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

• Published in: Journal of Immunology Vol. 178; no. 1; pp. 511 - 519
• Main Authors: Keane, Michael P, Gomperts, Brigitte N, Weigt, Samuel, Xue, Ying Ying, Burdick, Marie D, Nakamura, Hiromi, Zisman, David A, Ardehali, Abbas, Saggar, Rajan, Lynch, Joseph P., III, Hogaboam, Cory, Kunkel, Steven L, Lukacs, Nicholas W, Ross, David J, Grusby, Michael J, Strieter, Robert M, Belperio, John A
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.01.2007
• Subjects: Animals; Antibodies - pharmacology; Bronchiolitis Obliterans - immunology; Bronchiolitis Obliterans - pathology; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - immunology; Cyclosporine - pharmacology; Female; Fibrosis; Graft Rejection - immunology; Humans; Interleukin-13 - analysis; Interleukin-13 - antagonists & inhibitors; Interleukin-13 - metabolism; Interleukin-4 - metabolism; Lung Transplantation - immunology; Male; Mice; Mice, Mutant Strains; Receptors, Interleukin-13 - antagonists & inhibitors; Receptors, Interleukin-13 - genetics; Receptors, Interleukin-13 - metabolism; Syndrome; Transforming Growth Factor beta - metabolism; Up-Regulation
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.1.511

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.