IL-13 fusion cytotoxin ameliorates chronic fungal-induced allergic airway disease in mice.
IL-13 has emerged as a major contributor to allergic and asthmatic responses, and as such it represents an attractive target in these diseases. In this study, IL-13-responsive cells in the lung were targeted via the intranasal administration of IL-13-PE38QQR (IL-13-PE), comprised of human IL-13 and a derivative of Pseudomonas exotoxin, to Aspergillus fumigatus-sensitized mice challenged with A. fumigatus spores, or conidia. Mice received 50, 100, or 200 ng of IL-13-PE or diluent alone (i.e., control group) on alternate days from day 14 to day 28 after the conidia challenge. The control group of mice exhibited significant airway hyperreactivity, goblet cell hyperplasia, and peribronchial fibrosis at day 28 after conidia. Although the two lower doses of IL-13-PE had limited therapeutic effects in mice with fungal-induced allergic airway disease, the highest dose of IL-13-PE tested significantly reduced all features of airway disease compared with the control group. Whole lung mRNA expression of IL-4Ralpha and IL-13Ralpha1 was markedly reduced, whereas bronchoalveolar lavage and whole lung levels of IFN-gamma were significantly elevated in mice treated with 200 ng of IL-13-PE compared with the control group. This study demonstrates that a therapy designed to target IL-13-responsive cells in the lung ameliorates established fungal-induced allergic airway disease in mice.
Blease
K
K
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Jakubzick
C
C
Schuh
J M
JM
Joshi
B H
BH
Puri
R K
RK
Hogaboam
C M
CM
D036002:ADP Ribose Transferases; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000281:Administration, Intranasal; D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000628:therapy; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002908:Chronic Disease; D004306:Dose-Response Relationship, Immunologic; D005098:Exotoxins / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005355:Fibrosis; D020397:Goblet Cells / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood; D007074:Immunoglobulin G / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology / Q000628:therapy; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D018793:Interleukin-13 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008808:Mice, Inbred CBA; D010865:Pilot Projects; D011550:Pseudomonas aeruginosa / Q000276:immunology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000235:genetics; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology*; D013601:T-Lymphocytes / Q000473:pathology; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D005098:Exotoxins; D007073:Immunoglobulin E; D007074:Immunoglobulin G; D007371:Interferon-gamma; D018664:Interleukin-12; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse