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

摘要: 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 naive and central memory T-cell compartments. In contrast, virus-specific comprise a more differentiated population. After finding the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor (RAS/MEK/ERK) pathway is preferentially activated human cells, we hypothesized MEK inhibitors would inhibit while sparing cells. Confirming our hypothesis, found including selumetinib inhibited cytokine production alloreactivity mediated by CD4(+) CD8(+) specific for herpesviruses cytomegalovirus Epstein-Barr virus. We then demonstrated short-term posttransplant administration of major histocompatibility complex major- minor-mismatched murine model significantly delayed onset GVHD-associated mortality without compromising myeloid engraftment, demonstrating vivo potential setting transplantation. These findings demonstrate targeting memory-dependent differences signaling potent selective approach to inhibition alloreactivity.