Abstract
Delayed immunological rejection after human lung transplantation causes chronic lung allograft dysfunction, which is associated with high mortality. Delayed rejection may be attributable to indirect alloantigen presentation by host antigen-presenting cells; however, its pathophysiology is not fully understood. The mitogen-activated protein kinase pathway is activated in T cells upon stimulation, and we previously showed that the MEK inhibitor, trametinib, suppresses graft-versus-host disease after murine bone marrow transplantation. We investigated whether trametinib suppresses graft rejection after two types of rat lung transplantation and analyzed its immunological mode of action. Major histocompatibility complex-mismatched transplantation from brown Norway rats into Lewis rats and minor histocompatibility antigen-mismatched transplantation from Fischer 344 rats into Lewis rats were performed. Cyclosporine (CsA) and/or trametinib were administered alone or consecutively. Acute and delayed rejection, lymphocyte infiltration, and pulmonary function were evaluated. Administration of trametinib after CsA suppressed delayed rejection, reduced inflammatory cell infiltration and fibrosis within the graft, and preserved pulmonary functions at Day 28. Trametinib suppressed functional differentiation of T and B cells in the periphery but preserved thymic T cell differentiation. Donor B cells within the graft disappeared by Day 14, indicating that delayed graft rejection at Day 28 was mainly due to indirect presentation by host antigen-presenting cells. Finally, trametinib administration without CsA preconditioning suppressed rejection after minor histocompatibility antigen-mismatched transplantation. Trametinib attenuates delayed rejection upon major histocompatibility complex-mismatched transplantation by suppressing indirect presentation and is a promising candidate to treat chronic lung allograft dysfunction in humans.