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

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-ac...

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Autores principales: Tada, Seiichiro, Anazawa, Takayuki, Shindo, Takero, Yamane, Kei, Inoguchi, Kenta, Fujimoto, Nanae, Nagai, Kazuyuki, Masui, Toshihiko, Okajima, Hideaki, Takaori, Kyoichi, Sumi, Shoichiro, Uemoto, Shinji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423917/
https://www.ncbi.nlm.nih.gov/pubmed/32851124
http://dx.doi.org/10.1097/TXD.0000000000001045
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author Tada, Seiichiro
Anazawa, Takayuki
Shindo, Takero
Yamane, Kei
Inoguchi, Kenta
Fujimoto, Nanae
Nagai, Kazuyuki
Masui, Toshihiko
Okajima, Hideaki
Takaori, Kyoichi
Sumi, Shoichiro
Uemoto, Shinji
author_facet Tada, Seiichiro
Anazawa, Takayuki
Shindo, Takero
Yamane, Kei
Inoguchi, Kenta
Fujimoto, Nanae
Nagai, Kazuyuki
Masui, Toshihiko
Okajima, Hideaki
Takaori, Kyoichi
Sumi, Shoichiro
Uemoto, Shinji
author_sort Tada, Seiichiro
collection PubMed
description 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.
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spelling pubmed-74239172020-08-25 The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation Tada, Seiichiro Anazawa, Takayuki Shindo, Takero Yamane, Kei Inoguchi, Kenta Fujimoto, Nanae Nagai, Kazuyuki Masui, Toshihiko Okajima, Hideaki Takaori, Kyoichi Sumi, Shoichiro Uemoto, Shinji Transplant Direct Pancreas and Islet Transplantation 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. Lippincott Williams & Wilkins 2020-08-12 /pmc/articles/PMC7423917/ /pubmed/32851124 http://dx.doi.org/10.1097/TXD.0000000000001045 Text en Copyright © 2020 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Pancreas and Islet Transplantation
Tada, Seiichiro
Anazawa, Takayuki
Shindo, Takero
Yamane, Kei
Inoguchi, Kenta
Fujimoto, Nanae
Nagai, Kazuyuki
Masui, Toshihiko
Okajima, Hideaki
Takaori, Kyoichi
Sumi, Shoichiro
Uemoto, Shinji
The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation
title The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation
title_full The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation
title_fullStr The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation
title_full_unstemmed The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation
title_short The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation
title_sort mek inhibitor trametinib suppresses major histocompatibility antigen-mismatched rejection following pancreatic islet transplantation
topic Pancreas and Islet Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423917/
https://www.ncbi.nlm.nih.gov/pubmed/32851124
http://dx.doi.org/10.1097/TXD.0000000000001045
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