Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity

Ruth J. Napier, Brian A. Norris, Alyson Swimm, Cynthia R. Giver, Wayne A.C. Harris, Julie Laval, Brooke A. Napier, Gopi Patel, Ryan Crump, Zhenghong Peng, William Bornmann, Bali Pulendran, R. Mark Buller, David S. Weiss, Rabindra Tirouvanziam, Edmund K. Waller, Daniel Kalman

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish (US)
Article numbere1004770
Pages (from-to)1-27
Number of pages27
JournalPLoS pathogens
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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