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
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
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DOI：
10.1182/blood-2010-06-287839
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发表时间：
2010-12-16
期刊：
影响因子：
20.3
通讯作者：
Blazar, Bruce R.
中科院分区：
文献类型：
--
作者：
Highfill, Steven L.;Rodriguez, Paulo C.;Blazar, Bruce R.
骨髓源性抑制细胞（MDSC）是一种明确定义的细胞群，其在荷瘤动物的组织中积累，并且已知其抑制免疫应答。在4天内，在粒细胞集落刺激因子和粒细胞巨噬细胞集落刺激因子中培养的骨髓细胞导致CD 11b（+）Ly 6 G（10）Ly 6C（+）MDSC的产生，其中大多数是白细胞介素-4 R α（IL-4 R（α +））和F4/80（+）。此类MDSC有效抑制体外同种异体T细胞反应。抑制依赖于精氨酸酶-1活性的L-精氨酸消耗。外源性IL-13产生了一个MDSC亚群（MDSC-IL-13），其具有更强的抑制作用，并导致β-内酰胺酶-1上调。抑制被逆转的抑制剂或添加过量的L-精氨酸的文化。尽管MDSC和MDSC-IL-13均抑制移植物抗宿主病（GVHD）致死率，但MDSC-IL-13更有效。MDSC-IL-13迁移至同种异源引发位点。GVHD抑制与有限的供体T细胞增殖、活化和促炎细胞因子产生相关。当使用精氨酸酶-1缺陷型MDSCIL-13时，GVHD抑制作用降低。MDSC-IL-13不降低供体T细胞的移植物抗白血病效应。在体内施用聚乙二醇化形式的人精氨酸酶-1（PEG-arg 1）导致L-精氨酸耗尽和显著的GVHD减少。MDSC-IL-13和聚乙二醇化形式的人GVHD-1代表了可以临床转化的预防GVHD的新策略。（血。2010;116（25）：5738-5747）
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 granulocy temacrophage colony-stimulating factor resulted in the generation of CD11b(+)Ly6G(10)Ly6C(+)MDSCs, the majority of which are interleukin-4R alpha (IL-4R(alpha+)) 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 MDSCIL-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. (Blood. 2010;116(25):5738-5747)