The Role of Donor T Cell-Derived GM-CSF in the Pathogenesis of Gastrointestinal Acute GVHD

项目总结 移植物抗宿主病(GVHD)是异基因造血干细胞最严重的并发症。 移植(HSCT)和大约50%的HSCT接受者发生，尽管常规免疫 预防措施。GVHD是由成熟的同种异体反应性供者来源的T细胞介导的，这些T细胞存在于移植物中 移植的时间，并最终造成组织损伤。在GVHD的急性期，通常 发生在移植后的前100天，炎症仅限于有限数量的靶器官， 尤其是皮肤、肝脏和胃肠道(GI)。移植物抗宿主病对胃肠道的损害尤其严重。 导致严重发病率和死亡率的严重事件。促炎性细胞因子在脑血管疾病中起关键作用 肠道移植物抗宿主病肠道移植物抗宿主病的病理生理学，通过激活免疫系统的先天和适应性手臂 虽然T细胞是GVHD的直接驱动力，但疾病的诱发和扩大依赖于这种串扰 在先天免疫细胞和获得性免疫细胞之间。然而，调节这一过程的细胞和细胞因子网络 对相互作用的理解还不完全。小鼠移植物抗宿主病模型的初步研究 已经确定GM-CSF是一种细胞因子，由GI中供者来源的CD4+T细胞产生 在移植物抗宿主病过程中。此外，干扰CD4+T细胞上的GM-CSF信号显著延长了小鼠的存活时间。 接受移植物抗宿主病的小鼠，减少了对结肠的炎症损害，表明这 细胞因子在移植物抗宿主病生物学中发挥重要作用。基于这些研究，这一总体假设 有观点认为，GM-CSF通过下游激活促进胃肠道炎症。 增强T细胞同种异体反应性的先天免疫群体。对特定目标1的研究将 确定GM-CSF应答的髓样细胞群在胃肠道炎症中的中介作用 GVHD。这一目标将使用新的遗传和基于抗体的方法来识别相关的GM-CSF- 依赖于天然免疫群体，并将决定这些细胞介体如何能够直接 促进促炎环境的形成。在特定目标2中的研究将通过以下方式定义机制路径 GM-CSF对GVHD患者T细胞同种异体反应的调节作用。这些实验将检验GM-CSF如何影响 供者来源的抗原提呈细胞(APC)产生IL-23，这是一种以前已经 已被证明在GVHD期间对诱导胃肠道炎症起关键作用，决定GM- APC中的CSF信号影响胃肠道中的间接同种异体抗原递呈，并表征GM-CSF如何 调节调节性T细胞室的重建。这项提议的总体目标是 提供有关GVHD在胃肠道内的病理生理学和调节的新见解，这将促进 临床相关策略的发展以减少异基因造血干细胞移植受者的这种并发症。

PROJECT SUMMARY Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic stem cell transplantation (HSCT) and occurs in approximately 50% of all HSCT recipients despite routine immune prophylaxis. GVHD is mediated by mature alloreactive donor-derived T cells, which are present in the graft at the time of transplant and ultimately cause tissue damage. During the acute phase of GVHD, which typically occurs in the first 100 days post-transplantation, inflammation is restricted to a limited number of target organs, specifically the skin, liver, and gastrointestinal (GI) tract. Damage to the GI tract from GVHD is a particularly serious event leading to significant morbidity and mortality. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD by activating both the innate and adaptive arms of the immune system. While T cells are the proximate drivers of GVHD, disease induction and amplification rely on this crosstalk between innate and adaptive immune cells. However, the cellular and cytokine networks which mediate this interplay are incompletely understood. Preliminary studies using well-characterized murine models of GVHD have identified GM-CSF as a cytokine which is produced at high levels by donor-derived CD4+ T cells in the GI tract during GVHD. Moreover, disruption of GM-CSF signaling in CD4+ T cells significantly prolongs survival in murine recipients undergoing GVHD and reduces inflammatory damage to the colon, indicating that this cytokine plays an important role in GVHD biology. Based on these studies, the overall hypothesis of this proposal is that GM-CSF promotes inflammation in the GI tract via the downstream activation of innate immune populations that potentiate T cell alloreactivity. Studies in Specific Aim 1 will determine the GM-CSF responsive myeloid cell populations that mediate inflammation in the GI tract during GVHD. This aim will employ novel genetic and antibody-based approaches to identify the relevant GM-CSF- dependent innate immune populations and will determine how these cellular mediators are able to directly contribute to the proinflammatory milieu. Studies in Specific Aim 2 will define the mechanistic pathways by which GM-CSF modulates T cell alloreactivity in GVHD. These experiments will examine how GM-CSF affects the production of interleukin-23 by donor-derived antigen presenting cells (APCs), a cytokine that has previously been shown to be crucial for the induction of gastrointestinal inflammation during GVHD, determine how GM- CSF signaling in APCs affects indirect alloantigen presentation in the GI tract, and characterize how GM-CSF modulates reconstitution of the regulatory T cell compartment. The overall objective of this proposal is to provide new insights into the pathophysiology and regulation of GVHD within the GI tract that will foster the development of clinically relevant strategies to mitigate this complication in allogeneic HSCT recipients.