Transplantation of cord blood

该项目的目的是制定一项协议，用于从否则致命的(900cGy)全身照射(TBI)中营救受害者。该方案的开发将使用临床前狗模型，将脐带血作为干细胞的来源。与其他来源的造血细胞相比，脐血移植导致的移植物抗宿主病(GVHD)较轻，尽管无血缘关系的供者和受者之间存在更大的主要组织相容性复合体(MHC)差异。可以为包括少数族裔/种族成员在内的大量患者快速确定部分MHC相合的脐带血单位。然而，要成功地将脐带血移植到成人体内，一个主要的问题是脐带血单位中含有的造血细胞数量很少。这导致了非常长的恢复时间 粒细胞和血小板计数以及移植排斥和死亡的高风险。因此，该项目将致力于使用成熟的犬造血细胞移植模型来预防排斥反应和提高低细胞数、部分MHC相合的脐带血的快速植入。为了促进低细胞剂量的脐带/新生儿血(UCNB)的移植，我们将研究三种不同的造血细胞来源的共输注，这些造血细胞来源可以储存并“现成”使用。首先，我们将在UCNB移植物中添加1、5或10个单位的冷冻保存的、MHC不匹配的UCNB。其次，我们将用承诺的髓系祖细胞补充低细胞剂量的UCNB移植物(来自项目4)。第三，我们将利用Notch-1受体的配体体外扩增UCNB来源的CD34祖细胞。我们将比较单独移植扩增的CD34 UCNB细胞和联合移植低细胞剂量的UCNB细胞。在所有病例中，移植后环孢素和 将给予霉酚酸酯预防移植物抗宿主病。如果GVHD持续存在，将采用项目6中开发的新策略。一旦达到可靠植入的条件，将确定UCNB造血细胞拯救去髓移植受体犬的“机会之窗”。在狗模型上完成这些临床前研究将对改善骨髓致死性脑损伤后需要超紧急抢救造血的患者的预后做出重大贡献。

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.