Blood Journal
Leading the way in experimental and clinical research in hematology

MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner

  1. Takero Shindo1,
  2. Tae Kon Kim1,
  3. Cara L. Benjamin1,
  4. Eric D. Wieder2,
  5. Robert B. Levy3, and
  6. Krishna V. Komanduri1,*
  1. 1 Adult Stem Cell Transplant Program and Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States;
  2. 2 Adult Stem Cell Transplant Program and Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United Kingdom;
  3. 3 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
  1. * Corresponding author; email: kkomanduri{at}med.miami.edu

Key points

  • RAS/MEK/ERK signaling is memory stage-dependent in human T cells, conferring susceptibility to selective inhibition of alloreactive T cells

  • MEK inhibitors selectively inhibit alloreactive but not herpesvirus-specific human T cells and inhibit murine GVHD

Abstract

Immunosuppressive strategies currently used in hematopoietic stem cell transplantation reliably decrease graft-versus-host disease (GVHD) rates, but also impair pathogen-specific immunity. Experimental transplant studies indicate that GVHD-initiating alloreactive T cells reside primarily in naïve and central memory T cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the RAS/MEK/ERK pathway is preferentially activated in naïve and central memory human T cells, we hypothesized that MEK inhibitors would preferentially inhibit alloreactive T cells, while sparing more differentiated virus-specific T cells. Confirming our hypothesis, we found that MEK inhibitors including selumetinib preferentially inhibited cytokine production and alloreactivity mediated by naïve and central memory human CD4+ and CD8+ T cells, while sparing more differentiated T cells specific for the human herpesviruses CMV and EBV. We then demonstrated that short-term post-transplant administration of selumetinib in an MHC major- and minor-mismatched murine model significantly delayed the onset of GVHD-associated mortality without compromising myeloid engraftment, demonstrating the in vivo potential of MEK inhibitors in the setting of hematopoietic stem cell transplantation. These findings demonstrate that targeting memory-dependent differences in T cell signaling is a potent and selective approach to inhibition of alloreactivity.

  • Submitted December 28, 2012.
  • Accepted March 31, 2013.