Immune response to tissue-restricted self-antigens induces airway inflammation and fibrosis following murine lung transplantation

V. Subramanian, S. Ramachandran, B. Banan, A. Bharat, X. Wang, N. Benshoff, D. Kreisel, A. E. Gelman, T. Mohanakumar*

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2359-2366
Number of pages8
JournalAmerican Journal of Transplantation
Volume14
Issue number10
DOIs
StatePublished - Oct 1 2014

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Keywords

  • Basic (laboratory) research
  • autoimmunity, fibrosis
  • lung transplantation
  • pulmonology
  • science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Subramanian, V., Ramachandran, S., Banan, B., Bharat, A., Wang, X., Benshoff, N., Kreisel, D., Gelman, A. E., & Mohanakumar, T. (2014). Immune response to tissue-restricted self-antigens induces airway inflammation and fibrosis following murine lung transplantation. American Journal of Transplantation, 14(10), 2359-2366. https://doi.org/10.1111/ajt.12908