title: IL-13 is pivotal in the fibro-obliterative process of bronchiolitis obliterans syndrome.
abstract: Acute allograft rejection is considered to be a predominately type 1 immune mediated response to the donor alloantigen. However, the type 2 immune mediated response has been implicated in multiple fibroproliferative diseases. Based on the fibro-obliterative lesion found during bronchiolitis obliterans syndrome (BOS), we hypothesized that the type 2 immune mediated response is involved in chronic lung allograft rejection. Specifically, whereas acute rejection is, in part, a type 1 immune response, chronic rejection is, in part, a type 2 immune response. We found the type 2 cytokine, IL-13, to be elevated and biologically active in human bronchoalveolar lavage fluid during BOS. Translational studies using a murine model of BOS demonstrated increased expression of IL-13 and its receptors that paralleled fibro-obliteration. In addition, in vivo neutralization of IL-13 reduced airway allograft matrix deposition and murine BOS, by a mechanism that was independent of IL-4. Furthermore, using IL-13Ralpha2(-/-) mice, we found increased fibro-obliteration. Moreover, anti-IL-13 therapy in combination with cyclosporin A had profound effects on reducing murine BOS. This supports the notion that IL-13 biological axis plays an important role during the pathogenesis of BOS independent of the IL-4 biological axis.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Keane
authors.forename: Brigitte N
authors.initials: BN
authors.lastname: Gomperts
authors.forename: Samuel
authors.initials: S
authors.lastname: Weigt
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Xue
authors.forename: Marie D
authors.initials: MD
authors.lastname: Burdick
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakamura
authors.forename: David A
authors.initials: DA
authors.lastname: Zisman
authors.forename: Abbas
authors.initials: A
authors.lastname: Ardehali
authors.forename: Rajan
authors.initials: R
authors.lastname: Saggar
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lynch
authors.forename: Cory
authors.initials: C
authors.lastname: Hogaboam
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: David J
authors.initials: DJ
authors.lastname: Ross
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Grusby
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.forename: John A
authors.initials: JA
authors.lastname: Belperio
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D005355:Fibrosis; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D016040:Lung Transplantation / Q000276:immunology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D053660:Receptors, Interleukin-13 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D018793:Interleukin-13; D053660:Receptors, Interleukin-13; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D016572:Cyclosporine