title: IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants.
abstract: Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture's syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA. burlingham@surgery.wisc.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
authors.forename: Robert B
authors.initials: RB
authors.lastname: Love
authors.forename: Ewa
authors.initials: E
authors.lastname: Jankowska-Gan
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Haynes
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Xu
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Bobadilla
authors.forename: Keith C
authors.initials: KC
authors.lastname: Meyer
authors.forename: Mary S
authors.initials: MS
authors.lastname: Hayney
authors.forename: Ruedi K
authors.initials: RK
authors.lastname: Braun
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Greenspan
authors.forename: Bagavathi
authors.initials: B
authors.lastname: Gopalakrishnan
authors.forename: Junchao
authors.initials: J
authors.lastname: Cai
authors.forename: David D
authors.initials: DD
authors.lastname: Brand
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Yoshida
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Cummings
authors.forename: David S
authors.initials: DS
authors.lastname: Wilkes
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D001989:Bronchiolitis Obliterans / Q000276:immunology*; D024043:Collagen Type II / Q000276:immunology; D024062:Collagen Type V / Q000276:immunology*; D004198:Disease Susceptibility; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D016040:Lung Transplantation / Q000276:immunology / Q000473:pathology; D011446:Prospective Studies; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D015703:Antigens, CD; D024043:Collagen Type II; D024062:Collagen Type V; D020381:Interleukin-17; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma