MyD88 in donor bone marrow cells is critical for protection from acute intestinal graft-vs.-host disease
MyD88 in donor bone marrow cells is critical for protection from acute intestinal graft-vs.-host disease
复制标题
DOI：
10.1038/mi.2015.96
复制
发表时间：
2015-10
影响因子：
8
通讯作者：
Ji-Young Lim;Young Kwan Lee;S. Lee;J. Ju;K. Eom;Yun Ju Kim;Nak-Gyun Chung;Dae-Chul Jeong;G. Park;Choi Ey;Chang-Ki Min
中科院分区：
文献类型：
--
作者：
Ji-Young Lim;Young Kwan Lee;S. Lee;J. Ju;K. Eom;Yun Ju Kim;Nak-Gyun Chung;Dae-Chul Jeong;G. Park;Choi Ey;Chang-Ki Min
了解供者骨髓（BM）表达的髓样分化因子88（MyD 88）在移植物抗-TNF-α的病理生理学中的作用。为了研究移植物抗宿主病（GVHD）的严重程度，我们研究了MyD 88缺陷型T细胞耗尽BM（MyD 88 KO TCD-BM）移植对GVHD严重程度的影响。移植MyD 88 KO TCD-BM加重了GVHD;严重的肠道损伤是明显的，T细胞大量浸润到受体肠道中，CD 11b + Gr-1+骨髓源性抑制细胞（MDSC）的扩增显著减少。来自MyD 88 KO小鼠的MDSC在诱导供体T细胞凋亡和抑制T细胞增殖方面存在缺陷。用来自野生型小鼠而不是MyD 88 KO小鼠的MDSC补充移植小鼠，减轻了MyD 88 KO TCD-BM受体中GVHD的严重程度，减少了肠道T细胞浸润。用脂多糖预处理BM供体以增加TCD-BM移植物中MDSC水平和MyD 88转录，减轻了GVHD严重程度和肠道T细胞浸润。在动物模型和人类患者中，T细胞/MDSC比率与肠道GVHD严重程度相关。该研究表明，来自供体BM的MyD 88依赖性MDSC扩增对于防止致命性肠道GVHD至关重要。
To understand the role of myeloid differentiation factor 88 (MyD88) expressed by donor bone marrow (BM) in the pathophysiology of graft-vs.-host disease (GVHD), we investigated the effects of transplantation of MyD88-deficient T cell-depleted BM (MyD88KO TCD-BM) on the severity of GVHD. Transplantation with MyD88KO TCD-BM aggravated GVHD; serious gut damage was evident, with high infiltration of T cells into the intestines of recipients and markedly reduced expansion of CD11b+ Gr-1+ myeloid-derived suppressor cells (MDSCs). MDSCs from MyD88KO mice were defective in inducing donor T-cell apoptosis and inhibiting T-cell proliferation. Supplementation of transplanted mice with MDSCs from wild-type mice, but not MyD88KO mice, attenuated GVHD severity with reduced intestinal T-cell infiltration in MyD88KO TCD-BM recipients. Pretreatment of BM donors with lipopolysaccharide to increase MDSC levels and MyD88 transcription in the TCD-BM transplant alleviated GVHD severity and intestinal T-cell infiltration. The T cell/MDSC ratios were correlated with intestinal GVHD severity in both animal models and human patients. This study indicates that MyD88-dependent MDSC expansion from donor BM is critical for protection against fatal intestinal GVHD.