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IL-13 Is Pivotal in the Fibro-Obliterative Process of Bronchiolitis Obliterans Syndrome¹

Michael P. Keane^*, Brigitte N. Gomperts, Samuel Weigt^*, Ying Ying Xue^*, Marie D. Burdick^||, Hiromi Nakamura^*, David A. Zisman^*, Abbas Ardehali, Rajan Saggar^*, Joseph P. Lynch, III^*, Cory Hogaboam, Steven L. Kunkel, Nicholas W. Lukacs, David J. Ross^*, Michael J. Grusby^¶, Robert M. Strieter^|| and John A. Belperio^2,*

^* Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Department of Pediatrics, and Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; ^¶ Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and ^|| Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908

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-13R2^–/– 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported, in part, by grants from the National Institutes of Health (HL080206 and HL086491 to J.A.B.; P50HL67665 to M.P.K. and R.M.S.; CA87879, P50CA90388, and HL66027 to R.M.S.; HL087186 and AR055075 to M.P.K.).

² Address correspondence and reprint requests to Dr. John A. Belperio, Department of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Room 14-154, Warren Hall, Box 711922, 900 Veteran Avenue, Los Angeles, CA 90095-1786. E-mail address: jbelperio{at}mednet.ucla.edu

³ Abbreviations used in this paper: BOS, bronchiolitis obliterans syndrome; BALF, bronchoalveolar lavage fluid; CsA, cyclosporin A; FBOS, future BOS; mBOS, murine BOS; NHLF, normal human lung fibroblast; qPCR, quantitative PCR; C_T, threshold cycle; SFM, serum-free medium; TBOS, treated BOS.