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

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273 Citations (Scopus)

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

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Arginase
Interleukin-13
Graft vs Host Disease
Grafts
Bone Marrow Cells
Bone
T-cells
Arginine
Bearings (structural)
Cells
T-Lymphocytes
Myeloid-Derived Suppressor Cells
Interleukins
Cell proliferation
Granulocyte Colony-Stimulating Factor
Granulocyte-Macrophage Colony-Stimulating Factor
Tumors
Animals
Chemical activation
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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

In: Blood, Vol. 116, No. 25, 16.12.2010, p. 5738-5747.

Research output: Contribution to journalArticle

Highfill, SL, Rodriguez, PC, Zhou, Q, Goetz, CA, Koehn, BH, Veenstra, R, Taylor, PA, Panoskaltsis-Mortari, A, Serody, JS, Munn, DH, Tolar, J, Ochoa, AC & Blazar, BR 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, vol. 116, no. 25, pp. 5738-5747. https://doi.org/10.1182/blood-2010-06-287839
Highfill, Steven L. ; Rodriguez, Paulo C. ; Zhou, Qing ; Goetz, Christine A. ; Koehn, Brent H. ; Veenstra, Rachelle ; Taylor, Patricia A. ; Panoskaltsis-Mortari, Angela ; Serody, Jonathan S. ; Munn, David H. ; Tolar, Jakub ; Ochoa, Augusto C. ; Blazar, Bruce R. / 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. In: Blood. 2010 ; Vol. 116, No. 25. pp. 5738-5747.
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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.",
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AU - Goetz, Christine A.

AU - Koehn, Brent H.

AU - Veenstra, Rachelle

AU - Taylor, Patricia A.

AU - Panoskaltsis-Mortari, Angela

AU - Serody, Jonathan S.

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