Bonde Sabrina, Chan Kun-Ming, Zavazava Nicholas
Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, United States of America.
PLoS One. 2008 Sep 15;3(9):e3212. doi: 10.1371/journal.pone.0003212.
Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES) cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs). Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we derived CD45(+) HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts.
Our data show, for the first time, the efficacy of ES-derived CD45(+) HPCs to engraft in allogenic recipients without the use of immunosuppressive agents, there by protecting cardiac allografts from rejection.
在对宿主进行适当预处理的情况下，骨髓细胞可诱导稳定的混合嵌合体，介导移植耐受的诱导。然而，由于需要严苛的预处理以及为防止排斥反应和移植物抗宿主病而使用毒性免疫抑制剂，其强烈的免疫原性阻碍了其在临床移植中的常规应用。另外，胚胎干细胞（ES细胞）已成为免疫原性较低的造血祖细胞（HPC）的潜在来源。然而，迄今为止，从ES细胞中生成稳定的造血细胞一直很困难。
方法/主要发现：在此，我们从转导了HOXB4的ES细胞中获得了CD45(+) HPC，并表明它们低表达MHC抗原。这一特性使它们能够在亚致死剂量照射的受体中跨MHC屏障长期植入，而无需免疫抑制剂。尽管供体细胞在外周血中在2个月内减少，但这些小鼠骨髓中的低水平嵌合体在100多天内得以维持。更重要的是，嵌合动物可免受供体类型心脏异体移植物的排斥。
我们的数据首次表明，ES来源的CD45(+) HPC在不使用免疫抑制剂的情况下植入同种异体受体的有效性，从而保护心脏异体移植物免受排斥。
