Mechanisms of hematopoietic stem cell engraftment

造血干细胞植入机制

• 批准号: 10400400
• 负责人: Sandra Pinho
• 金额: $ 45.31万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400400
• 关键词: Allogenic; Allografting; Automobile Driving; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Cells; Clinical; Cytometry; Data; Defect; Disease; Donor person; Dose; Eating; Endothelial Cells; Engineering; Engraftment; Failure; Flow Cytometry; Genetic Engineering; Genetic Transcription; Goals; Graft Rejection; HLA Antigens; Haplotypes; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Histocompatibility; Homing; Homologous Transplantation; Human; Immune; Immune Evasion; Immune Tolerance; Immune response; Immunologics; Immunoprecipitation; Immunosuppression; In Vitro; Innate Immune Response; Innate Immune System; Integrin alpha4beta1; Major Histocompatibility Complex; Malignant - descriptor; Mediating; Molecular; Molecular Target; Mus; Myelogenous; Myeloid Cells; Non-Malignant; Pathway interactions; Patients; Phagocytes; Phagocytosis; Recovery; Role; Series; Signal Pathway; Signal Transduction; Stem cell transplant; Stromal Cells; Testing; Time; Transplantation; Vascular Cell Adhesion Molecule-1; adaptive immune response; base; cell type; curative treatments; donor stem cell; hematopoietic stem cell niche; immunoregulation; improved outcome; in vivo; in vivo engraftment; innate immune checkpoint; innate immune function; innovation; insight; mouse model; novel; novel therapeutics; overexpression; prevent; receptor; response; stem cell engraftment; success; transcriptome sequencing; transplant model

PROJECT SUMMARY/ABSTRACT Hematopoietic stem cells (HSCs) possess the ability to replenish a new functional hematopoietic system in recipients following transplantation and are the only curative treatment for many hematopoietic malignancies and disorders. However, the availability of donor human leukocyte antigen (HLA)–matched allogeneic HSCs is often too low for successful transplantation. Haplotype mismatch (or haploidentical) transplantation, where donors are matched at half of the HLA loci, is an attractive alternative but is limited by increased rejection, often requiring high-dose immunosuppression to sustain donor grafts. Current clinical transplantation strategies primarily target the adaptive immune response, however innate immune cells have recently emerged as key actors in the allograft response in various transplantation models, contributing to both the success and/or rejection of the transplant. Thus, better understanding of the innate immune response in transplantation and how to target it, is critical. We have recently discovered a novel function for the HSC niche molecule Vascular Cell Adhesion Molecule-1 (VCAM1) on HSCs, in which VCAM1 acts as a “don’t-eat-me” signal for innate immune phagocytes in the context of haplotype mismatch transplantation. Hence, manipulating VCAM1 expression levels may represent a promising immuno-regulatory approach to control the activity of innate immune cells promoting haplotype mismatch engraftment. In our first and second aims, we propose to use mouse models of transplantation to dissect the cellular and molecular mechanisms by which VCAM1 promotes immune evasion from phagocytes in the context of major histocompatibility complex (MHC)-I presentation. In our third aim, we will assess the impact of engineering VCAM1 expression levels on donor stem cells in promoting engraftment across the histocompatibility barrier. This proposal will provide valuable insights in the role of MHC-I engagement in controlling the function of innate immune cells, and illuminate new molecular targets to improve outcomes in immunologically mismatched stem cell transplantation assays.

项目概要/摘要 造血干细胞（HSC）具有补充新功能造血系统的能力 移植后的受者，是许多造血系统恶性肿瘤的唯一治疗方法 失调。然而，供体人类白细胞抗原 (HLA) 匹配的同种异体 HSC 的可用性通常是有限的。 太低而无法成功移植。单倍型错配（或单倍体）移植，其中供体 与一半的 HLA 基因座相匹配，是一种有吸引力的替代方案，但受到排斥增加的限制，通常需要 高剂量免疫抑制以维持供体移植物。目前的临床移植策略主要针对 然而，先天免疫细胞最近已成为适应性免疫反应的关键参与者 各种移植模型中的同种异体移植反应，有助于移植的成功和/或排斥 移植。因此，更好地了解移植中的先天免疫反应以及如何针对它是非常重要的。 批判的。我们最近发现了 HSC 利基分子血管细胞粘附的新功能 HSC 上的 Molecule-1 (VCAM1)，其中 VCAM1 充当先天免疫吞噬细胞的“别吃我”信号 在单倍型错配移植的背景下。因此，操纵 VCAM1 表达水平可能 代表了一种有前途的免疫调节方法来控制先天免疫细胞的活性，促进 单倍型错配植入。在我们的第一个和第二个目标中，我们建议使用以下小鼠模型 移植以剖析 VCAM1 促进免疫逃避的细胞和分子机制 来自主要组织相容性复合体 (MHC)-I 呈现背景下的吞噬细胞。在我们的第三个目标中，我们 将评估改造 VCAM1 表达水平对供体干细胞促进植入的影响 跨越组织相容性障碍。该提案将为 MHC-I 参与的作用提供有价值的见解 控制先天免疫细胞的功能，并阐明新的分子靶点以改善结果 免疫学不匹配的干细胞移植测定。