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

• 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; GVHD; antigen presenting cells; GVL; 移植片対宿主病

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DC刺激功能的能力。与对照DC一起，与SAHA处理的DC共同培养时，T细胞增殖少。 Saha处理的DC还分泌了IL-6，IL-12和TNF-A。接下来，我们评估了SAHA共培养对DC表型的影响。 SAHA降低了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并减少体内同种异体T细胞的反应。 SAHA处理的DC的受体显示出GVHD死亡率和临床评分显着降低。T细胞经历淋巴细胞减少症引起的增殖（LIP）的特征是效应子和抗肿瘤功能要比幼稚的T细胞更大。但是这些T细胞在引起GVHD的能力尚不清楚。我们检验了以下假设：通过利用特征良好的同种异体骨髓移植（BMT）的特征化的鼠实验模型，通过使用良好的鼠类实验模型（BMT），与幼稚T细胞相比，与天真T细胞相比，供体T细胞会引起更严重的GVHD。与我们的假设相反，在非炎性或辐照条件下，供体T细胞的唇唇降低了GVHD，这是由生存，临床，病理和生化参数所确定的，而不是幼稚的T细胞。与幼稚的供体T细胞相比，唇部T细胞在同种异体BMT后体内和体外表现出降低的膨胀。同种异体BMT后，在多种菌株中观察到GVHD死亡率和严重程度的降低。通过细胞耗竭的体内机理研究表明，CD44HI“记忆”表型T细胞的增加，而不是CD4+ CD25+ T细胞子集的增加对于减少GVHD至关重要。这些数据表明，与引起同种异体移植排斥，自身免疫或抗肿瘤免疫的能力相比，T细胞的唇调节急性GVHD严重程度。