azd-6244 and Graft-vs-Host-Disease

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 naive and central memory T-cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor kinase (RAS/MEK/ERK) pathway is preferentially activated in naive 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 naive and central memory human CD4(+) and CD8(+) T cells while sparing more differentiated T cells specific for the human herpesviruses cytomegalovirus and Epstein-Barr virus. We then demonstrated that short-term posttransplant administration of selumetinib in a major histocompatibility complex 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.

Topics: Animals; Benzimidazoles; Blotting, Western; Bone Marrow Transplantation; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cells, Cultured; Cytokines; Cytomegalovirus; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Flow Cytometry; Graft vs Host Disease; Herpesvirus 4, Human; Humans; Immunologic Memory; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phosphorylation; Rats; Transplantation Tolerance; Transplantation, Homologous

Topics: Animals; Benzimidazoles; Bone Marrow Transplantation; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Graft vs Host Disease; Humans; Immunologic Memory; MAP Kinase Kinase 1; Transplantation Tolerance