Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice
Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice
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DOI：
10.1172/jci39165
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Teshima, Takanori
中科院分区：
文献类型：
--
作者：
Asakura, Shoji;Hashimoto, Daigo;Teshima, Takanori
异基因造血干细胞移植（HSCT）是一种有效的治疗血液系统恶性肿瘤的方法。它的有益作用依赖于供体来源的T细胞靶向白血病细胞，即所谓的移植物抗白血病（GVL）效应。GVL的诱导通常与移植物抗宿主病（GVHD）的伴随发展相关，GVHD是同种异体HSCT的主要并发症。介导GVL和GVHD的T细胞被造血来源的宿主抗原呈递细胞上呈递的同种异体抗原激活，并且还不清楚非造血细胞上的同种异体抗原表达如何影响GVL活性。在这里，我们表明，在小鼠模型的MHC匹配，轻微的组织相容性抗原不匹配的骨髓移植，宿主上皮细胞上的同种异体抗原表达驱动供体T细胞凋亡和功能障碍，在GVHD过程中，导致GVL活性的损失。在GVHD过程中，参与诱导T细胞耗竭的分子程序性死亡-1（PD-1）和PD配体-1（PD-L1）分别在活化的T细胞和靶组织上上调，表明宿主上皮同种异体抗原表达驱动的T细胞缺陷可能由PD-1/PD-L1途径介导。与此一致，PD-1/PD-L1相互作用的阻断部分恢复了T细胞效应子功能并改善了GVL。这些结果阐明了以前未被认识到的意义的同种异体抗原表达的非造血细胞在GVL和GVHD的GVL的分离，更有效的HSCT可能在人类患者。
Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-presenting cells of hematopoietic origin, and it is not well understood how alloantigen expression on non-hematopoietic cells affects GVL activity. Here we show, in mouse models of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation, that alloantigen expression on host epithelium drives donor T cells into apoptosis and dysfunction during GVHD, resulting in a loss of GVL activity. During GVHD, programmed death-1 (PD-1) and PD ligand-1 (PD-L1), molecules implicated in inducing T cell exhaustion, were upregulated on activated T cells and the target tissue, respectively, suggesting that the T cell defects driven by host epithelial alloantigen expression might be mediated by the PD-1/PD-L1 pathway. Consistent with this, blockade of PD-1/PD-L1 interactions partially restored T cell effector functions and improved GVL. These results elucidate a previously unrecognized significance of alloantigen expression on non-hematopoietic cells in GVL and suggest that separation of GVL from GVHD for more effective HSCT may be possible in human patients.