title: Alloimmunity-induced autoimmunity as a potential mechanism in the pathogenesis of chronic rejection of human lung allografts.
abstract: BACKGROUND
  Bronchiolitis obliterans syndrome (BOS) is a major cause of morbidity and mortality after lung transplantation (LTx). We sought to better understand the relationship between alloimmune responses and autoimmunity and, subsequently, how autoimmunity leads to chronic rejection.
  
  
  METHODS
  We analyzed the development of donor-specific antibodies (Abs) in LTx by flow PRA and the development of Abs to K-α1 tubulin (K-α1T) and collagen V (ColV) by ELISA. The frequency of K-α1T- and ColV-specific T cells that secrete IFN-γ, IL-17 and IL-10 in LTx recipients was measured by ELISPOT.
  
  
  RESULTS
  In a retrospective analysis of 42 LTx recipients, we demonstrated a strong correlation between development of donor-specific anti-HLA Abs, Abs to self-antigens and BOS (p < 0.05). To test the hypothesis that alloimmunity is related to an immune response to self-antigens, we analyzed 103 LTx patients prospectively for the development of donor-specific Abs (DSA) and Abs to self-antigens. A total of 42.7% of recipients developed DSA and 30.1% developed Abs to K-α1T and ColV. Development of DSA preceded development of Abs to self-antigens. BOS(+) patients had higher frequency of T cells secreting IL-17 (p < 0.01) and IFN-γ (p < 0.05) with decreased IL-10 (p < 0.05) when compared with BOS(-) patients.
  
  
  CONCLUSIONS
  Based on these results we propose that alloimmune responses to donor HLA can induce autoimmune responses to airway epithelial self-antigens, characterized by activation of the IL-17 pathway. These immune responses to self-antigens along with alloimmunity contribute to the pathogenesis of BOS. Strategies to prevent development of autoimmunity may be play a key role in preventing the development of chronic rejection.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Saini
authors.forename: Joseph
authors.initials: J
authors.lastname: Weber
authors.forename: Sabarinathan
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Donna
authors.initials: D
authors.lastname: Phelan
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: Michael
authors.initials: M
authors.lastname: Liu
authors.forename: Nancy
authors.initials: N
authors.lastname: Steward
authors.forename: Aviva
authors.initials: A
authors.lastname: Aloush
authors.forename: Ramsey
authors.initials: R
authors.lastname: Hachem
authors.forename: Elbert
authors.initials: E
authors.lastname: Trulock
authors.forename: Bryan
authors.initials: B
authors.lastname: Meyers
authors.forename: G Alexander
authors.initials: GA
authors.lastname: Patterson
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D015551:Autoimmunity / Q000276:immunology*; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology*; D024062:Collagen Type V / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014404:Tubulin / Q000276:immunology*
chemical_list: D024062:Collagen Type V; D006680:HLA Antigens; D020381:Interleukin-17; D014404:Tubulin; D016753:Interleukin-10; D007371:Interferon-gamma