Durkin Emily T, Jones Kelly A, Rajesh Deepika, Shaaban Aimen F
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, USA.
Blood. 2008 Dec 15;112(13):5245-53. doi: 10.1182/blood-2007-12-128116. Epub 2008 Sep 16.
The failure of engraftment in human cases of in utero hematopoietic cell transplantation (IUHCT) in which no immunodeficiency exists suggests the presence of an unrecognized fetal immune barrier. A similar barrier in murine IUHCT appears to be dependent on the chimerism level and is poorly explained by a lack of T-cell tolerance induction. Therefore, we studied the effect of the chimerism level on engraftment and host natural killer (NK)-cell education in a murine model of IUHCT. The dose of transplanted cells was found to exhibit a strong correlation with both the engraftment rate and chimerism level. More specifically, a threshold level of initial chimerism (> 1.8%) was identified that predicted durable engraftment for allogeneic IUHCT, whereas low initial chimerism (< 1.8%) predicted a loss of engraftment. NK cells taken from chimeras above the "chimerism threshold" displayed durable calibration of alloresponsive Ly49A receptors and tolerance to donor antigens. Depletion of recipient NK cells stabilized engraftment in low-level chimeras (< 1.8%). These studies illustrate the importance of the early chimerism threshold in predicting long-term engraftment and host NK-cell tolerance after in utero transplantation.
在不存在免疫缺陷的人类子宫内造血细胞移植（IUHCT）病例中，植入失败提示存在未被识别的胎儿免疫屏障。小鼠IUHCT中的类似屏障似乎取决于嵌合水平，并且缺乏T细胞耐受性诱导难以解释这一现象。因此，我们在小鼠IUHCT模型中研究了嵌合水平对植入以及宿主自然杀伤（NK）细胞驯化的影响。发现移植细胞剂量与植入率和嵌合水平均密切相关。更具体地说，确定了初始嵌合的阈值水平（>1.8%），该阈值可预测异基因IUHCT的持久植入，而低初始嵌合（<1.8%）则预示植入失败。取自高于“嵌合阈值”的嵌合体中的NK细胞表现出对同种异体反应性Ly49A受体的持久校准以及对供体抗原的耐受性。受体NK细胞的耗竭可稳定低水平嵌合体（<1.8%）中的植入。这些研究说明了早期嵌合阈值在预测子宫内移植后长期植入和宿主NK细胞耐受性方面的重要性。
