Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13

Steven L. Highfill, Paulo C. Rodriguez, Qing Zhou, Christine A. Goetz, Brent H. Koehn, Rachelle Veenstra, Patricia A. Taylor, Angela Panoskaltsis-Mortari, Jonathan S. Serody, David H. Munn, Jakub Tolar, Augusto C. Ochoa, Bruce R. Blazar

Research output: Contribution to journalArticle

290 Scopus citations

Abstract

Myeloid-derived suppressor cells (MDSCs) are a well-defined population of cells that accumulate in the tissue of tumor-bearing animals and are known to inhibit immune responses. Within 4 days, bone marrow cells cultured in granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor resulted in the generation of CD11b +Ly6GloLy6C+ MDSCs, the majority of which are interleukin-4Rα (IL-4Rα+) and F4/80+. Such MDSCs potently inhibited in vitro allogeneic T-cell responses. Suppression was dependent on L-arginine depletion by arginase-1 activity. Exogenous IL-13 produced an MDSC subset (MDSC-IL-13) that was more potently suppressive and resulted in arginase-1 up-regulation. Suppression was reversed with an arginase inhibitor or on the addition of excess L-arginine to the culture. Although both MDSCs and MDSC-IL-13 inhibited graft-versus-host disease (GVHD) lethality, MDSC-IL-13 were more effective. MDSC-IL-13 migrated to sites of allopriming. GVHD inhibition was associated with limited donor T-cell proliferation, activation, and proinflammatory cytokine production. GVHD inhibition was reduced when arginase-1-deficient MDSC-IL-13 were used. MDSC-IL-13 did not reduce the graft-versus-leukemia effect of donor T cells. In vivo administration of a pegylated form of human arginase-1 (PEG-arg1) resulted in L-arginine depletion and significant GVHD reduction. MDSC-IL-13 and pegylated form of human arginase-1 represent novel strategies to prevent GVHD that can be clinically translated.

Original languageEnglish (US)
Pages (from-to)5738-5747
Number of pages10
JournalBlood
Volume116
Issue number25
DOIs
StatePublished - Dec 16 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Highfill, S. L., Rodriguez, P. C., Zhou, Q., Goetz, C. A., Koehn, B. H., Veenstra, R., Taylor, P. A., Panoskaltsis-Mortari, A., Serody, J. S., Munn, D. H., Tolar, J., Ochoa, A. C., & Blazar, B. R. (2010). Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood, 116(25), 5738-5747. https://doi.org/10.1182/blood-2010-06-287839