title: Complement activation is not required for obliterative airway disease induced by antibodies to major histocompatibility complex class I: Implications for chronic lung rejection.
abstract: BACKGROUND
  The role of non-complement activating antibodies (ncAbs) to mismatched donor human leukocyte antigen (HLA) in the pathogenesis of chronic lung rejection is not known. We used a murine model of obliterative airway disease (OAD) induced by Abs to major histocompatibility major histocompatibility complex (MHC) class I and serum from donor-specific Abs developed in human lung transplant (LTx) recipients to test the role of ncAbs in the development of OAD and bronchiolitis obliterans syndrome (BOS).
  
  
  METHODS
  Anti-MHC ncAbs were administered intrabronchially in B.10 mice or in C3 knockout (C3KO) mice. Lungs were analyzed by histopathology. Lymphocytes secreting interleukin (IL)-17, interferon-γ, or IL-10 to collagen V and K-α1 tubulin (Kα1T) were enumerated by enzyme-linked immunospot assay. Serum antibodies to collagen V and Kα1T were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression in lungs was determined by real-time polymerase chain reaction. Donor-specific Abs from patients with BOS and control BOS-negative LTx recipients were analyzed by C1q assay.
  
  
  RESULTS
  Administration of ncAbs in B.10 mice or C3KO resulted in OAD lesions. There were significant increases in IL-17- and interferon-γ-secreting cells to collagen V and Kα1T, along with serum Abs to these antigens. There was also augmented expression of monocyte chemotactic protein-1, IL-6, IL-1β, vascular endothelial growth factor, transforming growth factor-β, and fibroblastic growth factor in mice administered ncAbs by Day 3. Among 5 LTx recipients with BOS, only 1 had C1q binding donor-specific Abs.
  
  
  CONCLUSIONS
  Complement activation by Abs to MHC class I is not required for development of OAD and human BOS. Therefore, anti-MHC binding to epithelial and endothelial cells can directly activate pro-fibrotic and pro-inflammatory cascades leading to immune response to self-antigens and chronic rejection.
authors.affiliation: Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takenaka
authors.forename: Vijay
authors.initials: V
authors.lastname: Subramanian
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: Donna
authors.initials: D
authors.lastname: Phelan
authors.forename: Ramsey
authors.initials: R
authors.lastname: Hachem
authors.forename: Elbert
authors.initials: E
authors.lastname: Trulock
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Gelman
authors.forename: G Alexander
authors.initials: GA
authors.lastname: Patterson
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Hoshinaga
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000818:Animals; D000906:Antibodies / Q000009:adverse effects* / Q000276:immunology*; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology*; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D016040:Lung Transplantation / Q000276:immunology*; D008214:Lymphocytes / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D000906:Antibodies; D003176:Complement C3; D015395:Histocompatibility Antigens Class I; D020381:Interleukin-17; D016753:Interleukin-10; D007371:Interferon-gamma