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供体树突状细胞（DC）群体