title: Immune response to tissue-restricted self-antigens induces airway inflammation and fibrosis following murine lung transplantation.
abstract: Immune responses against lung-associated self-antigens (self-Ags) are hypothesized to play a role in the development of chronic lung graft rejection. We determined whether immune responses to lung self-Ags, K-alpha-1-tubulin (Kα1T) and Collagen V (Col-V) in the absence of alloimmunity, could promote airway inflammation and fibrosis. Following syngeneic murine orthotopic lung transplantation (LTx) we administered antibodies (Abs) to either Kα1T or Col-V or in combination to both of these self-Ags. As compared to recipients of isotype control Abs, Kα1T Abs and/or Col-V Abs-treated recipients had marked lung graft cellular infiltration and bronchiolar fibrosis. This inflammation was also associated the accumulation of Kα1T and Col-V-specific interferon-γ+ and IL-17+ T cells. Notably, the administration of Abs to Kα1T led to cellular and humoral immune responses to Col-V prior to development of fibrosis, and vice versa, indicating that epitope spreading can occur rapidly in an alloantigen independent manner. Collectively, these data support a model of chronic LTx rejection where the progressive loss of self-tolerance through epitope spreading promotes airway fibrosis. Strategies that target autoreactive Abs may be useful to inhibit chronic rejection of lung grafts.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: V
authors.initials: V
authors.lastname: Subramanian
authors.forename: S
authors.initials: S
authors.lastname: Ramachandran
authors.forename: B
authors.initials: B
authors.lastname: Banan
authors.forename: A
authors.initials: A
authors.lastname: Bharat
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Benshoff
authors.forename: D
authors.initials: D
authors.lastname: Kreisel
authors.forename: A E
authors.initials: AE
authors.lastname: Gelman
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001991:Bronchitis / Q000276:immunology / Q000517:prevention & control*; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001323:Autoantibodies
keywords: Basic (laboratory) research; autoimmunity, fibrosis; lung transplantation; pulmonology; science