Using donor pDC to optimize GvHD and GvL in allogeneic stem cell transplantation

使用供体 pDC 优化同种异体干细胞移植中的 GvHD 和 GvL

基本信息

批准号：
8837590
负责人：
Edmund K Waller
金额：
$ 32.37万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-11 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837590
关键词：
Acute Graft Versus Host Disease Address Affect Allogenic Allografting Blood Blood Component Removal CSF3 gene CXCR4 gene Cells Clinical Clinical Data Clinical Trials Contracts Data Dendritic Cells Disease model Enrollment Equilibrium Gene Expression Goals Graft Rejection Health Hematopoietic Stem Cell Mobilization Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Homing Human Immune Immunity Interferons Kinetics Knowledge Lead Lymphoid Methods Modeling Mus National Heart, Lung, and Blood Institute Nature Organ Transplantation Outcome Pathogenesis Pathology Patients Population Pre-Clinical Model Publishing Randomized Regulatory T-Lymphocyte Relapse Reporting Research Risk Role Signal Transduction Site Source Stem cell transplant Stem cells T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Translating Translations Transplant Recipients Transplantation Work base cancer immunotherapy chemokine receptor chronic graft versus host disease clinical practice graft vs host disease high risk improved in vivo innovation insight leukemia migration mortality novel strategies pre-clinical reconstitution research study tumor

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research is to improve survival for patients after allogeneic stem cell transplantation by limiting graft-versus-host disease (GvHD) while maintaining the graft-versus-leukemia effect of donor ts immune cells. Clinical data from the BMT CTN 0201 clinical trial, in which transplant recipienw ith leukemia or MDS were randomized to receive BM versus G-CSF-mobilized blood stem cell allografts, found identical overall survival comparing the two graft sources, with less chronic GvHD in BM recipients. Among recipients of BM allografts, better survival was seen among recipients of larger numbers of plasmacytoid dendritic cells (pDC) and naïve T-cells compared with patients who received fewer of these donor cells. Surprisingly, lower rates of severe acute GvHD (but not relapse) were seen in recipients of BM allografts containing more naïve donor T-cells. Our recent published data shows that 1) highly purified donor pDC limit severe GvHD in murine BMT by facilitating expansion of donor regulatory T-cells (Treg) through interferon-γ- and IDO-dependent signaling with donor naïve T-cells; 2) plerixafor, a CXCR4 antagonist that mobilizes hematopoietic stem cells, also efficiently mobilizes pDC and naïve T-cells. Our overall hypothesis is that donor pDC in the hematopoietic stem cell graft favorably regulate the site of donor T-cell activation and donor T-cell immune polarization. Clinical translation of this approach is limited by gaps in understanding how donor pDC and T-cells cells interact to regulate GvHD. First, what is the optimal graft source or mobilization strategy to enhance the ability of pDC to limit severe GvHD? Second, what is the nature of interaction between donor pDC and naïve T-cells that leads to increased Treg activity? Third, how do pDC in the graft regulate post-transplant immunity, including graft-versus-leukemia GvL? Three aims will test our overall hypothesis: 1. To determine the method of collecting hematopoietic stem cells that optimizes the content and immunological activity of donor pDC and naïve T-cells. 2. To test how pDC precursors in the donor stem cell graft and their progeny in vivo regulate homing and allo-reactivity of effector and regulatory T-cells in allo-HSCT recipients. 3. To define the relationship between the content of pDC and naïve T-cells in grafts collected from healthy donors with post-transplant immune reconstitution, including GvL and GvHD activities. According to the overall hypothesis, GvHD can be reduced, GvL can be maintained, and transplant outcomes can be improved by increasing the content of immature donor pDC in allo-HSCT recipients at higher risk for graft rejection and/or GvHD. Mechanistic experiments with mice and an innovative clinical trial of plerixafor mobilization in humans will test this hypothesi by studying Treg induction and in vivo migration of donor T-cells and pDC. Knowledge gained from this project will improve outcomes for patients undergoing allogeneic stem cell transplants and will have applications in cancer immunotherapy and organ transplantation.

描述（由申请人提供）：本研究的长期目标是通过限制移植物抗宿主病（GvHD）同时维持供体ts免疫的移植物抗白血病效应，提高同种异体干细胞移植后患者的生存率来自 BMT CTN 0201 临床试验的临床数据，其中患有白血病或 MDS 的移植受者被随机接受 BM 与 G-CSF 动员的血液干细胞。研究发现，两种移植来源的总体生存率相同，而骨髓同种异体移植受者的慢性 GvHD 较少，与患者相比，浆细胞样树突状细胞 (pDC) 和初始 T 细胞数量较多的受者的生存率更高。令人惊讶的是，接受较少这些供体细胞的骨髓同种异体移植受者的严重急性 GvHD（但不复发）的发生率较低。我们最近发表的数据表明，1) 高度纯化的供体 pDC 通过与供体幼稚 T 的干扰素-γ-和 IDO 依赖性信号传导促进供体调节性 T 细胞 (Treg) 的扩增，从而限制小鼠 BMT 中严重的 GvHD。 -细胞；2) plerixafor，一种动员造血干细胞的 CXCR4 拮抗剂，也能有效地动员 pDC 和幼稚 T 细胞。造血干细胞移植物中的 pDC 有利地调节供体 T 细胞激活和供体 T 细胞免疫极化的位点，但由于对供体 pDC 和 T 细胞如何相互作用以调节 GvHD 的理解存在缺陷，因此该方法的临床转化受到限制。，增强 pDC 限制严重 GvHD 能力的最佳移植来源或动员策略是什么？第二，供体 pDC 和初始 T 细胞之间导致 Treg 活性增加的相互作用的本质是什么？移植物中的 pDC 是否调节移植后免疫，包括移植物抗白血病 GvL？三个目标将检验我们的总体假设： 1. 确定收集造血干细胞的方法，以优化供体 pDC 和幼稚细胞的含量和免疫活性2. 测试供体干细胞移植物及其后代中的 pDC 前体如何在体内调节效应 T 细胞和调节 T 细胞的归巢和同种异体反应性。 3. 明确移植后免疫重建的健康供体移植物中 pDC 和幼稚 T 细胞含量之间的关系，包括 GvL 和 GvHD 活性。根据总体假设，GvHD 可以降低。通过增加移植物排斥和/或 GvHD 风险较高的异基因 HSCT 受者中未成熟供体 pDC 的含量，可以维持 GvL，并改善移植结果。在小鼠中进行的一项创新性临床试验将通过研究 Treg 诱导以及供体 T 细胞和 pDC 的体内迁移来测试这一假设，从该项目中获得的知识将改善接受同种异体干细胞移植的患者的治疗结果。在癌症免疫治疗和器官移植中的应用。