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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

2010; Elsevier BV; Volume: 116; Issue: 25 Linguagem: Inglês

10.1182/blood-2010-06-287839

1528-0020

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

Immune Cell Function and Interaction

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.