Enhancement of Lympho-Hematopoietic Recovery after UCBT

项目1的中心假设是，脐带血（UCB）衍生的调节性T细胞（Treg）和胸腺祖细胞（Tprog）的组合将通过消除严重急性GVHD的风险和增强免疫恢复来优化UCB的安全性。在目前的资助期间，我们在开发了一种扩增培养方法之后，开始了第一次UCB Treg的非人临床试验，该方法常规产生Treg，该Treg在体外和体内使用异种GVHD小鼠模型都具有高度抑制性。在此期间，我们还评估了常用的免疫抑制剂对Treg的作用，其浓度在移植受体中常规可达到。在这些结果的基础上，我们开始了第二次临床试验，使用雷帕霉素（Rapa），而不是环孢素A与霉酚酸酯（MMF）的组合，以优化体内扩增和半衰期以及效力。在下一个资助期，我们的目标是开发一种综合的、基于细胞的方法，最终降低急性GVHD的风险，减少移植后长期免疫抑制的需要，并提高免疫重建的速度。为了实现这些目标，我们将首先使用新开发的用于大规模Treg制造的改进方法来建立Treg的最大耐受剂量，然后证明部分HLA匹配的Treg在预防急性GVHD中的效力和现有的HLA不匹配的Treg在治疗急性GVHD中的效力。我们还将测试T细胞免疫重建的新方法，通过确定UCB移植物中Treg和T效应细胞的最佳平衡而无需移植后GVHD预防，随后将Tprog添加到该治疗平台以增强胸腺生成和T细胞免疫重建。 免疫重建在这些研究结束时，我们将证明UCB Treg的安全性和效力，并建立一种新的治疗模式，无需药理学免疫抑制，以评估Tprog的安全性和有效性。

The central hypothesis of Project 1 is that a combination of umbilical cord blood (UCB)-derived T regulatory (Treg) cells and thymic progenitors (Tprog) will optimize the safety of UCB by eliminating the risk of severe acute GVHD and enhancing immune recovery. During the current funding period, we initiated the first-inhuman clinical trials with UCB Treg after having developed an expansion culture methodology that routinely yielded Treg that were highly suppressive both in vitro and in vivo using a xenogenic GVHD murine model. During this period, we also evaluated the effect of commonly used immunosuppressive agents on Treg at concentrations routinely achievable in transplant recipients. On the basis of these results, we initiated a second clinical trial with UCB-Tregs using rapamycin (Rapa) rather than Cyclosporin A in combination with mycophenolate mofetil (MMF) to optimize in vivo expansion and half life as well as potency. Over the next grant period, our goal is to develop an integrated, cell-based approach that will ultimately reduce the risk of acute GVHD, permit a reduction in the need for prolonged posttransplant immunosuppression, and enhance the pace of immune reconstitution. To accomplish these goals, we will first establish the maximum tolerable dose of Treg using newly developed improved methods for large scale Treg manufacture, and then demonstrate the potency of partially HLA matched Treg in prevention and ¿off the shelf¿ HLA unmatched Treg in treatment of acute GVHD. We will also test novel approaches to T cell immune reconstitution by determining the optimal balance of Treg and T effector cells in the UCB graft without posttransplant GVHD prophylaxis, and subsequently adding Tprog to this treatment platform to enhance thymopoiesis and T cell immune reconstitution. At the conclusion of these studies, we will have demonstrated the safety profile and potency of UCB Treg and established a new treatment paradigm without pharmacologic immunosuppression for evaluating safety and efficacy of Tprog.