Mechanisms of hematopoietic stem cell engraftment

项目摘要/摘要 造血干细胞(HSCs)具有在体内补充新的功能造血系统的能力 移植后的受体，是许多血液系统恶性肿瘤的唯一根治方法 精神错乱。然而，供者人类白细胞抗原(Hla)相合的同种异体造血干细胞的可用性通常是 对于成功的移植来说太低了。单倍型不匹配(或单倍体相合)移植，供者是 在一半的HLA基因座匹配，是一个有吸引力的替代方案，但受限于增加的排斥反应，通常需要 大剂量免疫抑制以维持供者移植物。目前的临床移植策略主要针对 获得性免疫反应，然而，先天免疫细胞最近已成为关键的参与者 不同移植模型中的同种异体移植反应，有助于移植成功和/或排斥 移植。因此，更好地理解移植中的先天免疫反应以及如何针对它，是 危急时刻。我们最近发现了HSC利基分子血管细胞黏附的新功能 HSCs上的分子-1(VCAM1)，其中VCAM1作为先天免疫吞噬细胞的“不吃我”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 代表了一种很有前途的免疫调节方法来控制先天免疫细胞促进 单倍型不匹配植入。在我们的第一个和第二个目标中，我们建议使用 移植研究VCAM1促进免疫逃避的细胞和分子机制 在主要组织相容性复合体(MHC)-I呈递的背景下来自吞噬细胞。在第三个目标中，我们 将评估工程VCAM1表达水平对供者干细胞促进植入的影响 跨越组织相容性障碍。这项提议将对MHC-I参与的作用提供有价值的见解 在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 免疫失配的干细胞移植试验。

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.