Transduction of donor hematopoietic stem-progenitor cells with Fas ligand enhanced short-term engraftment in a murine model of allogeneic bone marrow transplantation.
Transduction of donor hematopoietic stem-progenitor cells with Fas ligand enhanced short-term engraftment in a murine model of allogeneic bone marrow transplantation.
复制标题
DOI：
10.1182/blood-2002-01-0118
复制
发表时间：
2002-11
期刊：
影响因子：
20.3
通讯作者：
K. Whartenby;E. Straley;Heeje Kim;F. Racke;V. Tanavde;K. Gorski;Linzhao Cheng;D. Pardoll;C. Ci
中科院分区：
文献类型：
--
作者：
K. Whartenby;E. Straley;Heeje Kim;F. Racke;V. Tanavde;K. Gorski;Linzhao Cheng;D. Pardoll;C. Ci
fas介导的细胞凋亡是激活的T细胞在抗原刺激克隆扩增产生特异性细胞免疫应答后被清除的主要生理机制。由于活化的T细胞是同种异体移植排斥反应的主要效应因子，我们假设在移植前对同种异体骨髓（BM）细胞进行基因修饰可以提供一些保护，免受宿主T细胞的攻击，从而增强骨髓移植（BMT）中的供体细胞植入。我们进行了研究，以确定在同种异体BMT模型中，慢病毒载体介导的Fas配体（FasL）转导到谱系抗原阴性（lin(-)）小鼠BM细胞（lin(-) BM）的结果。fasl修饰的lin（-）脑转移瘤在体外杀死表达fasl的T细胞。与对照组相比，接受同种异体FasL(+) lin（-）脑转移瘤移植的小鼠在非清髓性调节后具有增强的短期移植物。在这些时间点，我们观察到受体小鼠没有主要的肝毒性或造血或免疫损伤。这些结果表明，在BMT的背景下，操纵淋巴造血干细胞祖细胞表达FasL或其他免疫调节基因是潜在的治疗方法。
Fas-mediated apoptosis is a major physiologic mechanism by which activated T cells are eliminated after antigen-stimulated clonal expansion generates a specific cellular immune response. Because activated T cells are the major effectors of allograft rejection, we hypothesized that genetically modifying allogeneic bone marrow (BM) cells prior to transplantation could provide some protection from host T-cell attack, thus enhancing donor cell engraftment in bone marrow transplantation (BMT). We undertook studies to determine the outcome of lentiviral vector-mediated transduction of Fas ligand (FasL) into lineage antigen-negative (lin(-)) mouse BM cells (lin(-) BMs), in an allogeneic BMT model. FasL-modified lin(-) BMs killed Fas-expressing T cells in vitro. Mice that received transplants of allogeneic FasL(+) lin(-) BMs had enhanced short-term engraftment, after nonmyeloablative conditioning, as compared to controls. We observed no major hepatic toxicity or hematopoietic or immune impairment in recipient mice at these time points. These results suggest potential therapeutic approaches by manipulating lymphohematopoietic stem-progenitor cells to express FasL or other immune-modulating genes in the context of BMT.