Transplantation of cord blood

该项目的目的是制定一个协议，以拯救受害者，否则致命的（900 cGy）全身照射（TBI）。方案开发将使用临床前犬模型进行，其中脐带血作为干细胞来源。与其他来源的造血细胞相比，脐带血移植导致的移植物抗宿主病（GVHD）较轻，尽管无关供体和受体之间的主要组织相容性复合体（MHC）差异较大。部分MHC匹配的脐带血单位可以快速确定大量的患者，包括少数民族/种族群体的成员。然而，对于成功地将脐带血移植到成人中，一个主要问题是脐带血单位中所含的造血细胞数量少。这导致恢复的时间非常长， 粒细胞和血小板计数以及移植物排斥和死亡的高风险。因此，该项目将重点关注实际干预措施，以防止排斥反应，并使用成熟的狗造血细胞移植模型，提高低细胞数，部分MHC匹配脐带血的快速植入。为了促进低细胞剂量脐带/新生儿血（UCNB）移植物的植入，我们将研究三种不同造血细胞来源的共输注，这些细胞来源可以储存并“现成”使用。首先，我们将用1、5或10个单位的冷冻保存的MHC不匹配的UCNB补充UCNB移植物。第二，我们将用定向髓系祖细胞补充低细胞剂量的UCNB移植物（来自项目4）。第三，我们将使用Notch-1受体的配体离体扩增UCNB衍生的CD 34+祖细胞。我们将比较扩增的CD 34 + UCNB细胞单独移植以及与低细胞剂量UCNB移植物联合移植。在所有情况下，移植后环孢霉素和 将给予吗替麦考酚酯以预防GVHD。如果GVHD持续存在，将纳入项目6中制定的新策略。一旦达到可靠植入的条件，将确定UCNB造血细胞可以拯救骨髓清除受体犬的“机会窗口”。在狗模型中完成这些临床前研究将对改善骨髓致死性TBI后需要超紧急造血抢救的患者的结局做出重大贡献。

The purpose of this project is to develop a protocol for rescuing victims from otherwise lethal (900cGy) total body irradiation (TBI). The protocol development will done using the preclinical dog model with umbilical cord blood as a source of stem cells. Cord blood transplantation results in less severe graft-versus-host disease (GVHD) compared to other sources of hematopoietic cells despite greater major histocompatibility complex (MHC)-disparity between the unrelated donor and recipient. A partially-MHC-matched cord blood unit can be rapidly identified for a large number of patients including members of minority ethnic/racial groups. However, for successful transplantation of cord blood into adults, a major problem is the low number of hematopoietic cells contained in cord blood units. This results in a very prolonged time to recovery of granulocytes and platelet counts and a high risk of graft rejection and mortality. Therefore, this project will focus on practical interventions to prevent rejection and enhance rapid engraftment of low cell number, partially-MHC-matched cord blood using the well-established dog model of hematopoietic cell transplantation. To facilitate engraftment of a low cell dose umbilical cord/neonatal blood (UCNB) graft, we will study the co-infusion of three distinct hematopoeitic cell sources that can be stockpiled and used "off-the-shelf". First, we will supplement the UCNB graft with 1, 5 or 10 units of cryopreserved, MHC-mismatched UCNB. Second, we will supplement low cell dose UCNB grafts with committed myeloid progenitor cells (from Project 4). Third, we will ex vivo expand UCNB derived CD34+ progenitor cells using the ligand for Notch-1 receptor. We will compare transplantation of expanded CD34+ UCNB cells alone and also in combination with a low cell dose UCNB graft. In all cases postgrafting cyclosporine and mycophenolate mofetil will be given to prevent GVHD. If GVHD persists, new strategies will be incorporated as developed in Project 6. Once conditions are achieved for reliable engraftment, the "window of opportunity" during which UCNB hematopoietic cells can rescue myeloablated recipient dogs will be determined. Completion of these pre-clinical studies in the dog model will be a major contribution to improving the outcome of patients who require ultra-urgent rescue of hematopoiesis after marrow-lethal TBI.