Lee L A, Sergio J J, Sykes M
Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital, Boston 02129, USA.
Transplantation. 1996 Jan 15;61(1):125-32. doi: 10.1097/00007890-199601150-00024.
Natural killer (NK) cells effect hybrid resistance, in which parental hematopoietic cell grafts are rejected by F1 recipients. NK cells can also resist engraftment of fully MHC-mismatched allogeneic marrow. However, studies of NK cell-mediated alloresistance have relied on short-term proliferation, colony, or survival assays; therefore, their results may not reflect effects of NK cells on the engraftment of allogeneic pluripotent hematopoietic stem cells (PHSC). We have now addressed the role of NK cells in resisting engraftment of these most primitive hematopoietic cells, which provide long-term repopulation of multiple hematopoietic lineages. We took advantage of a nonmyeloablative conditioning regimen that permits allogeneic marrow engraftment and induction of mixed chimerism in mice to evaluate the effect of host NK cell depletion with mAb PK136 on long-term competitive repopulating ability of allogeneic marrow. Mice were pretreated with depleting anti-CD4 and anti-CD8 mAbs, then received 3 Gy of whole body irradiation and 7 Gy of thymic irradiation prior to allogeneic bone marrow transplantation. Depending on the strain combination used, statistically significant increases in long-term allogeneic repopulation of both myeloid and lymphoid cell lineages were observed in recipients depleted of NK cells before bone marrow transplantation compared with controls. Depletion of host NK cells alone was sufficient to enhance donor PHSC engraftment. However, a statistically significant increase in allogeneic reconstitution in NK cell-depleted chimeras compared with control chimeras was not observed in every experiment, and differences were most readily apparent in a strain combination in which recipient NK cells have been shown to have high resistance to engraftment of donor short-term repopulating cells. Chronic (16 weeks) anti-NK1.1 treatment resulted in higher levels of donor-type repopulation than that in animals receiving only pretransplant NK cell depletion. Our studies demonstrate for the first time that host NK cells resist engraftment of allogeneic long-term repopulating PHSC, and provide a model for studying the elements that determine what is regarded as "self" and "non-self" by newly developing NK cells.
自然杀伤（NK）细胞发挥杂种抗性作用，即F1受体排斥亲代造血细胞移植。NK细胞也能抵抗完全MHC不匹配的异基因骨髓植入。然而，对NK细胞介导的同种异体抗性的研究一直依赖于短期增殖、集落或存活分析；因此，其结果可能无法反映NK细胞对异基因多能造血干细胞（PHSC）植入的影响。我们现在研究了NK细胞在抵抗这些最原始造血细胞植入中的作用，这些细胞能长期重建多个造血谱系。我们利用一种非清髓性预处理方案，该方案允许异基因骨髓植入并在小鼠中诱导混合嵌合体形成，以评估用单克隆抗体PK136清除宿主NK细胞对异基因骨髓长期竞争性再植能力的影响。小鼠先用耗竭性抗CD4和抗CD8单克隆抗体进行预处理，然后在异基因骨髓移植前接受3 Gy的全身照射和7 Gy的胸腺照射。根据所用的品系组合，与对照组相比，在骨髓移植前清除NK细胞的受体中，观察到髓系和淋巴系细胞谱系的长期异基因再植有统计学意义的增加。单独清除宿主NK细胞就足以增强供体PHSC的植入。然而，并非在每个实验中都观察到与对照嵌合体相比，NK细胞清除的嵌合体中同种异体重建有统计学意义的增加，并且在受体NK细胞已被证明对供体短期再植细胞植入具有高抗性的品系组合中差异最为明显。慢性（16周）抗NK1.1治疗导致供体型再植水平高于仅接受移植前NK细胞清除的动物。我们的研究首次证明宿主NK细胞抵抗异基因长期再植PHSC的植入，并提供了一个模型来研究决定新发育的NK细胞将什么视为“自身”和“非自身”的因素。
