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。我们首先在体外分析了SAHA抑制dc刺激功能的能力。与SAHA处理的dc共培养时，T细胞增殖低于对照dc。SAHA处理的dc分泌的IL-6、IL-12和TNF-a也较少。接下来，我们评估了SAHA共培养对dc表型的影响。SAHA可降低dc上CD40、MHCⅱ类和CD80的表达。接下来，我们在体内评估SAHA是否抑制dc并降低同种异体T细胞的反应。接受SAHA治疗的dc患者GVHD死亡率和临床评分显著降低。经历淋巴减少诱导增殖（LIP）的T细胞比初始T细胞具有更大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。我们利用具有良好特征的小鼠同种异体骨髓移植（BMT）实验模型，验证了经历过LIP的供体T细胞会比原始T细胞引起更严重的GVHD的假设。与我们的假设相反，在非炎症或辐照条件下，供体T细胞的LIP与初始T细胞相比，在存活、临床、病理和生化参数方面都显著降低了GVHD。与原始供体T细胞相比，；同种异体骨髓移植后，LIP T细胞在体内和体外的增殖均减少。同种异体骨髓移植后，多个菌株的GVHD死亡率和严重程度均有所降低。通过细胞耗损进行的体内机制研究表明，CD44hi“记忆”表型T细胞的增加，而不是CD4+CD25+ T细胞亚群的增加，对GVHD的减少至关重要。这些数据表明，T细胞的LIP调节急性GVHD的严重程度，而不是它们引起异体移植物排斥反应、自身免疫或抗肿瘤免疫的能力。

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.