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PLoS Pathog. 2015 Mar 30;11(3):e1004770. doi: 10.1371/journal.ppat.1004770. eCollection 2015 Mar.

Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity.

Author information

1
Microbiology and Molecular Genetics Graduate Program, Emory University School of Medicine, Atlanta, Georgia, United States of America.
2
Immunology and Molecular Pathogenesis Graduate Program, Emory University School of Medicine, Atlanta, Georgia, United States of America.
3
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
4
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.
5
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America; Center for Cystic Fibrosis Research, Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America; Institut de Génétique Moléculaire de Montpellier (IGMM), CNRS UMR5535, Université Montpellier, Montpellier, France.
6
Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri, United States of America.
7
MD Anderson Cancer Center, University of Texas, Houston, Texas, United States of America.
8
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America; Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America; Yerkes National Primate Research Center, Atlanta, Georgia, United States of America.
9
Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America; Yerkes National Primate Research Center, Atlanta, Georgia, United States of America; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
10
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America; Center for Cystic Fibrosis Research, Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.

Abstract

Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics "emergency hematopoiesis," a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.

PMID:
25822986
PMCID:
PMC4379053
DOI:
10.1371/journal.ppat.1004770
[Indexed for MEDLINE]
Free PMC Article

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