In Utero Transplantation

描述（由申请人提供）：本提案的长期目标是确定是否可以通过促进细胞（间充质干细胞和同种反应性自然杀伤细胞）的共移植来提高子宫内造血干细胞移植的成功率。我们假设使用这些细胞将提高供体干细胞的竞争力，并最终提高子宫内造血移植后实现的嵌合水平。从理论上讲，子宫内造血干细胞移植可以治疗和治愈许多淋巴造血系统的遗传性疾病。目标疾病可能包括血红蛋白病、免疫缺陷和脑白质病变。大多数这些疾病在出生前就产生了有害的影响，因此在子宫内进行治疗是必要的。子宫内治疗的可行性得到了各种自然发生的人类和动物嵌合体的支持，这些嵌合体表现出高度稳定的混合嵌合体。然而，在实验模型和人类胎儿中取得的成功并不令人鼓舞，因为所取得的嵌合水平将无法成功治疗人类胎儿疾病。两个主要的例外是胎羊模型和供体细胞具有竞争优势的环境，例如体重/体重小鼠和具有严重免疫缺陷的胎儿（例如X-SCID）。虽然胎儿理论上可能是治疗的理想候选者，但很明显，存在重大障碍，阻止临床相关嵌合水平的实现。如果胎儿移植的潜力要成为临床现实，就必须开发能够提高供体细胞竞争力的移植方法。在这个应用中，我们将确定是否植入和嵌合可以改善造血促进细胞的使用。我们还将评估这些促进细胞降低子宫内移植物抗宿主疾病风险的能力。如果我们的假设是正确的，那么在子宫内治疗造血和免疫疾病应该既安全又成功。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to determine if the success of in utero hematopoietic stem cell transplantation can be improved with co-transplantation of facilitating cells (mesenchymal stem cells and alloreactive natural killer cells). We hypothesize that the use of these cells will improve the competitiveness of donor stem cells and ultimately increase the level of chimerism that is achieved after in utero hematopoietic transplantation. Theoretically, in utero transplantation of hematopoietic stem cells should treat and cure many heritable disorders of the lymphohematopoietic system. Target diseases potentially include hemoglobinopathies, immune deficiencies, and leukodystophies. Most of these disorders exert their deleterious effects prior to birth making the rationale for in utero treatment imperative. The feasibility of in utero therapy is supported by a variety of natural occurring human and animal chimeras that demonstrate high levels of stable mixed chimerism. However, successes in both experimental models and in the human fetus have not been as encouraging as the levels of chimerism achieved would not be expected to successfully treat human fetal disease. Two major exceptions are the fetal-sheep model and settings where there is a competitive advantage for donor cells as for example in W/W mice and in fetuses with severe immune defects (e.g. X-SCID). While the fetus may theoretically be an ideal candidate for therapy it is clear that significant barriers exist that prevent clinically relevant levels of chimerism from being achieved. Transplantation methods that will improve the competitiveness of donor cells must be developed if the potential of fetal transplantation is going to become a clinical reality. In this application we will determine if engraftment and chimerism can be improved with the use of hematopoietic facilitating cells. We also will evaluate the ability of these facilitating cells to reduce the risk of in utero graft verses host disease. If our hypotheses are correct, then in utero treatment for hematopoietic and immune disorders should be both safer and successful.