Dependence of murine obstructive airway disease on CD40 ligand.
BACKGROUND
Human lung transplantation carries a poor prognosis because of chronic rejection in the form of obliterative bronchiolitis syndrome (OBS). Using the mouse model of heterotopic tracheal transplantation, we examined the role of costimulation in the allograft rejection that characterizes obstructive airway disease (OAD).


METHODS
C57BL/6 or BALB/c tracheae were implanted into wild-type control, CD28-/-, muMT (B-cell deficient), or CD40L-/- recipient mice. Grafts were explanted from 7 to 42 days posttransplantation and evaluated.


RESULTS
Thickening of the basement membrane and a decrease in patent luminal area were first noted at 2 weeks in wild-type allogeneic trachea recipients and to a slightly lesser degree in CD28-/- recipients. In contrast, CD40L-/- recipient mice showed no evidence of cellular infiltrates or fibrosis in transplanted tracheae. To determine whether CD40L interacted with host or donor CD40, CD40-deficient tracheae were transplanted into CD40L+/+, CD40+/+ wild-type mice. Wild-type mice rejected CD40-/- tracheae. Tracheae were transplanted into B-cell-deficient mice to determine the role of B-cell CD40 in chronic pulmonary allograft rejection. The OAD reaction was identical in wild-type and B-cell-deficient mice.


CONCLUSIONS
Development of OAD in the mouse trachea transplant model is primarily dependent on CD40L and is relatively CD28 independent. The ability of mice to reject CD40-/- tracheae demonstrated that host, not donor, CD40 is required for rejection. Furthermore, the ability of B-cell-deficient mice to reject allogeneic tracheae demonstrated that B-cell CD40-mediated responses are not required for the development of OAD.
Rumbley
C A
CA
Department of Medicine, University of Pennsylvania Medical Center, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA. Rumbleyc@mail.med.upenn.edu
Silver
S J
SJ
Phillips
S M
SM
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D001485:Basement Membrane / Q000473:pathology; D001989:Bronchiolitis Obliterans / Q000209:etiology*; D018106:CD28 Antigens / Q000502:physiology; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000502:physiology*; D006084:Graft Rejection; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014132:Trachea / Q000473:pathology / Q000637:transplantation*; D014184:Transplantation, Homologous
D018106:CD28 Antigens; D019013:CD40 Antigens; D023201:CD40 Ligand