De novo production of K-α1 tubulin-specific antibodies: Role in chronic lung allograft rejection

Trudie A. Goers, Sabarinathan Ramachandran, Aviva Aloush, Elbert Trulock, G. Alexander Patterson, Thalachallour Mohanakumar

Research output: Contribution to journalArticle

157 Scopus citations

Abstract

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-αl tubulin-specific Ab identified the epithelial Ag as K-αl tubulin. Binding of the de novo-produced anti-K-αl 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.

Original languageEnglish
Pages (from-to)4487-4494
Number of pages8
JournalJournal of Immunology
Volume180
Issue number7
DOIs
StatePublished - Apr 1 2008

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