IL-13 is pivotal in the fibro-obliterative process of bronchiolitis obliterans syndrome.
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.
Keane
Michael P
MP
Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Gomperts
Brigitte N
BN
Weigt
Samuel
S
Xue
Ying Ying
YY
Burdick
Marie D
MD
Nakamura
Hiromi
H
Zisman
David A
DA
Ardehali
Abbas
A
Saggar
Rajan
R
Lynch
Joseph P
JP
Hogaboam
Cory
C
Kunkel
Steven L
SL
Lukacs
Nicholas W
NW
Ross
David J
DJ
Grusby
Michael J
MJ
Strieter
Robert M
RM
Belperio
John A
JA
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
D000906:Antibodies; D018793:Interleukin-13; D053660:Receptors, Interleukin-13; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D016572:Cyclosporine