title: MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner.
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 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.
authors.affiliation: Adult Stem Cell Transplant Program and Department of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: Takero
authors.initials: T
authors.lastname: Shindo
authors.forename: Tae Kon
authors.initials: TK
authors.lastname: Kim
authors.forename: Cara L
authors.initials: CL
authors.lastname: Benjamin
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieder
authors.forename: Robert B
authors.initials: RB
authors.lastname: Levy
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Komanduri
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D016207:Cytokines; D048369:MAP Kinase Kinase 1