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

使用供体树突状细胞优化同种异体干细胞移植中的 GvHD 和 GvL

• 批准号: 10402871
• 负责人: Edmund K Waller
• 金额: $ 74.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402871
• 关键词: AMD3100; Address; Adoptive Cell Transfers; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Allografting; Antigen-Presenting Cells; Biological Models; Blood; Blood Cells; Blood Component Removal; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; Bone marrow failure; CSF3 gene; CXCR4 gene; Cell Compartmentation; Cell physiology; Cells; Clinical; Clinical Trials; Communicable Diseases; Cytometry; Data; Dendritic Cells; Drug Receptors; Enzymes; FLT3 gene; FLT3 ligand; Future; Gene Expression Profile; Generations; Goals; Graft Rejection; Harvest; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemoglobinopathies; Homing; Human; Immune; Immunity; Immunologics; Incidence; Injections; Interleukins; Intervention; Knockout Mice; Luciferases; Lymphoid; Marrow; Mediating; Medicine; Methods; Molecular; Mus; Neuropeptides; Operating Rooms; Opportunistic Infections; Organ; Organ Transplantation; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Physicians; Population; Procedures; Publishing; Quality of life; Recurrent disease; Regulatory T-Lymphocyte; Relapse; Research; Sampling; Severities; Solid; Source; Stem cell transplant; T-Lymphocyte; Technical Expertise; Techniques; Testing; Time; Tissues; Toxic effect; Transgenic Mice; Translating; Transplant Recipients; Transplantation; Work; adaptive immunity; allotransplant; antagonist; base; bone marrow allograft; cancer cell; chemokine; chemokine receptor; chronic graft versus host disease; clinical application; clinical practice; cost effective; cytokine; engineered stem cells; graft vs host disease; graft vs leukemia effect; hematopoietic engraftment; immunoregulation; improved; in vivo; mortality; mortality risk; novel; novel strategies; post-transplant; pre-clinical; preclinical study; secondary lymphoid organ; single-cell RNA sequencing; stem cells; transplant model

ABSTRACT: The overarching goal is to identify and enrich donor dendritic cell (DC) populations that reduce graft-versus-host disease (GvHD) and improve survival after allogeneic bone marrow transplantation (allo-BMT). Our proposal is grounded on published findings that the content of donor DC in the bone marrow graft and in the blood of transplant recipients have significant impact on clinical outcomes, improving survival by decreasing GvHD-mortality without increasing relapse. Preclinical data from murine BMT model systems also show that donor plasmacytoid dendritic cells (pDC) from bone marrow but not G-CSF mobilized grafts improve survival by decreasing the severity of GvHD. The ability of donor pDC to limit GvHD is dependent upon their expression of chemokine receptors, cytokines, neuropeptides and catabolic enzymes, but it is not known whether the same DC subset produces all these factors, or whether there are multiple sub-populations of DC, each with different functions. Another key question is how homing of donor DC to lymphoid and GvHD-target organs regulates T cell immunity including GvHD and graft-versus-leukemia (GvL). Answering these questions and identifying cost- effective procedures for collecting grafts containing immune-regulatory DC will facilitate application of these exciting observations to clinical practice. To progress towards our overall goal, we propose three specific aims: Aim 1. To identify the phenotype and gene expression profile of the most potent immuno-regulatory subset of donor DC present in bone marrow and other graft sources. Hypothesis: bone marrow contains subsets of DC progenitors that secrete immune-regulatory interleukins and chemokines that limit GvHD by facilitating the generation of donor-derived induced-Treg (iTreg). Aim 2. To define the mechanism by which donor bone marrow DC progenitors limit GvHD without affecting the GvL activity of donor T cells. Hypothesis: bone marrow contains a subset of DC progenitors that limit GvHD by generating iT-reg from naïve donor T cells in GVHD target tissues while GvL is mediated by donor T cells activated in secondary lymphoid organs. Aim 3. To define a stem cell mobilization approach that yields an engrafting number of stem cells and increased numbers of immuno-regulatory DC progenitors Hypothesis: treatment of donors with a short- course of Flt3-L will increase the numbers of immune-regulatory donor DC and a single injection of plerixafor will mobilize these DC and hematopoietic stem cells into the blood where they can be collected by apheresis. Our work to define mechanisms by which DC regulate immunity in allo-BMT will inform broad fields of medicine.

摘要：总体目标是识别和丰富减少供体的树突状细胞（DC）种群 移植物抗宿主病（GVHD）并改善同种异体骨髓移植后的存活率（Allo-BMT）。 我们的建议基于发表的发现，即捐赠者DC在骨髓移植物和 移植受者的血液对临床结果有重大影响，从而改善了生存率 GVHD年道形无继电器。来自Murine BMT模型系统的临床前数据还表明 来自骨髓的供体纤溶酶树突状细胞（PDC），但不能动员G-CSF的移植物改善生存率 降低GVHD的严重程度。供体PDC限制GVHD的能力取决于它们的表达 趋化因子受体，细胞因子，神经肽和分解代谢酶，但不知道是否相同 DC子集产生所有这些因素，或者是否有多个DC的子选集 功能。另一个关键问题是将供体DC归为淋巴机和GVHD目标器官如何调节T 细胞免疫力，包括GVHD和移植物 - 白细胞（GVL）。回答这些问题并确定成本 - 收集含有免疫调节DC的移植物的有效程序将有助于应用这些 临床实践的令人兴奋的观察。为了朝着我们的整体目标迈进，我们提出了三个具体目标： 目的1。确定最有效免疫调节的表型和基因表达谱 供体DC的子集存在于骨髓和其他移植物来源中。假设：骨髓包含 DC祖细胞的子集分泌免疫调节性白细胞介绍和趋化因子，将GVHD限制在 促进捐助者衍生的诱导 - 特雷格（ITREG）的产生。 目标2。定义供体骨髓直流祖细胞限制GVHD的机制 影响供体T细胞的GVL活性。假设：骨髓包含DC祖细胞的子集 通过在GVL介导的GVHD目标时间中，从幼稚的供体T细胞中产生IT-reg来限制GVHD 由供体T细胞在继发性淋巴器官中激活。 目的3。定义一种干细胞动员方法，该方法产生大量干细胞和 免疫调节直流祖细胞的数量增加了假设：用短供体的供体的治疗 FLT3-L的过程将增加免疫调节供体DC的数量和单一注射Plerixafor 将动员这些DC和造血干细胞进入血液中，可以通过格式收集它们。 我们为定义DC调节Allo-BMT免疫学的机制的工作将为广泛的医学领域提供信息。