IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants.
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.
Burlingham
William J
WJ
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA. burlingham@surgery.wisc.edu
Love
Robert B
RB
Jankowska-Gan
Ewa
E
Haynes
Lynn D
LD
Xu
Qingyong
Q
Bobadilla
Joseph L
JL
Meyer
Keith C
KC
Hayney
Mary S
MS
Braun
Ruedi K
RK
Greenspan
Daniel S
DS
Gopalakrishnan
Bagavathi
B
Cai
Junchao
J
Brand
David D
DD
Yoshida
Shigetoshi
S
Cummings
Oscar W
OW
Wilkes
David S
DS
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
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