Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production
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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Journal Article•
TL;DR: The LPS-derived MDSCs with specific markers were able to suppress natural inflammatory response and improve inflammatory injury through reversing Th1/Th2 ratio, increasing Treg proportion and decreasing IL-4 concentration, implying that asthma may be effectively targeted using a novel MDSC-based cell therapy approach.
Abstract: Objective Myeloid-derived suppressor cells (MDSCs) have recently been implicated in the pathogenesis of asthma through inhibiting T cell response. However, the issue of whether Lipopolysaccharide (LPS)-derived MDSCs regulate the immune response in an asthma environment is currently unclear. We sought to characterize the pathogenic function of various subtypes of MDSCs in asthma mediated by ovalbumin in mice model, in order to show that LPS-induced MDSCs can shift the balance back to normal in a Th2-dominant asthmatic environment. Materials and methods Subgroups of MDSCs with Ly6C+Ly6G+, Ly6C-Ly6G+, Ly6C+Ly6G- or Ly6C-Ly6G- expression were isolated by flow cytometry and were co-cultured with spleen lymphocytes. The proportion of Th1, Th2, or Treg cells in the treated spleen lymphocytes were analyzed by flow cytometry. In an ovalbumin (OVA)-induced mouse asthma model, mice were intravenously injected (tail vein) by MDSCs with specific marker, then the lung function and tissue pathology, IL-4 content in bronchoalveolar lavage fluid (BALF) and peripheral blood, and proportion of Th1, Th2, or Treg cells in peripheral blood were analyzed. Results Ly6C+Ly6G+ MDSCs transferred into asthmatic mice via intravenous injection suppressed the infiltration of inflammatory cells into the lung and Th2 cytokine in BALF and blood. We observed a significant increase of Treg cells in the spleen lymphocytes co-cultured with Ly6C+Ly6G+, Ly6C-Ly6G+, Ly6C+Ly6G-, Ly6C-Ly6G- or CD11b+ MDSCs. The adoptive transfer of Ly6C+Ly6G+, Ly6C-Ly6G+, CD11b+ MDSCs resulted in decrease of Penh, total cell number, eosinophil and neutrophil percentage in BALF, and concentration of IL-4 in BALF and serum, thus improving the inflammatory injury, histopathology and lung function in the mice with asthma. The up-regulation of the Th1/Th2 ratio and Treg frequency were observed after adoptive transfer of Ly6C+Ly6G+, Ly6C-Ly6G+, Ly6C+Ly6G-, Ly6C-Ly6G- and CD11b+ MDSCs. Conclusions The LPS-derived MDSCs with specific markers were able to suppress natural inflammatory response and improve inflammatory injury through reversing Th1/Th2 ratio, increasing Treg proportion and decreasing IL-4 concentration. These findings imply that LPS-derived MDSCs inhibit Th2 cell-medicated response against allergen. We propose that asthma may be effectively targeted using a novel MDSC-based cell therapy approach.
8 citations
Dissertation•
01 Jan 2010
TL;DR: The data show that IL-33 can induce in the lungs the cardinal pathological characteristics of asthma, and that it appears to act upstream of other important mediators such as IL-13 and the eotaxins.
Abstract: Asthma is a chronic disease characterised by variable airflow obstruction, bronchial hyperresponsiveness and airways inflammation. At an immunological level Th2 inflammation and the presence of activated eosinophils and mast cells are key features of asthma. ST2, the receptor for the novel cytokine IL-33, is expressed upon Th2 lymphocytes and mast cells but its role in clinical and experimental asthma remains unclear. IL-33 has been shown to induce local and systemic eosinophilia when administered to the peritoneum of mice. In this thesis I have set out to test the hypothesis that the activation of mast cells by IL-33 acting on cell surface ST2 plays a critical role in allergic airways inflammation.
I began by studying the function of ST2 on mast cells in vitro. I found that ST2 was expressed at an early stage of development, and correlated closely with the expression of the stem cell factor receptor (c-kit), a marker present on mast cells from a progenitor stage. Despite this mast cells generated form ST2 gene deleted mice proliferated and matured normally. When mast cells were activated by IL-33, acting in an ST2-dependent manner, pro-inflammatory cytokines and chemokines were released that have potential roles in asthma, specifically IL-6, IL-13, MIP-1α and MCP-1.
To extend these findings I looked at the role of ST2 in allergic airways inflammation. I first optimised and validated an ovalbumin and adjuvant based ‘short’ twelve day model of murine asthma and demonstrated that ST2 gene deletion results in attenuated eosinophilic inflammation. In addition to being ST2 dependent it is possible that this adjuvant based short model is mast cell dependent, unlike longer adjuvant based models which are mast cell and ST2 independent. Therefore I went on to study an adjuvant-free model of asthma which has been demonstrated to be mast cell dependent. In this adjuvant-free model of asthma the airway inflammation was attenuated in ST2 gene deficient mice compared with wild type mice, while AHR was unaffected. There was an associated reduction in IgE production and thoracic lymph node recall Th2 cytokine responses.
I then examined the effect of ST2 activation in the lungs. When IL-33 was administered directly to the airways of naive mice it induced the features of experimental asthma. There was extensive eosinophilic inflammation within the lung tissue and airspaces. The Th2 cytokines IL-5 and IL-13, and the eosinophil chemoattractant chemokines eotaxin-1 and eotaxin-2 were detected at increased concentrations. Significant airways hyperresponsiveness was also generated. Using ST2 gene deleted mice I demonstrated that these effects were ST2 specific. Although I have shown that mast cells are activated by IL-33 in vitro, I used mast cell deficient mice to demonstrate that the eosinophilic inflammation generated by IL-33 is unaffected by the absence of mast cells.
These data show that IL-33 can induce in the lungs the cardinal pathological characteristics of asthma, and that it appears to act upstream of other important mediators such as IL-13 and the eotaxins. Furthermore the IL-33 receptor ST2 is required in an adjuvant free model of asthma, which is more akin to human disease. Placing these findings in the context of recent evidence that IL-33 is released by structural cells in response to damage or injury suggests that IL-33 may play a key role in initiating the immunological features of clinical asthma. As a consequence of this position in the hierarchy of inflammation IL-33 offers a promising direct target for novel biological therapies in asthma.
8 citations
Cites background from "Induction of Airway Mucus Productio..."
...Mice Model Method EØ AHR Ref C57Bl/6 OVA + Alum IL-4 (156) C57Bl/6 OVA + Alum IL-4 (214) C57Bl/6 OVA + Alum α-IL-4 (214) C57Bl/6 OVA + Alum IL-4 (215) C57Bl/6 OVA + Alum IL-4 (216) BALB/c OVA + Alum α-IL-4 NC (54) C57Bl/6 OVA + Alum IL-4 NC (217) BALB/c OVA + Alum IL-4 NC (100) BALB/c TF-OVA IL-4 NC (198,199) C57Bl/6 airways OVA(1) IL-4 (213) C57Bl/6 epicutaneous OVA(2) IL-4 NC (213) BALB/c GM-CSF + OVA(3) IL-4 (218)...
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...However when antigen-specific Th2 cells are transferred into naïve wild type or SCID mice then airways challenge induces eosinophilic inflammation, mucus hyper-secretion and AHR(180,198,199)....
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...In this adjuvant-free model of asthma the airway inflammation was attenuated in ST2 gene deficient mice compared with wild type mice, while AHR was unaffected....
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...Transfer of polarised antigen-specific Th1 cells followed by airways challenge results in neutrophilic rather than eosinophilic inflammation and fails to induce AHR(180,198,199)....
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09 Oct 2015
TL;DR: In this paper, the authors proposed an alternative approach to turn off the "reservoir" of pathogenic allergen-sensitised effector and memory T cells in established allergic asthma.
Abstract: Allergic asthma is a chronic inflammatory disease of the lower airways resulting, in many cases, from dysregulated Th2 CD4+ T-cell responses to inhaled environmental allergens. Allergic sensitisation, defined as the induction of Th2 mediated allergen-specific responses for the clinical disease, is a key risk factor for asthma. Although current therapies are relatively safe and effective at controlling symptoms they do not alter the chronic course of disease. Additionally, there are complications associated with chronic use of pharmacologic disease modifiers. Current allergen-specific immunotherapy aims to reintroduce immune-regulation, in an immune environment where regulation has failed. We propose an alternative approach to ‘turn off’ the ‘reservoir’ of pathogenic allergen-sensitised effector and memory T cells in established allergic asthma. Previously, it has been shown that antigen targeted genetically to be expressed in resting dendritic cells (DC) inactivates naive, memory and effector CD4+ and CD8+ T cells and this could provide a therapeutic approach. In this study, I will investigate, using the model allergen ovalbumin (OVA), whether genetically-targeting antigen to DC can prevent allergic sensitisation and allergen-induced airway inflammation. In addition, the project will determine whether antigen-encoding bone marrow cell (BM) transfer under non-myeloablative conditions terminates the established allergic airway disease. I also develop a robust murine model of airway inflammation elicited by the major ryegrass pollen allergen Lol p 1 in which therapeutic strategies could be tested. In addition, I produce a lentivirus vector encoding Lol p 1 which can be used to test therapeutic strategies in conjunction with the model developed. Transgenic (Tg) mice genetically-engineered to express OVA in DC under control of the CD11c promoter (11c.OVA mice) were sensitised with OVA323-339/alum intraperitoneally and intranasally challenged with OVA. When splenocytes and mediastinal lymph nodes (MLNs) of OVA323-339-sensitised and OVA challenged mice were restimulated in vitro with OVA323-339 peptide, IL-4, IL-5, IL-13 levels were significantly decreased in OVA-expressing 11c.OVA transgenic relative to control mice. Also little or no inflammatory cell infiltrate was present in bronchoalveolar lavage fluid (BALF) in OVA-expressing mice after sensitisation and i.n. challenge. Next, using non-myeloablative conditions, OVA-encoding or non-Tg BM was transferred to OVA323-339/alum-sensitised and OVA-intranasally challenged BALB/c mice. Production of IL-4, IL-5 and IL-13 by OVA323-339 restimulated spleen cells and MLN cells was dramatically reduced in recipients of OVA-encoding, but not non-Tg, BM. Eosinophil content in BALF and histological evidence of mucus hypersecretion were also reduced indicating reversal of pathogenic processes associated with dysregulated T-cell responses. For Lol p 1, BALB/c mice were sensitised with crude ryegrass pollen extract (containing Lol p 1)/alum intraperitoneally. When splenocytes of the sensitised mice were restimulated in vitro with ryegrass pollen extract, IL-4, IL-5, IL-13 levels were significantly increased in sensitised vs sham-sensitised mice. Ryegrass pollen extract/alum-sensitised BALB/c mice also showed significant airway inflammation when challenged intranasally with Lol p 1 compared to mice challenged with PBS. Significantly, when fused with the transmembrane portion of the human transferrin receptor the plant allergen Lol p 1 was successfully expressed and targeted to the membrane of mammalian cells. When lentiviral vectors encoding Lol p 1 under control of a truncated DC-specific (11c960) promoter were generated and tested these effectively transduced hematopoietic progenitor cells based on reported gene expression. This indicated that lentiviral vectors encoding a plant allergen targeted to DC could be could be successfully engineered. From the findings of my studies I conclude that expression of OVA in DC prevents allergic priming and consequently respiratory immune responses to respiratory antigen challenge. Allergen-encoding BM transfer under non-myeloablative conditions terminates established allergic T-cell responses and reduces allergen-induced airway inflammation. Lol p 1 is a good model for clinically relevant allergic responses and the lentiviral approach could provide a potential robust method for the induction of tolerance to terminate allergen-induced airway inflammation.
7 citations
Cites background from "Induction of Airway Mucus Productio..."
...IL-4 contributes to pathology by promoting a Th2 response (Finkelman et al. 1988, Coyle et al. 1995, Corry et al. 1996, Cohn et al. 1997, Henderson et al. 2000, Finkelman et al. 2010) by inducing Th2 cell differentiation and expansion, rather than as a direct effector (Kaplan et al. 1996)....
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TL;DR: Wang et al. as discussed by the authors explored the efficacy and mechanism of total flavonoids from QZQ (TFCH) on allergic asthma using an Ovalbumin (OVA)-induced mice model.
7 citations
TL;DR: It is demonstrated that sensitization and subsequent aerosol inhalational challenge of latex allergen extract promotes allergic airway inflammation characterized by elevated IL-5 and IL-13 and eosinophils.
Abstract: Latex allergy is important due to serious health impacts and widespread use of its products. Latex allergic reactions can be induced in skin and mucosal surfaces including the respiratory tract. The development of murine models of allergic airway inflammation has provided a framework to dissect out the cellular and molecular mechanisms of allergic respiratory inflammation. In this study we have developed a new mouse model of latex allergic airway inflammation using aerosol inhalation. The allergic inflammatory responses were characterized in this model. Mice were injected intraperitoneally with 0, 10, 50, or 200 μg of latex extract and their serum anti-latex IgE titers were determined. In the second stage, a standard protocol of inhalation was designed and three doses of latex extract solutions including 1%, 0.1%, and 0.01% were used to induce allergic airway inflammation. Bronchoalveolar lavage cytokines (IL-5 and IL-13) and serum anti-latex IgE and IgG1 titers were determined by ELISA. Eosinophil levels in lung, peripheral blood, bronchoalveolar lavage and bone marrow were also evaluated. Histological analysis of lung tissue was also performed after latex inhalation. The aerosol inhalation of 1% latex allergens solution and presensitization with 50 μg of latex in this study resulted in the development of allergic airway inflammation characterized by elevated allergen specific IgE and IgG1, peripheral blood, bronchoalveolar lavage and bone marrow eosinophilia. Histological analysis of the lung revealed an inflammatory response characterized by eosinophil accumulation. Elevated levels of Th2 cytokines IL-5 and IL-13 also were shown in bronchoalveolar lavage samples. These studies demonstrate that sensitization and subsequent aerosol inhalational challenge of latex allergen extract promotes allergic airway inflammation characterized by elevated IL-5 and IL-13 and eosinophils.
7 citations
References
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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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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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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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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
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