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Journal ArticleDOI

Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production

Lauren Cohn1, Robert J. Homer1, Anthony Marinov1, John A. Rankin1, Kim Bottomly1 
17 Nov 1997-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 186, Iss: 10, pp 1737-1747
TL;DR: It is suggested that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.
Abstract: Airway inflammation is believed to stimulate mucus production in asthmatic patients. Increased mucus secretion is an important clinical symptom and contributes to airway obstruction in asthma. Activated CD4 Th1 and Th2 cells have both been identified in airway biopsies of asthmatics but their role in mucus production is not clear. Using CD4 T cells from mice transgenic for the OVA-specific TCR, we studied the role of Th1 and Th2 cells in airway inflammation and mucus production. Airway inflammation induced by Th2 cells was comprised of eosinophils and lymphocytes; features found in asthmatic patients. Additionally, there was a marked increase in mucus production in mice that received Th2 cells and inhaled OVA, but not in mice that received Th1 cells. However, OVA-specific Th2 cells from IL-4–deficient mice were not recruited to the lung and did not induce mucus production. When this defect in homing was overcome by administration of TNF-α, IL-4 −/− Th2 cells induced mucus as effectively as IL-4 +/+ Th2 cells. These studies establish a role for Th2 cells in mucus production and dissect the effector functions of IL-4 in these processes. These data suggest that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.

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Citations
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Journal ArticleDOI
TL;DR: Over the next few years, the emerging experience with anti-IgE in patients will provide a more complete understanding of the mechanisms whereby IgE contributes to disease, as well as the therapeutic potential of its inhibition.
Abstract: Asthma and the predisposition to produce IgE are inherited as linked traits in families In patients IgE levels correlate with asthma severity and bronchial hyperresponsiveness The concept that IgE plays a critical role in asthma pathogenesis has driven the development of IgE blockers, which are currently being introduced into clinical use This review focuses on the mechanisms whereby IgE participates both in immediate hypersensitivity responses in the airways and in the induction of chronic allergic bronchial inflammation The molecular genetic events that give rise to IgE production by B cells and the cellular and cytokine factors that support IgE production in the bronchial mucosal microenvironment are discussed It is clear that much remains to be learned regarding the roles of IgE in asthma and the genetic and environmental influences that lead to its production Over the next few years, the emerging experience with anti-IgE in patients will provide a more complete understanding of the mechanisms whereby IgE contributes to disease, as well as the therapeutic potential of its inhibition

194 citations

Journal ArticleDOI
TL;DR: In vivo pathways that lead to mucus induction are defined and indicate that, whereas IL-13 mediates a dominant pathway for CD4 Th induced inflammation, other inflammatory stimuli activate the epithelium to produce mucus by different pathways.
Abstract: Mucus hyperproduction in asthma results from Th2-induced airway inflammation. Controversy exists about the precise mechanism of this Th2 effect. Although we showed that mucus can be induced by Th2 cells in the absence of interleukin (IL)-4, IL-5, eosinophils, and mast cells, but not without IL-4Ralpha signaling, others demonstrated that IL-4 and IL-9 can directly stimulate airway epithelial mucus. Using a system in which in vitro-generated T cell receptor transgenic Th2 cells are transferred into recipient mice and activated in the respiratory tract with inhaled antigen, we now show that CD4 Th cells can stimulate mucus only through a common, IL-13-mediated pathway. All Th cytokines depend on IL-13 for this effect and IL-13 acts, not through intermediate inflammatory cells, but on structural cells within the lung, likely the airway epithelium itself. The potency of IL-13 is shown, requiring its complete blockade for a significant reduction in mucus production. We show that mucus induction by Th2 cells does not require nuclear factor-kappaB, unlike mucins induced by gram-negative infection. These studies define in vivo pathways that lead to mucus induction and indicate that, whereas IL-13 mediates a dominant pathway for CD4 Th induced inflammation, other inflammatory stimuli activate the epithelium to produce mucus by different pathways.

192 citations


Cites background or methods from "Induction of Airway Mucus Productio..."

  • ...This PBS as previously described (4), for 20 min/d for a total of 7 d index was calculated for each mouse lung and then the mean of over a period of 9 d (four consecutive days exposed, 2 d rested, the HMI was calculated for each experimental group....

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  • ...10 CD4 Th1 or Th2 cells were transferred that received IL-13 / or IL-13 / Th2 cells and IL-13 / into recipient mice, we previously showed that Th2, but not mice that received IL-13 / Th2 cells and inhaled OVA Th1, cells stimulate airway epithelial mucus (4)....

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  • ...Using a system in which in vitroor IL-5, and in inflammatory responses that were devoid generated T cell receptor transgenic Th2 cells are transferred of eosinophils or mast cells (4, 5)....

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  • ...Airway mucus staining in IL-4R / bone marrow Th1 cells typically do not stimulate mucus production due chimeras after transfer of Th2 to the inhibitory action of IFN- (4, 16)....

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  • ...murine models of antigen-induced airway inflammation, the IL-13 has a unique in vivo function in gastrointestinal expulinduction of mucus requires the presence of activated CD4 sion of the parasitic nematode, Nippostrongylus braziliensis Th2 cells (4)....

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Journal ArticleDOI
TL;DR: It is highlighted that although TLR3 may not be required for viral clearance, it is necessary to maintain the proper immune environment in the lung to avoid developing pathologic symptoms of disease.
Abstract: The detection of a viral infection by pattern recognition receptors (PAMPs) is an integral part of antiviral immunity In these studies we have investigated the role of TLR3, which recognizes dsRNA, in Respiratory Syncytial virus (RSV) infection using B6 background mice with a TLR3 deletion Although we observed no changes in viral growth, we did find that TLR3-/- mice demonstrated significant increases in mucus production in the airways of RSV-infected mice The qualitative assessment was observed by examining differentially stained lungs, followed by immunohistochemical staining for gob5, a mucus-associated protein The histopathologic observations were verified using quantitative gene expression analyses examining gob5 gene expression Changes in pulmonary mucus production were accompanied by an increase in pulmonary IL-13 as well as IL-5 expression and eosinophils in the airways of TLR3-/- mice Examining leukocytes in the airway indicated an accumulation of eosinophils in TLR3-/- mice, but not wild-type mice, after RSV infection Isolated lung draining lymph node cells from TLR3-/- mice produced significant increases in Th2-type cytokines, IL-5, and IL-13, compared with wild-type TLR3+/+ mice only after RSV infection To demonstrate a causative link, we depleted TLR3-/- mice of IL-13 during RSV infection and found that mucus and gob5 expression in the lungs was attenuated Together, these studies highlight that although TLR3 may not be required for viral clearance, it is necessary to maintain the proper immune environment in the lung to avoid developing pathologic symptoms of disease

187 citations

Journal ArticleDOI
TL;DR: It is demonstrated that targeting IL-13 alone regulates airway responses when administrated to mice with established allergic airway disease, even when administered before rechallenge of mice in which allergic disease had been previously established.
Abstract: The effectiveness of targeting IL-13 in models where airway hyperresponsiveness (AHR) and airway inflammation have already been established is not well-described. We investigated the effects of blocking IL-13 on the early and late phase airway responses and the development of AHR in previously sensitized and challenged mice. BALB/cByJ mice were sensitized (days 1 and 14) and challenged (days 28–30) with OVA. Six weeks later (day 72), previously sensitized/challenged mice were challenged with a single OVA aerosol and the early and late phase response and development of AHR were determined. Specific in vivo blockade of IL-13 was attained after i.p. injection of a soluble IL-13Rα2-IgG fusion protein (sIL-13Rα2Fc) on days 71–72 for the early and late responses and on days 71–73 for the development of AHR. sIL-13Rα2Fc administration inhibited the late, but not early, phase response and the OVA challenge-induced changes in lung resistance and dynamic compliance; as well, sIL-13Rα2Fc administration decreased bronchoalveolar lavage eosinophilia and mucus hypersecretion following the secondary challenge protocols. These results demonstrate that targeting IL-13 alone regulates airway responses when administrated to mice with established allergic airway disease. These data identify the importance of IL-13 in the development of allergen-induced altered airway responsiveness following airway challenge, even when administered before rechallenge of mice in which allergic disease had been previously established.

186 citations


Cites background from "Induction of Airway Mucus Productio..."

  • ...IL-4 is critical for Th2 cell induction (35), especially during the sensitization phase (20–22), but it has been shown that in the absence of IL-4, AHR, lung eosinophilia and mucus production can still be induced (36)....

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Journal ArticleDOI
TL;DR: The therapeutic potential of IL- 4 mutant protein receptor antagonists that inhibit both IL-4 and IL-13 in the treatment of allergic asthma are demonstrated.
Abstract: The closely related Th2 cytokines, IL-4 and IL-13, share many biological functions that are considered important in the development of allergic airway inflammation and airway hyperresponsiveness (AHR). The overlap of their functions results from the IL-4R alpha-chain forming an important functional signaling component of both the IL-4 and IL-13 receptors. Mutations in the C terminus region of the IL-4 protein produce IL-4 mutants that bind to the IL-4R alpha-chain with high affinity, but do not induce cellular responses. A murine IL-4 mutant (C118 deletion) protein (IL-4R antagonist) inhibited IL-4- and IL-13-induced STAT6 phosphorylation as well as IL-4- and IL-13-induced IgE production in vitro. Administration of murine IL-4R antagonist during allergen (OVA) challenge inhibited the development of allergic airway eosinophilia and AHR in mice previously sensitized with OVA. The inhibitory effect on airway eosinophilia and AHR was associated with reduced levels of IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid as well as reduced serum levels of OVA-IGE: These observations demonstrate the therapeutic potential of IL-4 mutant protein receptor antagonists that inhibit both IL-4 and IL-13 in the treatment of allergic asthma.

184 citations


Cites background from "Induction of Airway Mucus Productio..."

  • ...OVA challenge of naive mice receiving transfer of OVA-specific, IL4-deficient Th2 cells resulted in marked mucus hyperproduction in the airways, suggesting that IL-4 was not necessary (56)....

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References
More filters
Journal Article
TL;DR: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished.
Abstract: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.

7,567 citations


"Induction of Airway Mucus Productio..." refers background in this paper

  • ...The lower limit of sensitivity for each of the ELISAs was 0.6 ng/ml (IFNg ), 5 pg/ml (IL-4), 0.010 ng/ml (IL-5), and 200 pg/ml (IL-10)....

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  • ...CD4 Th2 cells make a different panel of cytokines, including IL-4, IL-5, and IL-10 (17, 18)....

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  • ...Assays were standardized with recombinant IFNg , IL-5, IL-10 (Endogen), and IL-4 (Collaborative Research, Inc.)....

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  • ...1 A ), and IL-10 (data not shown)....

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  • ...IL-4 2/2 OVA-specific Th2 cells produced comparable levels of IL-5 and IL-10 when compared to IL-4 1/1 OVA-specific Th2 cells, but IL-4 was produced only by IL-4 1/1 Th2 cells....

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Journal ArticleDOI
TL;DR: Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.
Abstract: Background. In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. Methods. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or...

2,898 citations


"Induction of Airway Mucus Productio..." refers background in this paper

  • ...Th2 cells secreting IL-4 and IL-5 have been shown to be present and activated in the bronchial wall of asthmatic individuals (9, 23)....

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Journal ArticleDOI
TL;DR: This paper used hybridoma monoclonal antibodies obtained after immunization of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes.
Abstract: Xenogeneic immunizations have the advantage of detecting a wide range of antigenic determinants because many commonly occurring proteins have diverged significantly during the course of evolution and are thus antigenic in other species. The broadness of xenogeneic responses, however, means that the antisera they produce are usually complex and require extensive absorptions to make them specific for a single antigen. This problem has now been overcome by generating hybridomas producing monoclonal antibodies (Kohler & Milstein 1975). These permit dissection ofthe xenogeneic response so that large amounts of individual antibodies can be obtained, each of which recognizes only one of the determinants recognized by a broadly reactive conventional antiserum. Williams et al. (1977) used hybridoma monoclonal antibodies obtained after immunizations of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes, i.e., differentiation antigens. Springer et al. (1978a) and Stern et al. (1978) used a similar approach to study mouse lymphocyte antigens. They prepared monoclonal antibodies by immunizing rats with mouse lymphocytes and showed that these monoclonals recognized previously undetected mouse cell surface determinants including a glycoprotein antigen that appears to be specific for macrophages (Springer et al. 1978b). Trowbridge (1978) also used rat anti-mouse immunizations to generate a monoclonal antibody against the non-polymorphic lymphocyte surface antigen T200.

1,916 citations


"Induction of Airway Mucus Productio..." refers methods in this paper

  • ...To generate Th1 or Th2 cells from DO11.10 mice, CD4 T cells were isolated by negative selection as previously described (31) using mAbs to CD8 (clone 53-6.72, clone 2.43 [ 32 ]), Class II MHC I-A d (212.A1 [33]) and anti‐Ig-coated magnetic beads (Advanced Magnetics, Inc....

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Journal ArticleDOI
21 Dec 1990-Science
TL;DR: Results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance in mice transgenic for a T cell receptor that reacts to this peptide.
Abstract: In order to examine the mechanisms by which clonal deletion of autoreactive T cells occurs, a peptide antigen was used to induce deletion of antigen-reactive thymocytes in vivo. Mice transgenic for a T cell receptor (TCR) that reacts to this peptide contain thymocytes that progress from the immature to the mature phenotype. Intraperitoneal administration of the peptide antigen to transgenic mice results in a rapid deletion of the immature CD4+ CD8+ TCRlo thymocytes. Apoptosis of cortical thymocytes can be seen within 20 hours of treatment. These results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance.

1,831 citations

Journal ArticleDOI
01 Nov 1991-Science
TL;DR: Some but not all of the in vitro properties of IL-4 are critical for the physiology of the immune system in vivo, but the serum levels of IgG1 and IgE are strongly reduced.
Abstract: Interleukin-4 (IL-4) promotes the growth and differentiation of many hematopoietic cells in vitro; in particular, it directs the immunoglobulin (Ig) class switch to IgG1 and IgE. Mice homozygous for a mutation that inactivates the IL-4 gene were generated to test the requirement for IL-4 in vivo. In the mutant mice T and B cell development was normal, but the serum levels of IgG1 and IgE were strongly reduced. The IgG1 dominance in a T cell-dependent immune response was lost, and IgE was not detectable upon nematode infection. Thus, some but not all of the in vitro properties of IL-4 are critical for the physiology of the immune system in vivo.

1,262 citations