Mechanisms of hematopoietic stem cell engraftment

项目总结/摘要 造血干细胞（HSC）具有补充新的功能性造血系统的能力， 是许多造血系统恶性肿瘤的唯一治愈性治疗， 紊乱然而，供体人白细胞抗原（HLA）匹配的同种异体HSC的可用性通常是不确定的。 对于成功的移植来说太低了。单倍型错配（或单倍型相合）移植，其中供体是 在一半的HLA基因座匹配，是一个有吸引力的替代方案，但受到增加的排斥反应的限制，通常需要 高剂量的免疫抑制来维持供体移植目前的临床移植策略主要针对 适应性免疫反应，然而先天免疫细胞最近已经成为免疫系统的关键参与者。 在各种移植模型中的同种异体移植物反应，有助于移植物的成功和/或排斥。 移植因此，更好地理解移植中的先天免疫应答以及如何靶向它， 很危险我们最近发现了一个新的功能，HSC的小生境分子血管细胞粘附 HSC上的VCAM 1分子，其中VCAM 1作为先天免疫吞噬细胞的"不要吃我"信号 在单倍型错配移植的背景下。因此，操纵VCAM 1表达水平可以 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， 单倍型错配移植。在我们的第一个和第二个目标中，我们建议使用小鼠模型， VCAM 1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呈递的背景下从吞噬细胞中分离。第三个目标，我们 将评估工程化VCAM 1表达水平对供体干细胞促进移植的影响 穿过组织相容性屏障该提案将为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 免疫不匹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.