MHC Class Ib Mismatch in Prenatal Transplantation

描述(申请人提供)：宫内造血干细胞移植(IUHSCTx)是一种可靠和安全地引入非常少量的矫正细胞的方法，这些细胞将被永久鉴定为“自身而不是异体细胞，而不是使用可能比疾病本身更有害的免疫抑制剂。然而，除了少数病例外，IUHSCTx在治疗其他不存在免疫缺陷的先天性疾病方面并不成功。在没有免疫抑制的情况下，仅在人类胎儿受体或非人灵长类IUHSCTx模型中实现了微嵌合体(&lt；0.3%)。这些水平对于大多数疾病的纠正来说太低了，而且还没有被证明可靠地预测耐受性。这些失败的原因尚不清楚，但可能与在完整的胎儿造血环境中对供者HSCs的竞争能力较弱有关，也可能与胎儿固有免疫系统中存在未知的免疫机制有关。这两种可能性都有证据；然而，本申请中描述的实验将专门探索同种异体移植在妊娠早期胎儿中的先天免疫屏障。从我们在小鼠身上的研究中，我们观察到IUHSCTx之后的植入与供体或宿主品系中Ib类抗原表达的错配以及另一品系中相应的抑制性NK受体的表达存在相关性。嫁接水平似乎是朝着Ib级错配的方向进行的，而不是按照1a级差距的程度。这些特征让人联想到KIR不匹配的单倍体相合骨髓移植。在这些实验中，我们假设供体/宿主在Qa-1/NKG2信号和Qa-2表达方面的不匹配调节了免疫功能受者的宫内造血干细胞移植的结果。胎儿NK细胞上Ib类非多态配体和NKG2抑制受体的发育连锁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胸腺前小鼠胎儿先天免疫的研究提供了很大的翻译相关性。为了评估我们的假设，我们将具体：1)表征Qa-1/NKG2错配对同种异体胎肝移植反应的影响；以及2)确定Qa-2错配在同种异体胎肝产前移植中的功能意义。这些新颖的实验结果将指导IUHSCTx的未来应用，并有可能扩大其在先天性疾病中的应用，如地中海贫血、镰状细胞疾病、囊性纤维化、糖尿病和各种代谢性疾病。此外，我们还将首次探索调节胎儿同种异体移植的先天免疫反应的机制。

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.