results demonstrate that intranasal IL-12 is effective in shifting the systemic immune response in the direction of Th1 in IFN-g-dependent manner, while decreasing pulmonary inflammation and airway reactivity independent of IFN-g. Thus, intranasal delivery of IL-12 may provide an approach for the treatment of asthma and may be useful as an adjuvant in local nasal immunotherapy (IT) and in asthma.
Clinical & Experimental Allergy, 2007
T-helper type 2 (Th2)-derived cytokines such as IL-4, IL-5, IL-9 and IL-13 play an important role in the synthesis of IgE and in the promotion of allergic eosinophilic inflammation and airway wall remodelling. We determined the importance of IL-13 alone, and of the four Th2 cytokines together, by studying mice in which either IL-13 alone or the Th2 cytokine cluster was genetically disrupted. The knock-out mice and their BALB/c wild-type (wt) counterparts were sensitized and repeatedly exposed to ovalbumin (OVA) aerosol. Bronchial responsiveness measured as the concentration of acetylcholine aerosol needed to increase baseline lung resistance by 100% (PC100) was decreased in IL-13-/-, but increased in IL-4/5/9/13-/- mice. Chronic allergen exposure resulted in airway hyperresponsiveness (AHR) in wt mice but not in both genetically modified mice. After allergen exposure, eosinophil counts in bronchoalveolar lavage fluid and in airways mucosa, and goblet cell numbers were not increased in IL-4/5/9/13-/- mice, and were only attenuated in IL-13-/- mice. Airway smooth muscle (ASM) hyperplasia after allergen exposure was prevented in both IL-13-/- and IL-4/5/9/13-/- mice to an equal extent. Similarly, the rise in total or OVA-specific serum IgE levels was totally inhibited. IL-13 is mainly responsible for AHR, ASM hyperplasia and increases in IgE, while IL-4, -5 and -9 may contribute to goblet cell hyperplasia and eosinophilic inflammation induced by chronic allergen exposure in a murine model. Both redundancy or complementariness of Th2 cytokines can occur in vivo, according to specific aspects of the allergic response.
2006
Background: An increasing prevalence of allergic diseases, such as atopic dermatitis, allergic rhinitis and bronchial asthma, has been noted worldwide. Allergic asthma strongly correlates with airway inflammation caused by the unregulated production of cytokines secreted by allergenspecific type-2 T helper (Th2) cells. This study aims to explore the therapeutic effect of the airway gene transfer of IL-12, IL-10 and TGF-β on airway inflammation in a mouse model of allergic asthma. Methods: BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injections with OVA and challenged by nebulized OVA. Different cytokine gene plasmids or non-coding vector plasmids were instilled daily into the trachea up to one day before the inhalatory OVA challenge phase. Results: Intratracheal administration of IL-10, IL-12 or TGF-β can efficiently inhibit antigeninduced airway hyper-responsiveness and is able to largely significantly lower the number of eosinophils and neutrophils in bronchoalveolar lavage fluid of ovalbumin (OVA) sensitized and challenged mice during the effector phase. Furthermore, the effect of IL-10 plasmids is more remarkable than any other cytokine gene plasmid. On the other hand, local administration of IL-4 gene plasmids before antigen challenge can induce severe airway hyper-responsiveness (AHR) and airway eosinophilia. Conclusion: Our data demonstrated that anti-inflammatory cytokines, particularly IL-10, have the therapeutic potential for the alleviation of airway inflammation in murine model of asthma.
Allergy, 2000
Background: Airway allergen exposure causes local eosinophilic cell in®ltration. This cellular in¯ammatory response is likely to involve the release of eosinophils from peripheral storage pools, and possibly also regeneration of eosinophils in the bone marrow. IL-12 is an inhibitory cytokine in allergic in¯ammation, shown to reduce eosinophilic cell in®ltration. The aim of the present study was to determine whether airway allergen exposure increases bone marrow eosinophil production, and, if so, whether IL-12 modulates this effect. Methods: Ovalbumin-sensitized C57BL/6 mice and IL-12 knockout (KO) mice were exposed to allergen via the airway route, and the in¯ammatory cell response was evaluated in bronchoalveolar lavage¯uid, blood, and bone marrow. Results: Allergen instillation intranasally produced a dose-dependent in¯ammatory response in the lower airways of sensitized mice. This in¯ammatory response was dominated by eosinophils, but there were also increases of both lymphocytes and neutrophils. Sensitization and airway allergen exposure also increased the IL-5-dependent growth of bone marrow cells in vitro. The enhanced bone marrow responsiveness in vitro was paralleled by an increased number of bone marrow eosinophils in vivo. After sensitization and repeated allergen exposure, IL-12 KO mice showed higher eosinophil levels in both BAL and bone marrow than parallel wild-type control mice. Furthermore, BAL-eotaxin levels were increased in IL-12 KO mice as opposed to parallel wild-type controls after allergen exposure. Conclusions: Airway allergen exposure induced systemic immunologic responses, including increased eosinophil numbers in both airways and bone marrow, and also enhanced IL-5 responsiveness in bone marrow cells. IL-12 may regulate airway eosinophilia at both the level of eosinophilopoiesis and the level of local recruitment of eosinophils into the airways.
Journal of Allergy and Clinical Immunology, 1999
Background: IL-2 has been shown to increase allergic airway responses in rats. Objective: The purpose of this study was to investigate whether induction of inflammation and enhancement of cysteinyl-leukotriene (cys-LT) synthesis were involved in the augmentation of airway responses caused by IL-2. Methods: Brown Norway rats received human recombinant IL-2 or saline subcutaneously twice a day from day 9 to day 14 after sensitization to ovalbumin (OVA). On day 14, rats underwent either lung lavage or were challenged with an aerosol spray of OVA, the airway responses and biliary excretion of cys-LTs were measured for a period of 8 hours after challenge, and the lung leukocyte numbers were determined after enzymatic digestion of lung tissues. Results: The early response after OVA increased from 184.2% ± 13.5% in the animals receiving saline (n = 10) to 309% ± 51% (baseline lung resistance) in IL-2-pretreated animals (n = 17; P < .05). The late response also increased from 19.6 ± 4.5 (area under the curve of baseline lung resistance vs time) in the animals receiving saline to 37 ± 5.4 after administration of IL-2 (P < .05). However, IL-2-treated animals had lower levels of biliary cys-LTs during the late response than saline-treated animals but similar levels during the early response. This difference could not be attributed to an increase in LT metabolism, which we assessed by the recovery of 3 H-LTC 4 instilled intratracheally in challenged or unchallenged rats. When compared with control animals, pretreatment with IL-2 increased all cell types retrieved from lung lavage fluid before OVA challenge (P < .05). After OVA challenge, the total cell yield from lung lavage fluid was also increased, mostly because of an increase in neutrophils (P < .05). Eosinophils and lymphocytes were greater in the lungs of IL-2-treated than vehicle-treated and OVA-challenged rats (P < .01), and IL-2-treated rats had a lower CD4 + /CD8 + ratio in the blood after challenge (P < .001). Conclusion: In conclusion, IL-2 increases early and late responses in rats, and it induces lung inflammation. Altered airway responses are not attributable to an increase in cys-LT production. (J Allergy Clin Immunol 1999;104:145-52.)
Lack of IL-12 signaling in human allergen-specific Th2 cells
Journal of immunology (Baltimore, Md. : 1950), 1996
IL-12 is a powerful skewer of CD4+ T cell responses toward the Th1 phenotype by inducing IFN-gamma production in naive Th cells. In the present study we addressed the question of whether IL-12 can reverse established Th2 responses into Th1/Th0 responses by inducing IFN-gamma production in memory Th2 cells. To this aim, allergen-specific CD4+ T cell clones (TCC) were generated from the peripheral blood of three atopic patients, and their cytokine profiles were analyzed. The majority of these TCC exhibited a strongly polarized Th2 cytokine profile, and the production of IFN-gamma could not be induced by exogenous IL-12. Only those TCC with low IFN-gamma levels in the absence of IL-12 responded to IL-12 by additional enhancement of IFN-gamma production. The IL-12 nonresponsiveness of the Th2 clones was further evident by the total lack of IL-12-induced phosphorylation of STAT4 (signal transducer and activator of transcription-4), a transcription factor that is typically involved in IL-...
Allergen-induced Th2-independent production of IL-4 in the airways of mice
Matters (Zürich), 2016
It is thought that release of cytokines from allergen-damaged epithelial cells induces production of an innate source of IL-4 and IL-13 that are important in initiating adaptive T-helper type II (Th2)-mediated allergic responses. However, detecting innate production of IL-4 or IL-13 in vivo is difficult due to high levels of adaptive production of IL-4 and IL-13 by Th2 cells. The IL-4 receptor (IL-4R) and the IL-4/13 co-receptor (IL-13R) share a common receptor subunit (IL-4Ra). Consequently, both IL-4 and IL-13 signal via the IL-4Ra-associated signaling molecule, signal transducer and activator of transcription factor 6 (STAT6). STAT6 signaling in T-cells, B-cells, and airway epithelial cells is essential for Th2 differentiation, isotype class switching to IgE, and mucus production, respectively. Therefore, Epi-STAT6 mice (STAT6-/-mice with airway epithelial-specific transgenic STAT6 expression) are defective in Th2 immune responses but can produce mucus in response to IL-4 and/or IL-13 in their airways. As compared to wildtype mice, allergen-challenged Epi-STAT6 mice were deficient in IgE production and the levels of IL-13 expressed were not above appropriate controls. However, significant levels of IL-4 and mucin gene expression were detected in their lungs. These observations support the existence of an allergen-responsive, non-Th2-derived source of IL-4 in the airways of mice.