Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects
Hidekazu Itamura, … , Krishna V. Komanduri, Shinya Kimura
Hidekazu Itamura, … , Krishna V. Komanduri, Shinya Kimura
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e86331. https://doi.org/10.1172/jci.insight.86331.
View: Text | PDF
Research Article Hematology Transplantation

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

  • Text
  • PDF
Abstract

The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.

Authors

Hidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V. Komanduri, Shinya Kimura

×

Figure 1

Trametinib suppressed gut graft-versus-host disease and spared naive T cells.

Options: View larger image (or click on image) Download as PowerPoint
Trametinib suppressed gut graft-versus-host disease and spared naive T c...
B6D2F1 recipients were irradiated (10.5 Gy) on day –1 and infused (on day 0) with 5 × 106 B6 BM cells and 2 × 106 B6 T cells. Recipients were administered vehicle or trametinib (0.1 or 0.3 mg/kg) once daily via oral gavage from day 0 through day 30. Combined data of 2 independent experiments (n = 11 in total) are shown for survival (with the log-rank test) (A), percentage body weight (BW) (with the 2-tailed Student’s t test at day 60) (B), and clinical graft-versus-host disease (GVHD) score (with the 2-tailed Student’s t test at day 58) (C). (D) Phosphorylation of ERK1/2 within CD4+ and CD8+ T cells in the recipient peripheral blood was assessed by flow cytometry on day 10. Dashed lines represent the results of the recipients of BM cells only, and percentages represent the frequencies of positive cells calculated by the Overton cumulative histogram subtracting algorithm. Data are representative of 3 independent experiments. (E) CD4/CD8 and naive/memory T cell subsets of splenocytes from the recipients on day 28 were analyzed by flow cytometry. The percentages represent the frequencies of CD4+, CD8+, naive (CD62L+CD44–), and memory (CD62L–CD44+) cells, respectively. Data are representative of 2 independent analyses. (F) H&E staining of the colonic mucosa of each group. Representative images from 2 independent experiments are shown. Original magnification, ×100. (G) Individual histopathological scores obtained from 3 mice are shown along with the means (2-tailed Student’s t test with Bonferroni correction). *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts