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: 10052895
• 负责人: Edmund K Waller
• 金额: $ 75.61万
• 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/10052895
• 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; CSF3 gene; CXCR4 gene; Cell Compartmentation; Cell physiology; Cells; Clinical; Clinical Trials; Communicable Diseases; Cytometry; Data; Dendritic Cells; Drug Receptors; Enzymes; 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; Pancytopenia; 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; 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：总体目标是识别和富集供体树突状细胞 (DC) 群体，从而减少 移植物抗宿主病（GvHD）并提高同种异体骨髓移植（allo-BMT）后的生存率。 我们的提议基于已发表的研究结果，即骨髓移植物和骨髓中供体 DC 的含量 移植受者的血液对临床结果有重大影响，通过减少 来自小鼠 BMT 模型系统的 GvHD 死亡率且不增加复发。 来自骨髓的供体浆细胞样树突状细胞 (pDC) 而不是 G-CSF 动员的移植物可通过以下方式提高存活率 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，但尚不清楚是否相同 DC子集产生所有这些因素，或者是否存在DC的多个子群，每个子群具有不同的 另一个关键问题是供体 DC 归巢至淋巴和 GvHD 靶器官如何调节 T。 细胞免疫包括 GvHD 和移植物抗白血病 (GvL)。 收集含有免疫调节 DC 的移植物的有效程序将有助于这些的应用 为了实现我们的总体目标，我们提出了三个具体目标： 目标 1. 鉴定最有效的免疫调节剂的表型和基因表达谱 供体 DC 存在于骨髓和其他移植来源中 假设：骨髓含有。 DC 祖细胞亚群分泌免疫调节白细胞介素和趋化因子，通过以下方式限制 GvHD 促进供体来源的诱导 Treg (iTreg) 的产生。 目标 2. 明确供体骨髓 DC 祖细胞在不影响 GvHD 的情况下限制 GvHD 的机制 影响供体 T 细胞的 GvL 活性假设：骨髓中含有 DC 祖细胞的子集。 通过在 GVHD 靶组织中的幼稚供体 T 细胞生成 iT-reg 来限制 GvHD，同时介导 GvL 由次级淋巴器官中激活的供体 T 细胞产生。 目标 3. 定义一种干细胞动员方法，产生一定数量的干细胞并 免疫调节 DC 祖细胞数量增加 假设：用短期疗法治疗供体 Flt3-L的疗程将增加免疫调节供体DC的数量和单次注射普乐沙福 会将这些 DC 和造血干细胞动员到血液中，并通过单采术收集它们。 我们在同种异体 BMT 中定义 DC 调节免疫机制的工作将为广泛的医学领域提供信息。