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 ob structive airway disease (OAD). Methods. C57BL16 or BALB/c tracheae were implanted into wild-type control, CD28(-/-), mu MT (B-cell deficient), or CD40L(-/-) recipient mice. Grafts w ere explanted from 7 to 42 days posttransplantation and evaluated. Results. Thickening of the basement membrane and a decrease in patent lumin al area were first noted at 2 weeks in wild-type allogeneic trachea recipie nts and to a slightly lesser degree in CD28(-/-) recipients. In contrast, C D40L(-/-) recipient mice showed no evidence of cellular infiltrates or fibr osis in transplanted tracheae. To determine whether CD40L interacted with h ost or donor CD40, CD40-deficient tracheae were transplanted into CD40L(+/), CD40(+/+) wild-type mice. Wild-type mice rejected CD40(-/-) tracheae. Tr acheae were transplanted into B-cell-deficient mice to determine the role o f B-cell CD40 in chronic pulmonary allograft rejection. The OAD reaction wa s identical in wild-type and B-cell-deficient mice. Conclusions. Development of OAD in the mouse trachea transplant model is pr imarily dependent on CD40L and is relatively CD28 independent. The ability of mice to reject CD40(-/-) tracheae demonstrated that host, not donor, CD4 0 is required for rejection. Furthermore, the ability of B-cell-deficient m ice to reject allogeneic tracheae demonstrated that B-cell CD40-mediated re sponses are not required for the development of OAD.