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

Seiichiro Tada; Takayuki Anazawa; Takero Shindo; Kei Yamane; Kenta Inoguchi; Nanae Fujimoto; Kazuyuki Nagai; Toshihiko Masui; Hideaki Okajima; Kyoichi Takaori; Shoichiro Sumi; Shinji Uemoto

doi:10.1097/TXD.0000000000001045

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

Transplant Direct. 2020 Aug 12;6(9):e591. doi: 10.1097/TXD.0000000000001045. eCollection 2020 Sep.

Affiliations

¹ Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Hematology/Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
³ Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

Abstract

Background: Potential adverse effects, such as functional impairment of islets, render conventional immunosuppressive drugs unsuitable for use in islet transplantation. In addition, as a single therapy, they cannot prolong islet allograft survival. Here, we investigated the utility of the mitogen-activated protein kinase inhibitor trametinib and asked whether it ameliorates acute rejection of transplanted islets without the need for conventional immunosuppressants.

Methods: Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. These mice received trametinib or vehicle (orally) for 28 days. Isolated islets from BALB/c mice were incubated in vitro with different concentrations of trametinib to determine viability and function.

Results: Trametinib (0.1 and 0.3 mg/kg) prolonged graft survival significantly (P = 0.0007 and P = 0.005, respectively) when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly on day 7 (P < 0.05). In addition, trametinib suppressed functional differentiation of naive CD4⁺ T cells in recipients. Expression of mRNA encoding inflammatory cytokines interleukin (IL)-2, tumor necrosis factor α, and interferon γ in recipients treated with trametinib was also inhibited (P < 0.001, P < 0.05, and P < 0.01, respectively). Trametinib also increased production of IL-4 and IL-10 (P < 0.05 and P = 0.20, respectively). In vitro, islets incubated with different concentrations of trametinib exhibited no harmful effects with respect to viability and function.

Conclusions: Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4⁺ T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for maintenance immunosuppressive therapy after allogeneic islet transplantation.