Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

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.

The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation

“…These findings are consistent with those of previous reports of BMT and lung transplantation models. 22 , 24 However, in contrast to the other reports, we did not observe trametinib dose-dependent prolongation of graft survival time and suppression of inflammatory cytokines. This may be because trametinib increased the immunogenicity of the transplanted grafts.…”

“…These results are in contrast to those of a previous study showing that a combination of cyclosporine plus trametinib is needed to suppress acute rejection of fully MHC-mismatched lung transplants in rat models. 24 Such differences between islet and organ transplantation may be attributed to the fact that primarily vascularized allografts induce direct, not indirect, T cell–mediated alloresponses associated with acute rejection. 29 In the direct pathway, T cells recognize intact donor MHC molecules on transplanted cells, whereas in the indirect pathway donor peptides are first processed and presented by host antigen-presenting cells.…”

“… 30 Our recent study suggests that trametinib might suppress the indirect pathway but not the direct pathway. 24 Therefore, we suggest that trametinib as a single agent can efficiently suppress acute rejection of a nonvascularized transplant such as an islet graft, which activates T cells via both direct and indirect pathways.…”

“…The dose of trametinib was determined based on previous studies. 22 , 24 After transplantation, nonfasting blood glucose levels were monitored daily for the first 14 d and then 3 times per week thereafter until graft rejection. Engraftment was established when the blood glucose level fell below 200 mg/dL for 2 consecutive days.…”

“… 21 , 22 However, using an MEK inhibitor as a single drug therapy after organ transplantation did not prolong graft survival in a fully major histocompatibility complex (MHC)-mismatched rodent model. 23 , 24 Therefore, the aim of the present report was to analyze the efficacy of a MEK inhibitor for allogeneic islet transplantation in a fully MHC-mismatched rodent model and to examine its effect on insulin secretion and cytotoxicity in vitro.…”