Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect
Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect
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DOI：
10.1182/blood.v97.9.2886
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发表时间：
2001-05-01
期刊：
影响因子：
20.3
通讯作者：
van den Brink, MRM
中科院分区：
文献类型：
--
作者：
Schmaltz, C;Alpdogan, O;van den Brink, MRM
在同种异体骨髓移植（BMT）中，供体T细胞主要负责抗宿主活性，导致移植物抗宿主病（GVHD），以及抗白血病活性，导致移植物抗白血病（GVL）效应。在同种异体骨髓移植小鼠亲本-> F1模型中，利用fasl缺陷或穿孔素缺陷的供体T细胞，研究了Fas配体（Fast）和穿孔素细胞毒性途径在GVHD和GVL活性中的相对贡献。发现fasl缺陷的B6。供体T细胞显示GVHD活性降低，但GVL活性保持完整。相反，缺乏穿孔素的B6。pfp（-/-）供体T细胞具有完整的GVHD活性，但GVL活性降低。来自B6、金或B6受体的脾T细胞。pfp(-/-) T细胞对宿主抗原具有相同的增殖和细胞因子反应；然而，来自B6受体的脾T细胞。在选择CD4（+）或CD8（+）供体T细胞的实验中，FasL途径对于CD4（+）和CD8+ T细胞的GVHD活性都很重要，而穿孔素途径对于CD8介导的GVL活性是必需的。这些数据在小鼠同种异体骨髓移植模型中证明，供体T细胞主要通过FasL效应途径介导GVHD活性，通过穿孔素途径介导GVL活性。这表明供体T细胞使用不同的细胞溶解途径，特异性阻断一种细胞毒性途径可用于预防GVHD而不干扰GVL活性。（血液病。2001;97:2886-2895）(C) 2001由美国血液病学会主办。
In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (Fast) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent --> F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp(-/-) donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6,gld or B6.pfp(-/-) T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp-/- T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay, In experiments with selected CD4(+) or CD8(+) donor T cells, the FasL pathway was important for GVHD activity by both CD4(+) and CD8+ T cells, whereas the perforin pathway was required for CD8-mediated GVL activity. These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity. (Blood. 2001;97: 2886-2895) (C) 2001 by The American Society of Hematology.