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RATIONALE Delayed immunological rejection following human lung transplantation causes chronic lung allograft dysfunction (CLAD), which is associated with high mortality. Delayed rejection may be attributable to indirect alloantigen presentation by host antigen-presenting cells (APCs); 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 following murine bone marrow transplantation. OBJECTIVES We investigated whether trametinib suppresses graft rejection following two types of rat lung transplantation and analyzed its immunological mode of action. METHODS Major histocompatibility complex (MHC)-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. MEASUREMENTS AND MAIN RESULTS 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 APCs. Finally, trametinib administration without CsA preconditioning suppressed rejection following minor histocompatibility antigen-mismatched transplantation. CONCLUSIONS Trametinib attenuates delayed rejection upon MHC-mismatched transplantation by suppressing indirect presentation and is a promising candidate to treat CLAD in humans.