title: 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.
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(+)Ly6G(lo)Ly6C(+) 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.
authors.affiliation: University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Highfill
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Christine A
authors.initials: CA
authors.lastname: Goetz
authors.forename: Brent H
authors.initials: BH
authors.lastname: Koehn
authors.forename: Rachelle
authors.initials: R
authors.lastname: Veenstra
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Taylor
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Ochoa
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000201:enzymology / Q000517:prevention & control*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D018793:Interleukin-13 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018793:Interleukin-13; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D001119:Arginase
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