The NK cell response to prenatal allotransplantation

描述（由申请人提供）：指导当前子宫内造血细胞移植（IUHCT）方法的一个主要假设是，妊娠早期胎儿的免疫系统不成熟，无法排斥供体细胞移植。由于这个原因，在适应性免疫系统成熟之前移植细胞会导致供体细胞被识别为“自身”而不是“外来”。然而，不涉及免疫缺陷疾病的IUHCT临床病例的反复失败迫使对这种胎儿免疫系统模型进行重新检查。一项对IUHCT临床和实验室报告的调查显示，当免疫缺陷的宿主也是自然杀伤（NK）细胞缺陷时，IUHCT的成功率更高。对小鼠的初步研究表明，NK细胞可作为IUHCT的早期免疫屏障。为了建立NK细胞的耐受性并确保成功移植，在NK细胞成熟之前必须达到最低水平的造血嵌合。低于这个“嵌合阈值”，宿主NK细胞可预见地排斥移植物。通过这种方式，嵌合阈值为过去临床IUHCT的失败提供了一个合乎逻辑的解释。幸运的是，嵌合阈值的确定极大地促进了嵌合水平与IUHCT后NK细胞耐受性产生的机制研究。这一概念推动了核心假设，即嵌合阈值提供了选择“友好”NK细胞表型和抑制“敌对”NK细胞表型所需的最小供体配体识别量。为了挑战这一假设，本提案中的实验将确定嵌合阈值对同种异体反应性NK细胞的影响：1)选择；2)细胞毒性;3)记忆。本提案中实验的预期结果是描述IUHCT后嵌合水平与NK细胞耐受性出现的机制。这一知识将对IUHCT领域产生巨大影响，因为它为早期胎儿对同种异体移植的免疫反应建立了一个新的范例。这直接影响到提高IUHCT成功的策略的发展，如供体细胞剂量、供体选择、加强移植和宿主免疫反应的治疗靶向。在更广泛的范围内，这些发现将指导胎儿NK细胞教育的进一步机制研究。

DESCRIPTION (provided by applicant): A primary assumption that guides current approaches to in utero hematopoietic cellular transplantation (IUHCT) is that the early-gestation fetus has an immature immune system that is incapable of rejecting a donor cell transplant. For this reason, transplanting the cells prior to the maturation of the adaptive immune system leads to recognition of the donor cells as "self" rather than "foreign". However, repeated failures in clinical cases of IUHCT that do not involve an immunodeficiency disease force a re-examination of this model of the fetal immune system. A survey of both clinical and laboratory reports of IUHCT reveal enhanced success when the immunodeficient host is also natural killer (NK) cell deficient. Preliminary studies in mice reveal that NK cells act as an early immune barrier to IUHCT. In order to establish NK cell tolerance and ensure successful engraftment, a minimum level of hematopoietic chimerism must be achieved prior to NK cell maturation. Below this "chimerism threshold", the host NK cells predictably reject the graft. In this way, the chimerism threshold offers a logical explanation for past failures of clinical IUHCT. Fortunately, the identification of the chimerism threshold greatly facilitates study of the mechanisms linking the chimerism level to the emergence of NK cell tolerance following IUHCT. This concept drives the central hypothesis that the chimerism threshold provides the minimum amount of donor ligand recognition necessary for the selection of "friendly" NK cell phenotypes and repression of "hostile" ones. To challenge this hypothesis, the experiment in this proposal will determine the impact of the chimerism threshold on alloreactive NK cell: 1) selection; 2) cytotoxicity; and 3) memory. The expected outcome for the experiments in this proposal is the delineation of the mechanisms linking the chimerism level to the emergence of NK cell tolerance following IUHCT. This knowledge will have a dramatic impact on the field of IUHCT as it establishes a new paradigm for the early fetal immune response to allotransplantation. This directly affects the development of strategies to enhance the success of IUHCT such as donor cell dose, donor selection, booster transplants and therapeutic targeting of the host immune response. On a broader scale, these findings will guide further mechanistic study of fetal NK cell education.