Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure
Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure
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DOI：
10.1182/blood-2004-03-1115
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发表时间：
2004-09-15
期刊：
影响因子：
20.3
通讯作者：
Young, NS
中科院分区：
文献类型：
--
作者：
Chen, J;Lipovsky, K;Young, NS
将亲代淋巴结（LN）细胞输注到亚致死剂量照射的杂交F1受体中，建立了骨髓（BM）衰竭的小鼠模型。受累动物在2 - 3周内发生致死性全血细胞减少症，伴有BM寡克隆T细胞浸润和严重骨髓发育不全，表现为总BM细胞减少约10倍，BM Lin（-）Sca 1（+）c-Kit（+）细胞减少15倍，脾集落形成单位减少100倍，和100倍的造血祖细胞和干细胞下降，如通过体内辐射保护所估计的。H2（B/B）和H2（d/d）单倍型LN细胞均为效应细胞。血清干扰素-γ（IFN-γ）浓度升高2- 3倍。骨髓细胞严重凋亡，Fas（+）和膜联蛋白V+细胞比例高。将来自临床受影响供体的5 × 10（5）个BM细胞和来自H2相同健康小鼠的10（6）个BM细胞共移植不能挽救致死辐射受体。受体外周血和骨髓中的细胞结构明显较低，细胞混合物未能产生支持骨髓细胞体外生长的基质饲养层。来自骨髓衰竭后供者的致病性T细胞似乎能够破坏来自完全相容的健康供者的造血祖细胞、干细胞和基质细胞，作为“无辜的旁观者”。“这种作用可以被抗IFN-γ抗体部分消除。(C)2004年，美国血液学会。
Infusion of parental lymph node (LN) cells into sublethally irradiated hybrid F1 recipients created a murine model for bone marrow (BM) failure. Affected animals developed fatal pancytopenia within 2 to 3 weeks, accompanied by BM oligoclonal T-cell infiltration and severe marrow hypoplasia indicated by approximately 10-fold declines in total BM cellularity, 15-fold declines in BM Lin(-)Sca1(+)c-Kit(+) cells, 100-fold declines in spleen colony-forming units, and 100-fold declines in hematopoietic progenitor and stem cells as estimated by irradiation protection in vivo. LN cells of both H2(b/b) and H2(d/d) haplo-types were effectors. Serum interferon-gamma (IFN-gamma) concentration increased 2- to 3-fold. Marrow cells were severely apoptotic, with high proportions of Fas(+) and annexin V+ cells. Cotransplantation of 5 x 10(5) BM cells from clinically affected donors and 10(6) BM cells from H2 identical healthy mice could not rescue lethally irradiated recipients. Recipients had significantly lower cellularity in peripheral blood and BM, and cell mixtures failed to produce a stromal feeder layer to support marrow cell growth in vitro. Pathogenic T cells from donors after BM failure appeared capable of destroying hematopoietic progenitor, stem, and stromal cells from fully compatible healthy donors as "innocent bystanders." This effect can be partially abrogated by anti-IFN-gamma antibody. (C) 2004 by The American Society of Hematology.