title: Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma.
abstract: IL-13 and IL-4 are key contributors to the asthmatic phenotype. The temporal role of these cytokines in airway function, inflammation, and remodeling were assessed in a chronic murine model of Asperigillus fumigatus-induced allergic asthma. IL-13 and IL-4 protein levels were significantly elevated by 30 days after conidia challenge in A. fumigatus-sensitized mice. Furthermore, IL-13Ralpha1 mRNA expression was significantly elevated 7 days after conidia challenge and remained elevated until day 21. In contrast, IL-13Ralpha2 mRNA expression, although constitutively expressed in naive lung, was absent in the lungs of A. fumigatus-sensitized mice both before and after conidia challenge. Membrane-bound IL-4R mRNA expression was significantly elevated 7 days after conidia challenge; however, soluble IL-4R mRNA expression was increased 30 days after conidia challenge. Immunoneutralization of IL-13 between days 14 and 30 or days 30 and 38 after fungal sensitization and challenge significantly attenuated airway hyperresponsiveness, collagen deposition, and goblet cell hyperplasia at day 38 after conidia challenge; however, the effects of IL-4 immunoneutralization during the same time periods were not as marked. IFN-gamma and IL-12 release after Aspergillus Ag restimulation was elevated from spleen cells isolated from mice treated with IL-4 anti-serum compared with IL-13 anti-serum or normal rabbit serum-treated mice. This study demonstrates a pronounced therapeutic effect of IL-13-immunoneutralization at extended time points following the induction of chronic asthma. Most importantly, these therapeutic effects were not reversed following cessation of treatment, and IL-13 anti-serum treatment did not alter the systemic immune response to Ag restimulation, unlike IL-4 immunoneutralization. Therefore, IL-13 provides an attractive therapeutic target in allergic asthma.
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. kblease@med.umich.edu
authors: K
authors: K
authors: Blease
authors: C
authors: C
authors: Jakubzick
authors: J
authors: J
authors: Westwick
authors: N
authors: N
authors: Lukacs
authors: S L
authors: SL
authors: Kunkel
authors: C M
authors: CM
authors: Hogaboam
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000008:administration & dosage; D001232:Aspergillus fumigatus / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020397:Goblet Cells / Q000473:pathology; D006965:Hyperplasia; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology* / Q000627:therapeutic use*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008808:Mice, Inbred CBA; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000517:prevention & control; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013172:Spores, Fungal / Q000276:immunology; D013997:Time Factors
chemical_list: D000946:Antigens, Fungal; D016207:Cytokines; C508183:Il13ra1 protein, mouse; D007106:Immune Sera; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D003094:Collagen