Reisner Yair, Gur Hilit, Reich-Zeliger Shlomit, Martelli Massimo F, Bachar-Lustig Esther
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Ann N Y Acad Sci. 2003 May;996:72-9. doi: 10.1111/j.1749-6632.2003.tb03235.x.
Studies in mice and humans demonstrate that transplantation of hematopoietic progenitors in numbers larger than commonly used ("megadose" transplants) overcomes major genetic barriers. In vitro studies suggest that veto cells, within the population of hematopoietic progenitors, facilitate this favorable outcome. Thus, when purified CD34(+) cells were added to bulk mixed-lymphocyte reactions (MLRs) they suppressed CTLs against the donor's stimulators, but not against stimulators from a third party. This tolerizing activity depends on cell contact and can be blocked by the caspase inhibitor BD-FMK, suggesting that the effector host T cells are deleted by apoptosis upon interaction with the CD34(+) cells. Early myeloid CD33(+) cells generated by short-term ex vivo expansion of CD34(+) cells also exhibit veto activity, and these cells can be grown in large numbers. Tolerance induction can be further enhanced by other veto cells. Perhaps the most potent veto cell is the CD8+ CTL. However, this cell is also associated with marked GVHD (graft-versus-host disease. GVHD can be separated from the veto activity by generating anti-third party CTLs under IL2 deprivation. Under such selective pressure only the stimulated clones which make IL2 can survive, while anti-host clones die. In vivo studies show that such anti-third party veto CTLs can be used safely for tolerance induction without GVHD.
对小鼠和人类的研究表明，移植数量超过常用量的造血祖细胞（“超大剂量”移植）能够克服主要的遗传障碍。体外研究表明，造血祖细胞群体中的否决细胞促成了这一有利结果。因此，当将纯化的CD34(+)细胞添加到大量混合淋巴细胞反应（MLR）中时，它们会抑制针对供体刺激物的细胞毒性T淋巴细胞（CTL），但不会抑制针对第三方刺激物的CTL。这种耐受活性取决于细胞接触，并且可以被半胱天冬酶抑制剂BD - FMK阻断，这表明效应宿主T细胞在与CD34(+)细胞相互作用时通过凋亡被清除。通过CD34(+)细胞的短期体外扩增产生的早期髓样CD33(+)细胞也表现出否决活性，并且这些细胞可以大量培养。其他否决细胞可以进一步增强耐受性诱导。也许最有效的否决细胞是CD8 + CTL。然而，这种细胞也与明显的移植物抗宿主病（GVHD）相关。通过在白细胞介素2（IL2）缺乏的情况下产生抗第三方CTL，可以将GVHD与否决活性分离。在这种选择性压力下，只有产生IL2的受刺激克隆能够存活，而抗宿主克隆则死亡。体内研究表明，这种抗第三方否决CTL可以安全地用于诱导耐受性而不会引发GVHD。
