MHC Class Ib Mismatch in Prenatal Transplantation

描述（由申请人提供）：子宫内造血干细胞移植（IUHSCTx）是一种可靠且安全地引入少量校正细胞的方法，这些细胞将被永久识别为“自我而不是外来”，而无需使用比疾病本身更有害的免疫抑制剂。然而，除少数病例外，IUHSCTx未能成功地用于治疗不存在免疫缺陷的其他先天性疾病。在没有免疫抑制的情况下，仅在IUHSCTx的人类胎儿受体或非人灵长类模型中实现了微嵌合（<0.3%）。这些水平对于大多数疾病的矫正来说太低了，也没有被证明可以可靠地预测耐受性。这些失败的原因尚不清楚，但可能与供体造血干细胞在完整的胎儿造血环境中的竞争能力差有关，或者可能与胎儿先天免疫系统中存在未被识别的免疫机制有关。这两种可能性都有证据；然而，在本应用程序中描述的实验将专门探讨先天免疫屏障的异体移植在早期妊娠胎儿。从我们对小鼠的研究中，我们观察到IUHSCTx后的移植与供体或宿主株中Ib类抗原表达与另一株中相应抑制性NK受体表达不匹配相关。嫁接水平似乎是在类b不匹配的方向上，而不遵循类la不匹配的程度。这些特征让人联想到基尔错配的单倍体骨髓移植。在这些实验中，我们假设供体/宿主在Qa-1/NKG2信号和Qa-2表达上的错配调节了免疫受体子宫内造血干细胞移植的结果。非多态性Ib类配体和胎儿NK细胞上的NKG2抑制受体的发育关联模式在灵长类动物和啮齿动物之间高度保守。这些惊人的相似性为研究胸腺前小鼠的胎儿先天免疫提供了巨大的翻译相关性。为了验证我们的假设，我们将具体地：1)表征Qa-1/NKG2错配在异体胎儿肝产前移植反应中的影响；2)确定Qa-2错配在异体胎儿肝产前移植中的功能意义。这些新颖的实验结果将指导未来IUHSCTx的应用，并有可能扩大其在先天性疾病如地中海贫血、镰状细胞病、囊性纤维化、糖尿病和各种代谢性疾病中的应用。此外，我们将首次探讨先天性免疫应答调节胎儿异体移植的机制。

DESCRIPTION (provided by applicant): In utero hematopoietic stem cell transplantation (IUHSCTx) is a way of reliably and safely introducing a very small number of corrective cells which will be permanently identified as "self rather than foreign without administering immunosuppressives that are potentially more harmful than the disease itself. However, except for a few cases, IUHSCTx has not been successful for the treatment of other congenital diseases in which no immunodeficiency exists. In the absence of immunosuppression, only microchimerism (<0.3%) has been achieved in human fetal recipients or non-human primate models of IUHSCTx. These levels are too low for the correction of most diseases and have not been demonstrated to reliably predict tolerance. The reasons for these failures are unclear but may relate to the poor competitive capacity for donor HSCs in the intact fetal hematopoietic environment or possibly the existence of an unrecognized immunologic mechanism in the fetal innate immune system. Evidence exists for both possibilities; however, the experiments described in this application will specifically explore the innate immune barrier to allotransplantation in early gestation fetus. From our studies in mice, we have observed that engraftment following IUHSCTx correlates with the existence of a mismatch in class Ib antigen expression in the donor or host strain and expression of the corresponding inhibitory NK receptor in the other strain. The level of engraftment appears to be in the direction of a class Ib mismatch and does not follow the degree of class la disparity. These characteristics are reminiscent of KIR-mismatched haploidentical bone marrow transplantation. In these experiments, we hypothesize that a donor/host mismatch in Qa-1/NKG2 signaling and Qa-2 expression regulates the outcome of in utero hematopoietic stem cell transplantation in immunocompetent recipients. The developmentally linked pattern of nonpolymorphic class Ib ligands and NKG2 inhibitory receptors on fetal NK cells is highly conserved between primates and rodents. These striking similarities provide great translational relevance for the study of fetal innate immunity in pre-thymic mice. To evaluate our hypothesis we will specifically: 1) Characterize the effect of a Qa-1/NKG2 mismatch in the response to the prenatal transplantation of allogeneic fetal liver; and 2) Determine the functional significance of a Qa-2 mismatch in the prenatal transplantation of allogeneic fetal liver. The results of these novel experiments will guide future application of IUHSCTx and potentially broaden its application to congenital diseases such as thalassemia, sickle cell disease, cystic fibrosis, diabetes mellitus, and various metabolic diseases. Additionally, for the first time, we will probe the mechanisms regulating the innate immune responses regulating fetal allotransplantation.