Authors:
Takero Shindo, Tae Kon Kim, Cara L. Benjamin, Eric D. Wieder, Robert B. Levy, and Krishna V. Komanduri
Summary:
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.
Source:
Blood; (04/10/13)