Document Detail


MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner.
MedLine Citation:
PMID:  23575444     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Takero Shindo; Tae Kon Kim; Cara L Benjamin; Eric D Wieder; Robert B Levy; Krishna V Komanduri
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-10
Journal Detail:
Title:  Blood     Volume:  121     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-07     Completed Date:  2013-08-06     Revised Date:  2014-06-08    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4617-26     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Benzimidazoles / administration & dosage*
Blotting, Western
Bone Marrow Transplantation*
CD4-Positive T-Lymphocytes / immunology*,  metabolism,  virology
CD8-Positive T-Lymphocytes / immunology*,  metabolism,  virology
Cells, Cultured
Cytokines / metabolism
Cytomegalovirus / pathogenicity
Cytomegalovirus Infections / immunology,  metabolism,  virology
Epstein-Barr Virus Infections / immunology,  metabolism,  virology
Flow Cytometry
Graft vs Host Disease / immunology,  pathology,  prevention & control*
Herpesvirus 4, Human / pathogenicity
Humans
Immunologic Memory / immunology*
MAP Kinase Kinase 1 / antagonists & inhibitors*,  metabolism
MAP Kinase Signaling System
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Phosphorylation / drug effects
Rats
Transplantation Tolerance / immunology*
Transplantation, Homologous
Grant Support
ID/Acronym/Agency:
R01 CA109326/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/AZD 6244; 0/Benzimidazoles; 0/Cytokines; EC 2.7.12.2/MAP Kinase Kinase 1
Comments/Corrections
Comment In:
Blood. 2013 Jun 6;121(23):4611-2   [PMID:  23744490 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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