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Reduced allostimulatory activity of host antigen-presenting cells regulates the severity of graft-versus-host disease while preserving a graft-versus-leukemia effect

宿主抗原呈递细胞的同种刺激活性降低可调节移植物抗宿主疾病的严重程度，同时保留移植物抗白血病效应

基本信息

批准号：
18591062
负责人：
MAEDA Yoshinobu
金额：
$ 2.5万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591062/
关键词：
GVHD antigen presenting cells GVL 移植片対宿主病

项目摘要

The activation of donor T cells by host dendritic cells (DCs) is critical to the induction of graft-versus-host disease (GVHD). We firstly analyzed the ability of SAHA to suppress the stimulatory function of DCs in vitro. T cells proliferated less when co-cultured with SAHA treated DCs than with control DCs. SAHA treated DCs also secreted less IL-6, IL-12 and TNF-a. We next evaluated effect of SAHA co-culture on the phenotype of DCs. SAHA decreased the expression of CD40, MHC Class II and CD80 on DCs. We next evaluated whether SAHA suppress DCs and reduce the responses of allogeneic T cells in vivo. Recipients of SAHA treated DCs showed significantly reduced GVHD mortality and clinical scores.T cells that undergo lymphopenia induced proliferation (LIP) are characterized by greater effector and anti-tumor function than naive T cells. But the ability of these T cells in causing GVHD is not known. We tested the hypothesis that donor T cells that had undergone LIP would cause more severe GVHD than naive T cells by utilizing well-characterized murine experimental models of allogeneic bone marrow transplantation (BMT). Contrary to our hypothesis, LIP of donor T cells either under non-inflammatory or irradiated conditions caused significantly reduced GVHD as determined by survival, clinical, pathological and biochemical parameters than naive T cells. Compared to naive donor T cells, ;LIP T cells demonstrated reduced expansion in vivo and in vitro after allogeneic BMT. The reduction in GVHD mortality and severity was observed across multiple strains after allogeneic BMT. In vivo mechanistic studies by cell depletion demonstrated that an increase in the CD44hi "memory" phenotype T cells and not the CD4+CD25+ T cell subset to be critical for the reduction in GVHD. These data demonstrate that LIP of T cells regulates acute GVHD severity in contrast to their ability to cause increased allograft rejection, autoimmunity or anti-tumor immunity.

宿主树突状细胞 (DC) 激活供体 T 细胞对于诱导移植物抗宿主病 (GVHD) 至关重要。我们首先分析了SAHA在体外抑制DCs刺激功能的能力。当与 SAHA 处理的 DC 共培养时，T 细胞的增殖速度低于与对照 DC 的增殖。 SAHA处理的DC也分泌较少的IL-6、IL-12和TNF-α。接下来我们评估了 SAHA 共培养对 DC 表型的影响。 SAHA 降低 DC 上 CD40、MHC II 类和 CD80 的表达。接下来我们评估了 SAHA 是否抑制 DC 并降低体内同种异体 T 细胞的反应。 SAHA 处理的 DC 受体表现出 GVHD 死亡率和临床评分显着降低。经历淋巴细胞减少诱导增殖 (LIP) 的 T 细胞的特点是比初始 T 细胞具有更强的效应和抗肿瘤功能。但这些 T 细胞引起 GVHD 的能力尚不清楚。我们利用特征良好的同种异体骨髓移植 (BMT) 小鼠实验模型测试了这样的假设，即接受 LIP 的供体 T 细胞会比初始 T 细胞引起更严重的 GVHD。与我们的假设相反，根据存活率、临床、病理和生化参数确定，供体 T 细胞在非炎症或辐射条件下的 LIP 与初始 T 细胞相比，导致 GVHD 显着降低。与初始供体 T 细胞相比，同种异体 BMT 后，LIP T 细胞在体内和体外均表现出增殖减少。同种异体 BMT 后，多种菌株的 GVHD 死亡率和严重程度均有所降低。通过细胞耗竭进行的体内机制研究表明，CD44hi“记忆”表型 T 细胞而非 CD4+CD25+ T 细胞亚群的增加对于 GVHD 的降低至关重要。这些数据表明，T 细胞的 LIP 调节急性 GVHD 的严重程度，而不是引起同种异体移植排斥、自身免疫或抗肿瘤免疫增加的能力。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lymphopenia-induced proliferation of donor T cells reduces their capacity for causing acute graft-versus-host disease.

淋巴细胞减少症诱导的供体 T 细胞增殖降低了其引起急性移植物抗宿主病的能力。

DOI：
10.1016/j.exphem.2006.10.010
发表时间：
2007
期刊：
Experimental hematology
影响因子：
2.6
作者：
Maeda,Yoshinobu;Tawara,Isao;Teshima,Takanori;Liu,Chen;Hashimoto,Daigo;Matsuoka,Ken-Ichi;Tanimoto,Mitsune;Reddy,Pavan
通讯作者：
Reddy,Pavan

Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft versus host disease

供体 T 细胞中联合 Th2 细胞因子缺乏会加重实验性急性移植物抗宿主病