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

Takero Shindo, Tae Kon Kim, Cara L. Benjamin, Eric D. Wieder, Robert B. Levy, Krishna V. Komanduri

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.