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1.
Brasília; CONITEC; 2024.
Non-conventional in Portuguese | BRISA/RedTESA | ID: biblio-1554036

ABSTRACT

INTRODUÇÃO: A asma afeta indivíduos de todas as idades e é a doença crônica mais comum entre as crianças. No Brasil, a condição é um dos problemas de saúde respiratória mais recorrentes e estima-se que 23,2% da população viva com a doença, representando aproximadamente 24% da população infantil. Mesmo com tratamento otimizado, cerca de 5-10% dos adultos e 2-5% das crianças apresentam sintomas persistentes, gerando altos custos em saúde com repetidas internações hospitalares devido às exacerbações, faltas no trabalho e na escola, além do prejuízo da qualidade de vida do paciente e familiares. A asma eosinofílica grave, na criança ou adolescente, é caracterizada pela presença de eosinófilos no sangue igual ou superior a 150 células/µL, e/ou eosinófilos detectados no escarro em uma proporção ≥ 2%, juntamente com resultados positivos para testes específicos de IgE ou teste cutâneo de leitura imediata. O tratamento da asma deve ser individualizado, de acordo com a gravidade da doença e o controle dos sintomas. No Brasil, de acordo com a bula atualizada em 2023, o medicamento em questão é indicado como tratamento complementar de manutenção da asma eosinofílica grave em pacientes adultos e pediátricos a partir de 6 anos de idade, porém, conforme PCDT de asma, o uso do mepolizumabe atualmente está restrito a pacientes adultos com asma eosinofílica grave refratária, associado ao tratamento com Corticosteroides Inalatórios (CI) + bro


Subject(s)
Humans , Child , Adolescent , Asthma/drug therapy , Interleukin-5/administration & dosage , Health Evaluation/economics , Unified Health System , Brazil , Cost-Benefit Analysis/economics
2.
Anaerobe ; 66: 102275, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32971206

ABSTRACT

Clostridiodes difficile infection (CDI) is the leading cause of hospital-acquired gastrointestinal infections in the U.S. While the immune response to C. difficile is not well understood, it has been shown that severe disease is accompanied by high levels of infiltrating immune cells and pro-inflammatory cytokine production. This study tests the roles of two type 2 cytokines, IL-4 and IL-5, in mediating protection in a murine model of disease. Administration of IL-5 protected from mortality due to CDI, and both IL-4 and IL-5 were protective against severe disease symptoms. Together, the results from this study increase our understanding of how type 2 immune signaling processes are protective from severe C. difficile infection.


Subject(s)
Clostridioides difficile/drug effects , Clostridium Infections/drug therapy , Eosinophils/immunology , Interleukin-4/administration & dosage , Interleukin-5/administration & dosage , Animals , Clostridioides difficile/immunology , Clostridium Infections/immunology , Humans , Immunity , Interleukin-4/immunology , Interleukin-5/immunology , Mice , Mice, Inbred C57BL
3.
Immunol Lett ; 150(1-2): 41-7, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23246474

ABSTRACT

IL-33 is an IL-1 family cytokine that elicits IL-5-dependent eosinophilia in vivo. We show here that IL-33 promotes minimal eosinophil hematopoiesis via direct interactions with mouse bone marrow progenitors ex vivo and that it antagonizes eosinophil hematopoiesis promoted by IL-5 on SCF and Flt3L primed bone marrow progenitor cells in culture. SCF and Flt3L primed progenitors respond to IL-33 by acquiring an adherent, macrophage-like phenotype, and by releasing macrophage-associated cytokines into the culture medium. IL-33-mediated antagonism of IL-5 was reproduced in part by the addition of GM-CSF and was inhibited by the actions of neutralizing anti-GM-CSF antibody. These findings suggest that the direct actions of IL-33 on bone marrow progenitors primed with SCF and Flt3L are antagonistic to the actions of IL-5 and are mediated in part by GM-CSF.


Subject(s)
Eosinophils/drug effects , Interleukin-5/pharmacology , Interleukins/pharmacology , Myelopoiesis/drug effects , Animals , Bone Marrow Cells/drug effects , Cell Differentiation/drug effects , Cells, Cultured , Cytokines/metabolism , Eosinophilia/chemically induced , Eosinophils/cytology , Eosinophils/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Interleukin-33 , Interleukin-5/administration & dosage , Interleukins/administration & dosage , Interleukins/adverse effects , Mice , Myelopoiesis/physiology
4.
Am J Reprod Immunol ; 68(6): 476-85, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22934542

ABSTRACT

PROBLEM: Various approaches have been developed to improve the antibody response of zona pellucida glycoprotein-3 (ZP3) vaccination. In this study, we investigated whether GM-CSF and IL-5 can be used as cytokine adjuvants to increase the humoral immune response generated by mouse ZP3 (mZP3) DNA vaccine. METHOD OF STUDY: Mice in experimental group were injected by GM-CSF 4 days before the co-immunization of IL-5 and mZP3 DNA vaccine. The contraception and the correlation with humoral and cellular immune responses were analyzed after immunization and mating. The effect of cytokine adjuvant on the maturation of DCs was evaluated. RESULTS: Co-immunization of GM-CSF and IL-5 with mZP3 DNA vaccine induced the highest level of serum IgG and IL-4 expression in CD4(+) T cells. Importantly, this strategy reduced mice fertility without disrupting normal ovarian morphology. GM-CSF enhanced the maturation of DCs evidenced by up-regulating the expression of MHC-II and CD86. CONCLUSION: GM-CSF and IL-5 co-administration enhanced humoral immune responses to mZP3, and this may be a potential strategy for development of immunocontraceptive vaccine.


Subject(s)
Contraception, Immunologic/methods , Egg Proteins/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Interleukin-5/immunology , Membrane Glycoproteins/immunology , Receptors, Cell Surface/immunology , Vaccines, DNA/immunology , Adjuvants, Immunologic/administration & dosage , Animals , Antibody Formation , CD4-Positive T-Lymphocytes/immunology , Cell Proliferation , Egg Proteins/genetics , Female , Fertility/drug effects , Fertility/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Immunoglobulin G/blood , Interferon-gamma/blood , Interleukin-4/blood , Interleukin-5/administration & dosage , Male , Membrane Glycoproteins/genetics , Mice , Mice, Inbred BALB C , Receptors, Cell Surface/genetics , Vaccination , Vaccines, DNA/administration & dosage , Zona Pellucida Glycoproteins
5.
Proc Natl Acad Sci U S A ; 109(16): 6187-92, 2012 Apr 17.
Article in English | MEDLINE | ID: mdl-22474386

ABSTRACT

IL-15 has potential as an immunotherapeutic agent for cancer treatment because of its ability to effectively stimulate CD8 T cell, natural killer T cell, and natural killer cell immunity. However, its effectiveness may be limited by negative immunological checkpoints that attenuate immune responses. Recently a clinical trial of IL-15 in cancer immunotherapy was initiated. Finding strategies to conquer negative regulators and enhance efficacy of IL-15 is critical and meaningful for such clinical trials. In a preclinical study, we evaluated IL-15 combined with antibodies to block negative immune regulator cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in an established murine transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 prostate tumor model. IL-15 treatment resulted in a significant prolongation of survival in tumor-bearing animals. Coadministration of anti-PD-L1 or anti-CTLA-4 singly with IL-15 did not improve animal survival over that of IL-15 alone. However, simultaneous administration of IL-15 with anti-CTLA-4 and anti-PD-L1 was associated with increased numbers of tumor antigen-specific tetramer-positive CD8 T cells, increased CD8 T-cell tumor lytic activity, augmented antigen-specific IFN-γ release, decreased rates of tumor growth, and improved animal survival compared with IL-15 alone. Furthermore, triple combination therapy was associated with inhibition of suppressive functions of CD4(+)CD25(+) regulatory T cells and CD8(+)CD122(+) regulatory T cells. Thus, simultaneous blockade of CTLA-4 and PD-L1 protected CD4 and/or CD8 T-cell activity from these regulatory T cells. Combining the immune stimulatory properties of IL-15 with simultaneous removal of two critical immune inhibitory checkpoints, we showed enhancement of immune responses, leading to increased antitumor activity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease Models, Animal , Prostatic Neoplasms/drug therapy , T-Lymphocyte Subsets/drug effects , Amino Acid Sequence , Animals , Antibodies/administration & dosage , Antibodies/immunology , B7-H1 Antigen/immunology , B7-H1 Antigen/metabolism , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CTLA-4 Antigen/immunology , CTLA-4 Antigen/metabolism , Cell Line, Tumor , Cytotoxicity, Immunologic/drug effects , Cytotoxicity, Immunologic/immunology , Flow Cytometry , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-5/administration & dosage , Kaplan-Meier Estimate , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Male , Mice , Mice, Inbred C57BL , Prostatic Neoplasms/immunology , Prostatic Neoplasms/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Treatment Outcome , Tumor Burden/drug effects , Tumor Burden/immunology
6.
Int Arch Allergy Immunol ; 145(4): 313-23, 2008.
Article in English | MEDLINE | ID: mdl-18004073

ABSTRACT

BACKGROUND: Eosinophils play a pivotal role in the generation of asthma inflammation. Interleukin (IL)-5 is the major activator of eosinophils. We hypothesize that modulating IL-5 activity could be an effective strategy for asthma therapy. In this study, we tested whether the plasmid encoding human IL-5 as a xenogeneic DNA vaccine could induce the production of autoantibodies, and be used for asthma treatment. METHODS: A eukaryotic plasmid encoding the human IL-5 was constructed, and used as a DNA vaccine. A mouse model of asthma was established to observe its antiasthma activities. Eosinophils in tissue, blood and the bronchoalveolar lavage were stained and counted. Airway hyperresponsiveness (AHR) was determined by whole body plethysmography. Antibody characters and cytokines were detected with immunological methods. RESULTS: Immunization with a plasmid encoding the human IL-5 as DNA vaccine reduced airway inflammation, reversed Th2 cytokines, and decreased AHR in mice. In addition, this immunization induced the production of polyclonal antibodies that were cross-reactive with native murine IL-5, and IgG1 and IgG2a were the major subclasses. Adoptive transfer of the purified antibodies from the sera of mice immunized with the plasmid encoding the human IL-5 resulted in similar antiasthma effects. CONCLUSIONS: Our results suggest that active vaccination against IL-5 may be a rational therapeutic approach for the treatment of asthma and potentially other eosinophilic disorders.


Subject(s)
Asthma/pathology , Asthma/therapy , Genetic Therapy , Immune Tolerance/genetics , Inflammation Mediators/administration & dosage , Interleukin-5/genetics , Plasmids/genetics , Animals , Asthma/immunology , Bronchial Hyperreactivity/immunology , Bronchial Hyperreactivity/pathology , Bronchial Hyperreactivity/prevention & control , COS Cells , Chlorocebus aethiops , DNA, Recombinant/administration & dosage , DNA, Recombinant/immunology , Disease Models, Animal , Humans , Inflammation Mediators/immunology , Interleukin-5/administration & dosage , Interleukin-5/immunology , Male , Mice , Mice, Inbred BALB C , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunology
7.
Clin Exp Allergy ; 37(7): 1023-32, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17581195

ABSTRACT

BACKGROUND: Asthma is characterized by increases in mature eosinophils and their progenitors within the bronchus and bone marrow. IL-5 plays a key role in eosinophil development in the bone marrow and at the site of allergic inflammation. We therefore studied the effects of nebulized IL-5 on eosinophils, their progenitors and in situ haemopoiesis within the airway and bone marrow. METHODS: Nine atopic asthmatics and 10 non-atopic non-asthmatic control volunteers inhaled 10 microg of IL-5 or placebo via a nebulizer in a double-blind, randomized, cross-over study. Bronchoscopy, bone marrow aspiration and peripheral blood sampling were performed 24 h after nebulization. Four weeks later, volunteers inhaled the alternative solution and underwent a repeat bronchoscopy and bone marrow aspiration. RESULTS: Inhalation of IL-5 significantly decreased CD34(+)/IL-5Ralpha mRNA(+) cells within the bronchial mucosa and the percentage of CD34(+) cells that were CCR3(+) within the bone marrow of atopic asthmatic, but not control, volunteers. Inhalation of IL-5 also induced a significant increase in bronchial mucosal eosinophils in the non-atopic non-asthmatic control volunteers, but not in the asthmatics. IL-5 had no effect on spirometry or airways hyper-reactivity in either group. CONCLUSIONS: Inhaled IL-5 modulated eosinophil progenitor numbers in both the airways and bone marrow of asthmatics and induced local eosinophilia in non-asthmatics.


Subject(s)
Asthma/metabolism , Bone Marrow Cells/metabolism , Bronchi/metabolism , Eosinophils/metabolism , Hematopoiesis , Interleukin-5/metabolism , Myeloid Progenitor Cells/metabolism , Administration, Inhalation , Adult , Antigens, CD34/analysis , Asthma/blood , Asthma/immunology , Asthma/pathology , Asthma/physiopathology , Bone Marrow Cells/drug effects , Bone Marrow Cells/immunology , Bronchi/drug effects , Bronchi/immunology , Bronchi/pathology , Bronchi/physiopathology , Cross-Over Studies , Double-Blind Method , Eosinophils/drug effects , Eosinophils/immunology , Forced Expiratory Volume , Hematopoiesis/drug effects , Humans , Interleukin-5/administration & dosage , Interleukin-5 Receptor alpha Subunit/analysis , Interleukin-5 Receptor alpha Subunit/genetics , Leukocyte Count , Middle Aged , Myeloid Progenitor Cells/drug effects , Myeloid Progenitor Cells/immunology , RNA, Messenger/analysis , Receptors, CCR3 , Receptors, Chemokine/analysis , Recombinant Proteins/metabolism , Severity of Illness Index
8.
J Immunol ; 179(1): 284-94, 2007 Jul 01.
Article in English | MEDLINE | ID: mdl-17579048

ABSTRACT

Although eosinophils play an essential role in allergic inflammation, their role has recently been under controversy. Epidemic studies suggest that hypereosinophilia induced by parasite infection could suppress subsequent Ag sensitization, although the mechanism has not been fully clarified. In this study, we investigated whether eosinophils could suppress the Ag-specific immune response in the airway. BALB/c mice were sensitized and airway challenged with OVA. Systemic hypereosinophilia was induced by delivery of an IL-5-producing plasmid. IL-5 gene delivery suppressed the Ag-specific proliferation and cytokine production of CD4+ T cells in the spleen. IL-5 gene delivery before OVA sensitization significantly suppressed airway eosinophilia and hyperresponsiveness provoked by subsequent OVA airway challenge, while delivery during the OVA challenge did not suppress them. This IL-5-induced immune suppression was abolished in eosinophil-ablated mice, suggesting an essential role of eosinophils. IL-5 treatment increased the production of TGF-beta1 in the spleen, and we demonstrated that the main cellular source of TGF-beta1 production was eosinophils, using eosinophil-ablated mice and depletion study. TGF-beta1, but not IL-5 itself, suppressed the Ag-specific immune response of CD4+ T cells in vitro. Furthermore, IL-5 treatment enhanced phosphorylation of Smad2 in CD4+ T cells. Finally, a TGF-beta type I receptor kinase inhibitor restored this IL-5-induced immune suppression both in vitro and in vivo. These results suggest that IL-5-induced hypereosinophilia could suppress sensitization to Ag via a TGF-beta-dependent mechanism, thus suppressed allergic airway inflammation. Therefore, hypereosinophilia could reveal an immunosuppressive effect in the early stage of Ag-induced immune response.


Subject(s)
Antigens/immunology , Bronchial Hyperreactivity/immunology , Bronchial Hyperreactivity/prevention & control , Hypereosinophilic Syndrome/immunology , Interleukin-5/administration & dosage , Ovalbumin/immunology , Transforming Growth Factor beta/physiology , Animals , Antigens/administration & dosage , Antigens/genetics , Bronchial Hyperreactivity/genetics , Bronchial Hyperreactivity/pathology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Cells, Cultured , Eosinophils/immunology , Eosinophils/metabolism , Gene Transfer Techniques , Growth Inhibitors/administration & dosage , Growth Inhibitors/biosynthesis , Growth Inhibitors/blood , Growth Inhibitors/genetics , Hypereosinophilic Syndrome/genetics , Hypereosinophilic Syndrome/pathology , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Interleukin-5/biosynthesis , Interleukin-5/blood , Interleukin-5/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , Mucus/immunology , Mucus/metabolism , Ovalbumin/administration & dosage , Ovalbumin/genetics , Plasmids/administration & dosage , Plasmids/immunology , Spleen/cytology , Spleen/immunology , Transforming Growth Factor beta/biosynthesis
9.
Immunol Lett ; 97(1): 123-9, 2005 Feb 15.
Article in English | MEDLINE | ID: mdl-15626484

ABSTRACT

Airway inflammation is thought to play a major role in the pathogenesis of bronchial asthma. The precise role of individual inflammatory cells, mediator and asthma related genes in allergic lung diseases is not completely understood. The uteroglobin-related protein (UGRP) 1 was proposed to be an asthma candidate gene and play a role in regulating lung inflammation, however its precise function in the airways remains obscure. In this investigation, we used a mouse model of allergic airway inflammation to establish a relationship between UGRP 1 and IL-5 in airway inflammation. Ovalbumin (OVA) challenged mice demonstrate eosinophilia in airway tissues and high levels of IL-5 in bronchoalveolar lavage (BAL) fluid analogous to that found in bronchial asthma. Interestingly, these "OVA-challenged" mice show down-regulation of Ugrp1 expression as compared with the control group. Regression analysis further demonstrates a significant negative correlation between Ugrp1 mRNA expression in the lung and IL-5 levels in BAL fluid with r = 0.948 and P < 0.0001 when IL-5 levels were normalized by log transformation. Intranasal instillation of IL-5 to mice revealed an inhibitory effect of IL-5 on the expression of Ugrp1 mRNA. Together, these results indicate an involvement of IL-5 in the down-regulation of Ugrp1 expression in airway inflammation such as allergic asthma disease.


Subject(s)
Carrier Proteins/metabolism , Hypersensitivity/metabolism , Interleukin-5/metabolism , Proteins/metabolism , RNA, Messenger , Respiratory System/metabolism , Administration, Intranasal , Animals , Carrier Proteins/genetics , Female , Gene Expression/drug effects , Interleukin-5/administration & dosage , Interleukin-5/genetics , Interleukin-5/pharmacology , Mice , Proteins/genetics , Secretoglobins , Uteroglobin
10.
Int Arch Allergy Immunol ; 134(2): 141-9, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15153794

ABSTRACT

BACKGROUND: Eosinophils play an important role in the pathogenesis of allergic diseases. Sensitization and exposure to cockroach allergen have been demonstrated to be one of the major risk factors for the development of bronchial asthma. However, little is known regarding the functional capacity of cockroach extract antigen to activate human eosinophils. OBJECTIVE: We investigated whether German cockroach extract can activate human eosinophils to release cytotoxic inflammatory mediators. METHODS: Purified eosinophils from the peripheral blood were incubated with various concentrations (0-200 microg/ml) of German cockroach extract antigen. Effector functions of eosinophils were checked by degranulation and superoxide anion production. In addition, we examined surface expression of CD11b and CD69, and intracellular activation of p38 mitogen-activated protein kinase (p38 MAP kinase) in cockroach-stimulated eosinophils. RESULTS: German cockroach extract induced degranulation and superoxide production from human eosinophils. In addition, incubation of eosinophils for 3 h with the cockroach extract resulted in an increased level of the surface expression of CD11b and CD69. Furthermore, cockroach-induced superoxide production from eosinophils was significantly inhibited by the pretreatment of cells with a p38 MAP kinase inhibitor SB202190. Indeed, a large amount of phosphorylated forms of p38 MAP kinase was detected in cockroach-stimulated eosinophils. CONCLUSIONS: Our results suggest that German cockroach extract induces activation of human eosinophils to release cytotoxic inflammatory mediators such as superoxide and granular proteins.


Subject(s)
Allergens/pharmacology , Cockroaches , Eosinophils/drug effects , Eosinophils/physiology , Inflammation Mediators/metabolism , Allergens/administration & dosage , Animals , Antigens, Differentiation/biosynthesis , Antigens, Differentiation/drug effects , Cell Degranulation/drug effects , Cytotoxicity, Immunologic/drug effects , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Eosinophil-Derived Neurotoxin , Eosinophils/metabolism , Exocytosis/drug effects , Humans , Interleukin-5/administration & dosage , Mitogen-Activated Protein Kinases/drug effects , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation/drug effects , Ribonucleases/drug effects , Ribonucleases/metabolism , Signal Transduction/drug effects , Superoxides/metabolism , p38 Mitogen-Activated Protein Kinases
12.
Ross Fiziol Zh Im I M Sechenova ; 90(10): 1262-9, 2004 Oct.
Article in Russian | MEDLINE | ID: mdl-15628183

ABSTRACT

By mehanographic method, contraktile responses of the airways smooth muscles in experimental bronchial asthma in porpoises intact and incubated with interleykin-5, were studied. Sensitization of ovalbumin animals results in development of hypersensitivity to inhalation of the fiber with external attributes of infringement of bronchial passableness such as cough and a shortness of breath. Morphologically the process is accompanied by destruction of epithelium of the bronchial tubes, development of an immune inflammation in a bronchial wall, and a hypertrophy of the muscular layer. In the sensitized animals, development of hyper-responsiveness of the airways smooth muscles to histamine was obvious as shown in a significant decrease of the threshold concentration and an increase in the maximal amplitude of reduction. Interleukin-5 was shown to strengthen this process. Responses to holinergic and R2-adrenerdic influences practically did not change. The data obtained corroborate the hypothesis of development of the interleukin-5-depending bronchial hyper-responsiveness in absence of eosinophile damage in the mucous membrane of the bronchial tubes.


Subject(s)
Asthma/physiopathology , Bronchial Hyperreactivity/physiopathology , Interleukin-5/administration & dosage , Muscle Contraction/drug effects , Muscle, Smooth/physiopathology , Animals , Asthma/pathology , Guinea Pigs , Interleukin-5/metabolism , Male , Muscle, Smooth/pathology , Respiratory Mucosa/pathology , Respiratory Mucosa/physiopathology
13.
J Immunol ; 171(10): 5470-81, 2003 Nov 15.
Article in English | MEDLINE | ID: mdl-14607953

ABSTRACT

Leukocyte infiltration is characteristic of lung injury and fibrosis, and its role during tissue repair and fibrosis is incompletely understood. We found that overexpression of IL-5 in transgenic mice (IL-5(TG)) or by adenoviral gene transfer increased bleomycin (blm)-induced lung injury, fibrosis, and eosinophilia. Surprisingly, blm-treated IL-5-deficient (IL-5(-/-)) mice also developed pronounced pulmonary fibrosis but characterized by marked T lymphocyte infiltration and absence of eosinophilia. In both murine strains however, induction of lung TGF-beta expression was evident. Purified lung eosinophils from blm-treated IL-5(TG) mice stimulated alpha-smooth muscle actin and collagen expression in mouse lung fibroblasts, without affecting proliferation. Furthermore instillation of purified eosinophils into murine lungs resulted in extension of blm-induced lung fibrosis, thus confirming a role for eosinophils. However, lung T lymphocytes from blm-treated IL-5(-/-) mice were able to stimulate fibroblast proliferation but not alpha-smooth muscle actin or collagen expression. Blocking T cell influx by anti-CD3 Abs abrogated lung fibrosis, thus also implicating T lymphocytes as a key participant in fibrosis. Pulmonary fibrosis in IL-5(TG) mice was preferentially associated with type 2 cytokines (IL-4 and IL-13), whereas fibrotic lesions in IL-5(-/-) animals were accompanied by proinflammatory cytokine (TNF-alpha, IL-1beta, and IFN-gamma) expression. We suggest that eosinophils and T cells contribute distinctly to the development of blm-induced lung fibrosis potentially via their production of different cytokine components, which ultimately induce TGF-beta expression that is intimately involved with the fibrosis.


Subject(s)
Bleomycin , Eosinophils/immunology , Lung/pathology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , T-Lymphocyte Subsets/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Bleomycin/administration & dosage , CD3 Complex/immunology , Cell Separation , Cells, Cultured , Coculture Techniques , Cytokines/biosynthesis , Cytokines/classification , Disease Models, Animal , Eosinophils/metabolism , Eosinophils/pathology , Eosinophils/transplantation , Genetic Vectors/administration & dosage , Inflammation/chemically induced , Inflammation/genetics , Inflammation/immunology , Interleukin-5/administration & dosage , Interleukin-5/biosynthesis , Interleukin-5/deficiency , Interleukin-5/genetics , Lung/drug effects , Lung/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Pulmonary Eosinophilia/chemically induced , Pulmonary Eosinophilia/genetics , Pulmonary Eosinophilia/immunology , Pulmonary Eosinophilia/pathology , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology , Th2 Cells/immunology , Th2 Cells/metabolism
14.
J Immunol ; 171(8): 4379-84, 2003 Oct 15.
Article in English | MEDLINE | ID: mdl-14530363

ABSTRACT

We have reported previously that HIV-TAT-dominant negative (dn) Ras inhibits eosinophil adhesion to ICAM-1 after activation by IL-5 and eotaxin. In this study, we evaluated the role of Ras in Ag-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of dnRas, which was fused to an HIV-TAT protein transduction domain (TAT-dnRas). Uptake of TAT-dnRas (t(1/2) = 12 h) was demonstrated in leukocytes after i.p. administration. OVA-sensitization significantly increased eosinophil and lymphocyte numbers in bronchoalveolar lavage fluid 24 h after final challenge. Treatment of animals with 3-10 mg/kg TAT-dnRas blocked the migration of eosinophils from 464 +/- 91 x 10(3)/ml to 288 +/- 79 x 10(3)/ml with 3 mg/kg of TAT-dnRas (p < 0.05), and further decreased to 116 +/- 63 x 10(3)/ml after 10 mg/kg TAT-dnRas (p < 0.01). Histological examination demonstrated that inflammatory cell infiltration (largely eosinophils and mononuclear cells) and mucin production around the airways caused by OVA were blocked by TAT-dnRas. OVA challenge also caused airway hyperresponsiveness to methacholine, which was dose dependently blocked by treatment with TAT-dnRas. TAT-dnRas also blocked Ag-induced IL-4 and IL-5, but not IFN-gamma, production in lung tissue. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by pretreatment with TAT-dnRas. By contrast, TAT-green fluorescent protein or dnRas lacking the TAT protein transduction domain did not block airway inflammation, cytokine production, or airway hyperresponsiveness. We conclude that Ras mediates Th2 cytokine production, airway inflammation, and airway hyperresponsiveness in immune-sensitized mice.


Subject(s)
Bronchial Hyperreactivity/immunology , Bronchial Hyperreactivity/prevention & control , Gene Products, tat/administration & dosage , HIV/immunology , Inflammation Mediators/administration & dosage , Lung/pathology , Recombinant Fusion Proteins/administration & dosage , ras Proteins/administration & dosage , Administration, Intranasal , Animals , Antigens/administration & dosage , Antigens/immunology , Bronchial Hyperreactivity/pathology , Cell Migration Inhibition , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Eosinophils/immunology , Eosinophils/pathology , Gene Products, tat/genetics , HIV/genetics , Humans , Injections, Intraperitoneal , Interleukin-5/administration & dosage , Kinetics , Lung/immunology , Lung/metabolism , Lymphocytes/immunology , Lymphocytes/pathology , Male , Mice , Mice, Inbred C57BL , Mucus/metabolism , Ovalbumin/administration & dosage , Ovalbumin/immunology , Recombinant Fusion Proteins/genetics , Th2 Cells/immunology , Th2 Cells/metabolism , Transduction, Genetic , ras Proteins/genetics , tat Gene Products, Human Immunodeficiency Virus
15.
J Allergy Clin Immunol ; 111(3): 558-66, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12642837

ABSTRACT

BACKGROUND: There is evidence that the cytokine IL-5 is a prominent feature of airway inflammation in asthma. OBJECTIVE: The aim of this study was to determine whether exogenous IL-5 could cause changes in lung physiology, the early and late airway response after antigen challenge, and airway inflammation in rats that do not have a propensity to develop these changes after sensitization and challenge. METHOD AND RESULTS: Intratracheal administration of IL-5 to ovalbumin sensitized Brown Norway SSN rats increased the airway responsiveness to methacholine (AHR) 20 hours after administration of IL-5 at the same time as an increase in neutrophils occurred in the lung lavage. This effect was dose dependent and was not caused by endotoxin. Concurrent intratracheal administration of 50 ng of anti-IL-5 monoclonal antibody with 10 microg of recombinant human IL-5 decreased the AHR and neutrophil influx. Pretreatment with 3 microg of IL-5 had no effect on the early and late airway response or on AHR after ovalbumin challenge. However, IL-5 increased lung re-sistance 20 hours after antigen challenge. Although total lung cells and differential counts did not differ significantly 8 hours after antigen challenge, the blood lymphocyte CD4/CD8 ratio decreased in IL-5 pretreated rats (P <.05). In addition, in situ hybridization showed a significant increase in cells within the airway wall expressing IL-4 and IL-5 mRNA in IL-5 treated/challenged rats compared to controls (P <.05). CONCLUSION: The intratracheal administration of IL-5 causes only part of the physiologic changes that are associated with asthma. Other factors are necessary to obtain the complete asthma phenotype.


Subject(s)
Interleukin-5/pharmacology , Respiratory System/drug effects , Respiratory System/physiopathology , Respiratory Tract Diseases/physiopathology , Animals , Blood Cells/pathology , Bronchoalveolar Lavage Fluid/cytology , Cell Differentiation/drug effects , Cytokines/genetics , Dose-Response Relationship, Drug , Eosinophils/pathology , Humans , Immunization , Immunoglobulin E/blood , Inflammation/physiopathology , Interleukin-5/administration & dosage , Intubation, Intratracheal , Lung/metabolism , Lymphocyte Subsets/pathology , Male , Methacholine Chloride/pharmacology , Ovalbumin/immunology , RNA, Messenger/metabolism , Rats , Rats, Inbred BN , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Stem Cells/pathology
16.
Am J Respir Crit Care Med ; 164(8 Pt 1): 1403-9, 2001 Oct 15.
Article in English | MEDLINE | ID: mdl-11704586

ABSTRACT

Asthma is characterized by the accumulation of activated T cells and eosinophils within the airway. Eosinophils derive from CD34(+) bone marrow progenitor cells under the influence of hematopoietic growth factors, subsequently migrating to the airways under the cooperative influence of interleukin (IL)-5 and chemokines, including eotaxin. We compared the relative effects of systemic versus local IL-5 on progenitor-cell mobilization and mature eosinophil phenotype by using flow cytometry, following the administration of intravenous (2 microg) or inhaled (15 microg) IL-5 to nine patients with mild asthma. Intravenous IL-5 induced a rapid reduction in circulating eosinophil counts followed by prolonged blood eosinophilia. Both intravenous (p < 0.002) and inhaled (p < 0.05) IL-5 significantly increased CD34(+)/CD45(+) lymphoblastoid eosinophil progenitors. Intravenous IL-5 increased mature eosinophil CCR3 expression from a baseline mean fluorescence intensity (MFI) of 658 +/- 51.7 to 995 +/- 93.2 at 24 h (p < 0.05), but had no effect on interleukin-5 receptor subunit alpha or CD11b expression. Lymphocyte CCR3 MFI was increased by intravenous IL-5 from 38.5 +/- 13.6 at baseline to 73.6 +/- 14.3 at 24 h (p < 0.05). Systemic IL-5 increased circulating eosinophil progenitors, suggesting a key role for systemic IL-5 in eosinophil mobilization. Further, IL-5 causes terminal maturation of the eosinophil by increasing CCR3 expression, potentially affecting CCR3-dependent chemotaxis by eosinophils and lymphocytes.


Subject(s)
Antigens, CD34/immunology , Asthma/immunology , Eosinophils/immunology , Interleukin-5/administration & dosage , Receptors, Chemokine/biosynthesis , Adult , Asthma/blood , CD11 Antigens/biosynthesis , Cell Movement , Double-Blind Method , Eosinophils/physiology , Female , Humans , Interleukin-5/pharmacology , Leukocyte Common Antigens/immunology , Male , Receptors, CCR3 , Receptors, Interleukin/biosynthesis
17.
Eur J Pharmacol ; 430(1): 123-33, 2001 Oct 26.
Article in English | MEDLINE | ID: mdl-11698072

ABSTRACT

We investigated the effects of F-1322 (N-[2-[4-(benzhydryloxy)piperidino]ethyl]-3-hydroxy-5-(3-pyridylmethoxy)-2-naphthamide), a new compound that inhibits both thromboxane A2 synthetase and 5-lipoxygenase and that functions as a histamine antagonist, on the Ascaris antigen-induced late asthmatic response and pulmonary eosinophilia in guinea pigs. Oral administration of F-1322 (10-100 mg/kg) inhibited the antigen-induced late asthmatic response in a dose-dependent manner. Histological analysis revealed that F-1322 prevented the accumulation of eosinophils in the airways and this was paralleled by a decrease in the number of eosinophils and lymphocytes recovered in bronchoalveolar lavage fluid. F-1322 (0.1-10 microM) inhibited eotaxin-induced chemotaxis and actin polymerization of eosinophils in vitro in a concentration-dependent manner, while oral administration of F-1322 dose-dependently suppressed the migration of eosinophils into the airways in vivo in response to infusion of interleukin 5 and eotaxin in combination. F-1322 may, thus, improve the late asthmatic response in this model, in part, by preventing the accumulation of eosinophils in the airways. The pharmacological profile of F-1322 indicates that this drug is likely to be useful in the treatment of allergic diseases such as asthma.


Subject(s)
Anti-Asthmatic Agents/pharmacology , Asthma/drug therapy , Eosinophilia/immunology , Lung Diseases/immunology , Naphthalenes/pharmacology , Airway Resistance/drug effects , Allergens , Animals , Antigens, Helminth , Asthma/etiology , Asthma/immunology , Bronchoalveolar Lavage Fluid/cytology , Cell Movement/drug effects , Cells, Cultured , Chemokine CCL11 , Chemokines, CC/administration & dosage , Chemotaxis , Disease Models, Animal , Eosinophils/drug effects , Eosinophils/immunology , Guinea Pigs , Interleukin-5/administration & dosage , Time Factors
18.
Thorax ; 56(12): 935-40, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11713356

ABSTRACT

BACKGROUND: Interleukin 5 (IL-5) has an important role in mobilisation of eosinophils from the bone marrow and in their subsequent terminal differentiation. A study was undertaken to determine whether inhaled and intravenous IL-5 could induce pulmonary eosinophilia and bronchial hyperresponsiveness (BHR) independently of these effects. METHODS: Nine mild asthmatics received inhaled (15 microg) or intravenous (2 microg) IL-5 or placebo in random order in a double blind, crossover study. Blood samples were taken before and at 0.5, 1, 2, 3, 4, 5, 24, and 72 hours following IL-5 or placebo, and bronchial responsiveness (PC(20) methacholine) and eosinophil counts in induced sputum were determined. RESULTS: Serum IL-5 levels were markedly increased 30 minutes after intravenous IL-5 (p=0.002), and sputum IL-5 levels increased 4 and 24 hours after inhaled IL-5 (p<0.05). Serum eotaxin was raised 24 hours after intravenous IL-5 but not after inhaled IL-5 or placebo. Blood eosinophils were markedly reduced 0.5-2 hours after intravenous IL-5 (p<0.05), followed by an increase at 3, 4, 5, and 72 hours (p<0.05). Sputum eosinophils rose significantly in all three groups at 24 hours but there were no differences between the groups. Bronchial responsiveness was not affected by IL-5. CONCLUSION: The effects of IL-5 appear to be mainly in the circulation, inducing peripheral mobilisation of eosinophils to the circulation without any effect on eosinophil mobilisation in the lungs or on bronchial responsiveness.


Subject(s)
Asthma/drug therapy , Interleukin-5/pharmacology , Administration, Inhalation , Adult , Analysis of Variance , Asthma/metabolism , Bronchial Provocation Tests , Cell Count , Chemokine CCL11 , Chemokines, CC/blood , Cross-Over Studies , Double-Blind Method , Enzyme-Linked Immunosorbent Assay , Female , Forced Expiratory Volume , Humans , Infusions, Intravenous , Interleukin-5/administration & dosage , Interleukin-5/analysis , Male , Pulmonary Eosinophilia/chemically induced , Sputum/cytology
19.
Clin Exp Immunol ; 122(3): 300-7, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11122232

ABSTRACT

Eosinophils have a variety of functions. Although increasing evidence links the presence of eosinophils to airway damage, studies have not examined in detail if, and how, eosinophils affect skin inflammation. The purpose of this study was to determine whether eosinophil infiltration augments the contact sensitivity reaction in vivo. Guinea-pigs were sensitized with 2, 4-dinitrochlorobenzene and challenged on the dorsal skin or on the right ear lobe. The number of eosinophils and macroscopic changes of the skin lesion in the presence or absence of human recombinant IL-5 (rIL-5) administered at the remote site was assessed. The reaction on the dorsal skin was acutely eczematous with considerable basophil infiltration. In contrast, eosinophils had extensively infiltrated the right ear lobe and major basic protein was deposited in the dermis. A subcutaneous injection of rIL-5 (10 pmol/kg) at the remote site (left ear lobe) 12 h after challenge induced transient blood eosinophilia and enhanced eosinophil accumulation in the challenged ear lobe. These changes were accompanied by increased ear swelling and severe erythema. In contrast, eosinophil infiltration was significantly inhibited by rIL-5 administered at the time of challenge. Ear thickness, as well as the erythema and oedema, were also reduced. These data suggest that marked eosinophil infiltration enhances skin inflammation in allergic contact dermatitis. Moreover, locally administered IL-5 functions remotely by controlling eosinophil recruitment into the skin. The guinea-pig model of contact sensitivity may be useful for evaluating therapies and pharmaceuticals targeted at eosinophil infiltration.


Subject(s)
Dermatitis, Allergic Contact/immunology , Dermatitis, Allergic Contact/pathology , Eosinophils/immunology , Interleukin-5/immunology , Animals , Dinitrochlorobenzene/administration & dosage , Female , Guinea Pigs , Humans , Injections, Subcutaneous , Interleukin-5/administration & dosage , Irritants/administration & dosage , Leukocyte Count , Skin/immunology , Skin/pathology , Time Factors
20.
J Immunol ; 164(4): 2142-50, 2000 Feb 15.
Article in English | MEDLINE | ID: mdl-10657668

ABSTRACT

The mechanisms regulating the selective migration and degranulation of eosinophils in the asthmatic lung and the subsequent development of airways hyperreactivity (AHR) have not been fully delineated. In this investigation, we have employed a novel transgene model to facilitate the dissection of the contributions of IL-5 and/or eotaxin to eosinophil function in the absence of complex tissue signals derived from the allergic lung. Gene transfer of IL-5 and/or eotaxin to the lungs of naive mice induced a pronounced and selective airways eosinophilia, but did not result in eosinophil degranulation or AHR. Airways eosinophilia occurred independently of the induction of a blood eosinophilia, but was markedly augmented by the coexpression of both cytokines and/or by the transient mobilization of eosinophils from the bone marrow by the administration of i.v. IL-5. However, for eosinophil degranulation and AHR to occur, the inhalation of Ag was required in association with IL-5 and eotaxin expression. Investigations in IL-5-deficient mice linked eosinophilia, and not solely IL-5 and eotaxin, with the induction of AHR. Furthermore, eosinophil degranulation and AHR were dependent on CD4+ T cells. Importantly, this investigation shows that IL-5 regulates eosinophilia within the lung as well as in the circulation and also amplifies eotaxin-induced chemotaxis in the airway compartment. Moreover, the interplay between these cytokines, CD4+ T cells, and factors generated by Ag inhalation provides fundamental signals for eosinophil degranulation and the induction of AHR.


Subject(s)
Bronchial Hyperreactivity/immunology , Cell Degranulation/immunology , Chemokines, CC , Chemotactic Factors, Eosinophil/biosynthesis , Chemotaxis, Leukocyte/immunology , Cytokines/biosynthesis , Eosinophils/immunology , Interleukin-5/biosynthesis , Lung/metabolism , Administration, Intranasal , Animals , Bronchial Hyperreactivity/etiology , Bronchial Hyperreactivity/pathology , Bronchial Hyperreactivity/virology , CD4-Positive T-Lymphocytes/immunology , Chemokine CCL11 , Chemotactic Factors, Eosinophil/genetics , Choline/administration & dosage , Choline/analogs & derivatives , Cytokines/genetics , Eosinophilia/immunology , Eosinophils/metabolism , Eosinophils/pathology , Genetic Vectors/administration & dosage , Injections, Intravenous , Interleukin-5/administration & dosage , Interleukin-5/genetics , Lung/immunology , Lung/virology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Ovalbumin/administration & dosage , Vaccinia virus/genetics , Vaccinia virus/growth & development
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