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De Novo Production of K-1 Tubulin-Specific Antibodies: Role in Chronic Lung Allograft Rejection¹

Trudie A. Goers^2,*, Sabarinathan Ramachandran^2,*, Aviva Aloush, Elbert Trulock, G. Alexander Patterson^* and Thalachallour Mohanakumar^3,*,

^* Department of Surgery, Department of Pulmonary Medicine, and Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110

Lung transplantation is the treatment option for a variety of end-stage pulmonary diseases. Posttransplant development of Abs against donor HLA and non-HLA Ags have been associated with acute and chronic rejection of transplanted organs. Development of bronchiolitis obliterans syndrome (BOS) following lung transplantation has been correlated with de novo production of anti-donor-HLA Abs. However, only a portion of the patients with BOS demonstrate detectable anti-donor-HLA Abs. Airway epithelium is considered as a major target for lung allograft rejection. In this study we demonstrate that many BOS⁺ patients (12 of 36) develop Abs reactive to epithelial cell Ag that are distinct from HLA. Furthermore, de novo production of antiepithelial cell Ab precedes clinical onset of BOS. N-terminal sequencing and blastx analysis as well as blocking with K-1 tubulin-specific Ab identified the epithelial Ag as K-1 tubulin. Binding of the de novo-produced anti-K-1 tubulin Abs to the airway epithelial cells resulted in the increased expression of transcription factors (TCF5 and c-Myc), leading to increased expression of fibrogenic growth factors, activation of cell cycle signaling, and fibroproliferation, the central events in immunopathogenesis of BOS following human lung transplantation.

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 by National Institutes of Health Grant HL56643 (to T.M.) and National Institutes of Health Training Grant 5T32AI07163 (to T.A.G.).

² T.A.G. and S.R. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. T. Mohanakumar, Washington University School of Medicine, Department of Surgery, Box 8109-3328 CSRB, 660 South Euclid Avenue, Saint Louis, MO 63110. E-mail address: kumart{at}wustl.edu

⁴ Abbreviations used in this paper: BOS, bronchiolitis obliterans syndrome; AEC, airway epithelial cell; HB-EGF, heparin-binding epidermal growth factor-like growth factor; HSP, heat shock protein; K-1, keratinocyte-alpha 1; KCL, kidney cell line; PKC, phosphokinase C; PRA, panel-reactive Abs; VEGF, vascular endothelial growth factor.