IL-17–dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants

TLDR

Bronchiolitis obliterans syndrome, a fibro‑obliterative occlusion of small airways, is the leading cause of lung transplant failure. The study aimed to determine whether cell‑mediated immunity to collagen type V contributes to BOS. Peripheral blood mononuclear cells were prospectively monitored for responses to collagens II and V over a seven‑year period. Strong col(V)-reactive PBMCs, driven by CD4⁺ Th17 cells and monocytes via IL‑17, TNF‑α, and IL‑1β, were common in lung transplant recipients and correlated with higher BOS incidence and severity, whereas other rejection markers were less predictive, indicating that de novo col(V)-specific autoimmunity drives airway obliteration.

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.