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Antibodies to MHC Class I Induce Autoimmunity: Role in the Pathogenesis of Chronic Rejection¹

Naohiko Fukami^*, Sabarinathan Ramachandran^*, Deepti Saini^*, Michael Walter, William Chapman^*, G. Alexander Patterson and Thalachallour Mohanakumar^2,*,

^* Department of Surgery, Department of Pathology and Immunology, Department of Internal Medicine, and Department of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, MO 63110

Alloimmunity to mismatched donor HLA-Ags and autoimmunity to self-Ags have been hypothesized to play an important role in immunopathogenesis of chronic rejection of transplanted organs. However, it is not known what role, if any, alloimmune response plays in inducing autoimmunity. To test whether Ab-developed posttransplantation to mismatched donor MHC induces autoimmunity and chronic rejection, we developed a murine model wherein anti-MHC class I Abs or control (C1.18.4/anti-keratin) were administered intrabronchially into native lungs. Animals receiving anti-MHC class I, but not control Abs, developed marked cellular infiltration around vessels and bronchiole of lung by day 15, followed by epithelial hyperplasia, fibrosis, and occlusion of the distal airways similar to chronic rejection following human lung transplantation. Lungs of mice receiving anti-MHC class I showed increased expression of chemokines, their receptors, and growth factors, and induced IL-17 as well as de novo Abs to self-Ags, K-1 tubulin, and collagen V. IL-17 neutralization by anti-IL-17 resulted in reduction of autoantibody and lesions induced by anti-MHC class I Abs. Thus, our results indicate that Abs to donor MHC can induce autoimmunity, mediated by IL-17, which plays a pivotal role in chronic rejection postlung transplantation. Therefore, approaches to prevent autoimmunity should be considered for the treatment of chronic rejection postlung 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 HL66452 (to T.M.) from National Heart, Lung, and Blood Institute, and the contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute.

² Address correspondence and reprint requests to Dr. Thalachallour Mohanakumar, Washington University School of Medicine, Department of Surgery, Box 1809-3328 CSRB, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: kumart{at}wustl.edu

³ Abbreviations used in this paper: LTx, lung transplantation; BMP, bone morphogenetic protein; BOS, bronchiolitis obliterans syndrome; ColV, collagen V; EC, endothelial cell; FGF, fibroblast growth factor; GC, germinal center; HSP-60, heat shock protein 60; O/N, overnight; RT, room temperature.

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