Recent insights into pathogenesis and control of asthma and atopic diseases.
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Animals↗
Biomedical subjects
M Wills-Karp
Publications and source records attributed to M Wills-Karp.
Immunologic basis of antigen-induced airway hyperresponsiveness.
The incidence, morbidity, and mortality of asthma has increased worldwide over the last two decades. Asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), and airway inflammation. The inflammatory response in the asthmatic lung is characterized by infiltration of the airway wall with mast cells, lymphocytes, and eosinophils. Although asthma is multifactorial in origin, the inflammatory process in the most common form of the disease (extrinsic asthma) is believed to be a result of inappropriate immune responses to common aero-allergens in genetically susceptible individuals. As such, it has been hypothesized that CD4+ T cells that produce a Th2 pattern of cytokines play a pivotal role in the pathogenesis of this disease. Through the release of cytokines such as IL-4, IL-13, and IL-5, these cells orchestrate the recruitment and activation of the primary effector cells of the allergic response, the mast cell and the eosinophil. Activation of these cells results in the release of a plethora of inflammatory mediators that individually or in concert induce changes in airway wall geometry and produce the symptoms of the disease. The aim of this review is to discuss our current understanding of the pathophysiologic mechanisms by which Th2 cytokines induce airway disease, and the factors that predispose to the generation of these pathogenic cells in response to inhalation of ubiquitous aero-allergens. Elucidation of the exact immunological basis for allergic asthma may yield immunotherapeutic strategies to reverse the development of pathogenic Th2-mediated immune responses and reduce the morbidity and mortality associated with this disease.
Allergens↗
The environment and asthma in U.S. inner cities.
The prevalence and severity of asthma has increased in the last 20 years, and the greatest increase has been seen among children and young adults living in U.S. inner cities. The reasons for this increase are obviously complex, but include environmental exposures to allergens and pollutants, changing patterns of medication, and the psychosocial stresses of living in poor inner-city neighborhoods. This paper presents an overview of environmental, immunologic, and genetic factors associated with asthma morbidity and mortality. This overview can be used to provide a framework for designing an interdisciplinary research program to address the complexities of asthma etiology and exacerbation. The strongest epidemiologic association has been found between asthma morbidity and the exposure of immunologically sensitive asthmatic patients to airborne allergens. Our current understanding of the process of sensitization suggests that there is a strong genetic predisposition to form IgE to allergenic proteins on airborne particles. Much of this work has been conducted with animal models, but in a number of instances, specific confirmation has been reported in humans. Sensitized individuals respond to inhaled exposure with immediate mast-cell dependent inflammation that may be augmented by pollutant particles, especially diesel exhaust particles. Relatively little is known about the methods of assessing exposure to airborne pollutants, especially biologically active particulates. However, to examine the relationship of morbidity in genetically predisposed individuals, it will be important to determine the most relevant method of making this assessment.
Adult↗
Interleukin-13: central mediator of allergic asthma.
The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4(+) T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.
Allergens↗
Resistance to antigen-induced airway hyperresponsiveness requires endogenous production of IL-12.
We have demonstrated previously that susceptibility of murine strains to the development of allergic airway responses is associated with a type 2 cytokine pattern. In the present study, we examine the in vivo role of IL-12 in the immune response to allergen exposure in susceptible (A/J) and resistant (C3H/HeJ, C3H) strains of mice. OVA sensitization and challenge induced significant increases in airway reactivity in A/J mice as compared with their PBS-challenged controls, while no increases in airway reactivity were observed in OVA-challenged C3H mice. OVA exposure of A/J mice resulted in marked increases in the Th2 cytokines, IL-4 and IL-10, in the bronchoalveolar lavage fluid, whereas increases in IFN-gamma were observed in C3H mice. Strikingly, anti-IL-12 mAb (1 mg/mouse) treatment resulted in threefold increases in airway reactivity in OVA-challenged resistant C3H mice, concomitant with significant increases in bronchoalveolar lavage levels of Th2 cytokines and decreases in IFN-gamma. IL-12 depletion of C3H mice also suppressed OVA-specific serum IgG2a levels and increased both serum OVA-specific IgG1 and IgE levels. Blockade of endogenous IL-12 levels in susceptible A/J mice resulted in further augmentation of type 2 immune responses. These results demonstrate that endogenous production of IL-12 is essential for resistance to Ag-induced airway hyperresponsiveness, and furthermore, that dysregulation of IL-12 production may lead to the development of deleterious type 2 immune responses to inhaled allergens.
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Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production.
The pleiotropic cytokine interleukin 4 (IL-4) has been shown to regulate many processes thought to be important in the allergic diathesis. To determine the mechanism(s) by which IL-4 mediates allergic airway responses to inhaled allergens, we compared the effects of antigen sensitization and challenge on the development of allergic airway responses in mice in which the gene for the signal transducer and activator of transcription factor 6 (Stat6) was disrupted to those of their wild-type littermates. Strikingly, Stat6-deficient mice failed to develop airway hyperresponsiveness (AHR), which was observed in their wild-type littermates after allergen provocation. Moreover, antigen-induced increases in mucus-containing cells were found to be completely Stat6 dependent. Consistent with the lack of Th2 cytokine responses in Stat6-deficient mice, no ovalbumin-specific immunoglobulin (Ig)E was detected in their serum. In contrast, Stat6 signaling only partially mediated antigen-induced eosinophilia with no role in vascular adhesion molecule 1 expression. These results indicate that Stat6 signal transduction is critical in the development of allergen-induced AHR and that agents that specifically inhibit this pathway may provide a novel strategy for the treatment of allergic disorders.
Animals↗
Development of murine allergic asthma is dependent upon B7-2 costimulation.
Allergic asthma is thought to be mediated by CD4+ T lymphocytes producing the Th2-associated cytokines, IL-4, and IL-5. Recently, the costimulatory molecules B7-1 and B7-2, which are expressed on the surface of APC, have been suggested to influence the development of Th1 vs Th2 immune responses. We examined the in vivo role of these costimulatory molecules in the pathogenesis of Th2-mediated allergen-induced airway hyperresponsiveness in a murine model of asthma. In this model, OVA-sensitized A/J mice develop significant increases in airway responsiveness, pulmonary eosinophilia, and pulmonary Th2 cytokine expression following aspiration challenge with OVA as compared with PBS-control animals. Strikingly, administration of anti-B7-2 mAb to OVA-treated mice abolished allergen-induced airway hyperresponsiveness, pulmonary eosinophilia, and elevations in serum IgG1 and IgE levels. Anti-B7-2 treatment of OVA-treated mice reduced both total lung IL-4 and IL-5 mRNA and bronchoalveolar lavage fluid IL-4 and IL-5 protein levels, with no significant changes in IFN-gamma message or protein levels. In contrast, treatment with anti-B7-1 mAbs had no effect on allergen-induced airway hyperresponsiveness, IgE production, or cytokine production, however, it significantly suppressed pulmonary eosinophilia. We conclude that B7-2 provides the necessary costimulatory signal required for the development of in vivo allergic responses to inhaled allergen exposure.
Animals↗
Interleukin-12 as a target for modulation of the inflammatory response in asthma.
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Asthma↗
B7-CD28/CTLA-4 costimulatory pathways are required for the development of T helper cell 2-mediated allergic airway responses to inhaled antigens.
We have previously demonstrated that the development of allergen-induced airway hyperresponsiveness in a murine model is CD4+ T cell dependent. In the present study, we examined the role of the B7/CD28-CTLA4 costimulatory T cell activation pathway in the pathogenesis of allergen-induced airway hyperresponsiveness in this murine model. Sensitized A/J mice develop significant increases in airway responsiveness, bronchoalveolar lavage eosinophils, serum IgE levels, and Th2-associated cytokine production following aspiration challenge with OVA. Administration of CTLA4-Ig either before Ag sensitization or before pulmonary Ag challenge abolished Ag-induced airway hyperresponsiveness and pulmonary eosinophilia. Examination of cytokine protein levels in the bronchoalveolar lavage showed a significant decrease in the level of the Th2 cytokine, IL-4, after CTLA4-Ig treatment either before sensitization or before challenge, with no significant change in the concentration of the Th1 cytokine, IFN-gamma. Further, the Ag-specific Ab isotypes IgG1 and IgE were significantly decreased in animals treated with CTLA4-Ig before challenge, while there was no significant change in the IgG2a Ab isotype. These data demonstrate that administration of CTLA4-Ig is effective in ablating allergen-induced airway dysfunction concomitant with a significant reduction in the Th2 response. We conclude that B7/CD28-CTLA-4 costimulation is required for the development of many of the immunologic and physiologic features of asthma, possibly by promoting a pathologic type 2-associated response.
Abatacept↗
Smooth muscle as a direct or indirect target accounting for bronchopulmonary hyperresponsiveness.
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Animals↗
Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice.
The functional role of interleukin (IL)-4 in the development of airway hyperresponsiveness (AHR) and pulmonary eosinophilia in response to sensitization and challenge of mice with sheep red blood cells (SRBC) was examined. Control- and SRBC-sensitized A/J mice were treated with an antibody to the murine IL-4 receptor (anti-IL-4R) 3 days before intratracheal challenge with the antigen or vehicle only. Blockade of IL-4R significantly reduced antigen-induced AHR and prevented increases in goblet cells and bronchoalveolar lavage (BAL) eosinophils. Treatment with anti-IL-4R did not affect antigen-induced increases in lung mRNA and BAL protein levels of IL-5 and interferon-gamma or IL-4 mRNA but did significantly increase IL-4 protein levels. Antigen-induced AHR was not reduced by treatment with antibodies to the adhesion molecules, vascular cell adhesion molecule-1 and very late activation antigen-4. Administration of IL-4 over a 7-day period did not increase airway reactivity or induce any changes in BAL cell numbers in naive mice. These results demonstrate that IL-4 is necessary for in vivo development of antigen-induced AHR, goblet cell metaplasia, and pulmonary eosinophilia.
Animals↗
The genetics of allergen-induced airway hyperresponsiveness in mice.
Airway hyperresponsiveness (AHR) is a fundamental aspect of asthma that has been shown to be influenced by both environmental and genetic factors. Antigen sensitization and challenge of the A/J inbred mouse strain induced AHR, eosinophilic airway inflammation, and lung goblet cell hyperplasia. We discuss the evidence that supports the role of T helper cells and their subsets in determining the airway inflammatory and contractile responses to antigen in a mouse model. Airway hyperresponsiveness and pulmonary eosinophilic inflammation induced by antigen challenge are associated with a Th2 pattern of cytokine expression in the murine lung. CD4+ T cells mediate the airway reaction to antigen, as depletion of CD4+ T cells attenuates the response. The presence of interleukin (IL)-4 induces the Th2 type of immune response, and this cytokine is required for mice to manifest AHR and inflammation to antigen. The Th1 type of immune response is stimulated by IL-12. Antigen-mediated AHR and inflammation are inhibited by IL-12 administration. Airway hyperresponsiveness in the noninflammatory state (without antigen treatment) is inherited in A/J and C3H/HeJ inbred mouse strains. One quantitative trait locus for AHR in progeny derived from these strains is located on murine chromosome 6. We propose that antigen-inducd AHR and inflammation also have heritable components. Based on the available immunological data, genes that influence the balance between Th1 and Th2 cells are logical candidate genes for antigen-induced AHR and inflammation. Knowledge of the genes that determine this phenotype will help us understand the mechanisms of human asthma.
Allergens↗
Mucosal IFN-gamma gene transfer inhibits pulmonary allergic responses in mice.
Th2 cytokines are associated with the airway inflammation and hyperreactivity in allergic asthma and are potential targets for developing novel therapies. The efficacy of a mucosal cytokine-gene transfer approach was examined in a mouse model for allergic asthma. We showed first that mucosal IFN-gamma gene transfer results in a significant expression of IFN-gamma in the pulmonary epithelium. Significantly, this approach inhibits both Ag- and Th2-cell-induced pulmonary eosinophilia and airway hyperreactivity. These findings suggest that mucosal IFN-gamma gene transfer is effective in modulating pulmonary allergic responses and provides a basis for developing a novel therapeutic approach.
Animals↗
Role of interleukin-4 in the development of allergic airway inflammation and airway hyperresponsiveness.
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Animals↗
Bloodborne markers in humans during multiday exposure to ozone.
Intermittent exposure of the human lung to ambient levels of ozone (O3) was assayed in systemic fluids by using serum alpha-tocopherol (ST) as a gauge of oxidative stress and the blastogenic activity of peripheral blood monocytes as an index of immune function. Healthy men (n = 10) were evaluated over 3 consecutive days (130 min/day) of chamber exposure to O3 and filtered air (FA); subjects alternated between rest and light treadmill exercise during exposures. For O3, the level was varied at 20-min intervals, i.e., 250, 350, 450, 450, 350, and 250 parts/billion, and concluded with 10 min at 250 parts/billion. ST was quantitated by high-performance liquid chromatography techniques, and T-lymphocyte blastogenesis was measured in cell cultures of peripheral blood monocytes by comparing [3H]thymidine incorporation in mitogen-stimulated (concanavalin A) and nonstimulated cells. After the third day of O3 at 20 h postexposure, ST levels were reduced significantly compared with the FA control subjects (down 14%; -0.96 mumol/l). Mitogen-activated T lymphocytes exhibited a 61% increase in blastogenic activity after 3 days of O3 exposure, significant compared with the proliferative activity of activated T lymphocytes collected after FA or before O3. Acute airway function was impaired by O3, e.g., on day 1, the forced vital capacity and forced expiratory volume in 1 s were decreased 8% (-0.92 liter) and 14% (-0.86 l/s), respectively, from preexposure values, and full recovery was delayed beyond 24 h. Effects of O3 exposure on cellular and biochemical markers increased in magnitude after each exposure and did not parallel the apparent adaptability of bronchial sensitivity to O3.
Adult↗
Cyclosporin A attenuates genetic airway hyperresponsiveness in mice but not through inhibition of CD4+ or CD8+ T cells.
We examined the influence of T lymphocytes on genetically determined airway hyperresponsiveness to acetylcholine (ACh) in mice. A/J and C3H/HeJ mice were treated with the T-cell suppressant cyclosporin A [(CsA) 25 to 100 mg/kg, intraperitoneally (i.p.), for 5 to 10 days], whereas control animals received the vehicle or remained untreated. CsA treatment induced a dose-dependent suppression of mitogen-stimulated spleen cell proliferation which was equivalent between the two strains. A/J control animals demonstrated approximately 8-fold greater ACh-stimulated airway responsiveness, assessed by the time-integrated peak inspiratory pressure (APTI) compared with C3H/HeJ control mice. ACh-induced APTI was attenuated by CsA in a dose- and time-dependent manner in the A/J strain; no significant changes occurred in the C3H/HeJ strain. To determine whether lymphocyte subtypes mediated this response, we depleted T-cell subsets with either rat anti-mouse CD4+ (L3T4) monoclonal antibody (GK1.5, 500 micrograms, i.p.) or anti-CD8+ monoclonal antibody (J1.2, 500 micrograms; or YTS169.4, 150 micrograms, i.p.) and assessed airway responsiveness. No significant change in airway responsiveness was detected in either strain after CD4+ or CD8+ T-cell depletion. Thus, although CsA administration attenuated spleen cell activation and was associated with a marked attenuation of airway responsiveness in mice with genetically hyperresponsive airways, CD4+ and CD8+ T cells do not appear to mediate this response.
Acetylcholine↗
Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice.
Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen-induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.
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CD4+ T lymphocyte modulation of ozone-induced murine pulmonary inflammation.
Inhalation of elevated levels of ozone produces a potent inflammatory response in the lung. The magnitude of this response to ozone exposure in mice is inbred strain dependent with the susceptible phenotype being exemplified by the C57BL/6J (B6) strain and the resistant phenotype by the C3H/HeJ (C3) strain. To examine the role of T lymphocytes in the regulation of ozone-induced pulmonary inflammation, mice were pretreated by an intraperitoneal injection of anti-Thy1.2 monoclonal antibody (mAb), anti-CD4+ mAb, or isotype-matched control antibodies (0.5 mg each) and subsequently exposed for 72 h to either filtered air or ozone (0.3 ppm). Immediately after ozone exposure, the cellular profile in the bronchoalveolar lavage fluids (BALF) was assessed. In isotype-treated controls of both strains of mice, ozone exposure induced significant increases in the numbers of macrophages, neutrophils, lymphocytes, and epithelial cells recovered in the BALF; however, the magnitude of each cell type recovered was significantly greater in B6 mice as compared with C3 mice. Both anti-Thy1.2 and anti-CD4+ monoclonal antibody treatments decreased the number of each cell type recovered in the B6 mice and increased the number of cells in the C3 mice. To determine if the CD4+ T-cell-derived cytokine interleukin (IL)-4 was involved in the differential effect of T-cell depletion on the ozone-induced inflammatory responses of C3 and B6 mice, mice were pretreated with either 400 ng of recombinant mouse IL-4 or vehicle, or 5.0 mg anti-IL-4 receptor monoclonal antibody or an isotype-matched antibody before either air or ozone exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗