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

• 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
• 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

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（由适用提供）：这项研究的长期目标是通过限制基层宿主病（GVHD）来改善同种异体干细胞移植后患者的存活率，同时维持供体TS免疫细胞的基层 - 伴随基质 - 白细胞效应。来自BMT CTN 0201临床试验的临床数据，其中移植受者被随机分配以接收BM与G-CSF-Mobilized血液干细胞合金，发现与BM受体中慢性GVHD较少的两个移植物相比，总体生存率相同。在BM合金的受体中，与接受这些供体细胞中较少的患者相比，在较大的血浆树突状细胞（PDC）（PDC）（PDC）（PDC）（PDC）和幼稚的T细胞的受体中可以看到更好的生存。令人惊讶的是，在含有更幼稚的供体T细胞的BM合金的受体中，出现了较低的严重急性GVHD（但未继电器）。我们最近发表的数据表明，1）通过支持供体调节性T细胞（TREG）通过干扰素-γ-和IDO依赖性信号与供体幼稚的T细胞的供体调节性T细胞（TREG），高度纯化的供体PDC极限限制了严重的GVHD。 2）Plerixafor，一种动员造血干细胞的CXCR4拮抗剂，也有效地动员了PDC和幼稚的T细胞。我们的总体假设是造血干细胞移植中的供体PDC很好地调节了供体T细胞激活和供体T细胞免疫极化的位点。这种方法的临床翻译受到理解供体PDC和T细胞细胞如何相互作用以调节GVHD的差异的限制。首先，什么是最佳的移植源或动员策略，以增强PDC限制严重GVHD的能力？其次，供体PDC和幼稚的T细胞之间相互作用的性质是什么？第三，移植物中的PDC如何调节移植后免疫力，包括移植物 - 抗链球菌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T细胞的含量和免疫学活性。 2。为了测试供体干细胞移植物中的PDC前体以及它们在体内的进展如何调节效应子的归巢和同种反应性和在Allo-HSCT受体中的调节T细胞。 3。定义PDC含量与从健康供体中收集的移植物中的T-Cells含量之间的关系，包括移植后免疫重建，包括GVL和GVHD活动。根据总体假设，可以减少GVHD，可以维持GVL，并通过增加Allo-HSCT接受者中未成熟供体PDC的含量来改善移植结果，以较高的谷物排斥和/或GVHD风险。小鼠的机理实验以及人类plerixafor动员的创新临床试验将通过研究Treg诱导和体内供体T细胞和PDC的体内迁移来检验这一假设。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结局，并将在癌症免疫疗法和器官移植中应用。