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

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

doi:10.1097/TXD.0000000000001045

Transplantation Direct (Sep 2020)

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

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

Affiliations

Seiichiro Tada, MD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takayuki Anazawa, MD, PhD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takero Shindo, MD, PhD: 2 Department of Hematology/Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kei Yamane, MD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kenta Inoguchi, MD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nanae Fujimoto, MSc: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kazuyuki Nagai, MD, PhD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Toshihiko Masui, MD, PhD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Hideaki Okajima, MD, PhD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kyoichi Takaori, MD, PhD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shoichiro Sumi, MD, PhD: 3 Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Shinji Uemoto, MD, PhD: 1 Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

DOI: https://doi.org/10.1097/TXD.0000000000001045
Journal volume & issue: Vol. 6, no. 9
p. e591

Abstract

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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.

Published in Transplantation Direct

ISSN: 2373-8731 (Online)
Publisher: Wolters Kluwer
Country of publisher: United States
LCC subjects: Medicine: Surgery
Website: http://journals.lww.com/transplantationdirect/Pages/default.aspx

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