Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease

项目摘要 移植物抗宿主病（GVHD）是同种异体移植的主要并发症， 造血干细胞移植（HSCT）。胃肠道（GI）损伤 急性GVHD是导致显著发病率和死亡率的特别严重的事件。 促炎细胞因子在肠道GVHD的病理生理学中起着关键作用，部分， 通过激活供体T细胞群，随后诱导组织损伤。初步 研究中，我们已经确定GM-CSF作为一种关键的细胞因子，在肿瘤的发生发展中起着重要作用。 胃肠道中急性GVHD的病理生理学。该提案的目的是定义 GM-CSF影响免疫系统的先天和适应性臂的机制途径 系统在GVHD期间在该组织部位中诱导炎症。我们的总体假设是 GM-CSF在胃肠道中诱导促炎环境， 作用归因于致病性骨髓细胞群的募集， 同种异体反应性供体T细胞反应的增强。具体目标1的研究将 表征响应GM-CSF信号传导的先天细胞群体，并定义 特异性GM-CSF应答细胞在介导胃肠道损伤中的功能作用 急性GVHD为了解决这个问题，我们将使用新的Csf 2 rbfl/fl小鼠，其中高表达的Csf 2 rbfl/fl小鼠是一种新的Csf 2 rbfl/fl小鼠。 GM-CSF受体的亲和β链具有侧翼lox β位点，这将允许骨髓细胞的增殖。 当与适当的谱系特异性Cre动物繁殖时，细胞特异性缺失。实验 具体目标2将定义GM-CSF影响T细胞介导的免疫应答的机制途径。 免疫系统中的炎症和调节功能，从而调节 GVHD的发生率。具体来说，我们将确定GM-CSF是否刺激IL-23的产生， 通过胃肠道中供体来源的APC，检查CD 4 + T细胞来源的GM-CSF是否促进 间接同种异体抗原呈递供体来源的APC在结肠，并确定GM的作用- CSF在GVHD期间调节性T细胞区室重建中的作用具体研究 目的3将确定CD 4 + GM-CSF+ T细胞是否代表稳定的T细胞谱系， 受白细胞介素7（IL-7）信号转导调节。为了解决这个问题，我们将构建一个新的 GM-CSF命运报告小鼠，这将使我们能够对免疫细胞群进行命运图， GM-CSF并确定其对IL-7的应答。本提案的总体目标是： 对胃肠道内GVHD的病理生理学和调节的新见解， 临床相关策略的发展，以减轻这种并发症在同种异体HSCT 并改善血癌患者的预后。

PROJECT SUMMARY Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). Damage to the gastrointestinal (GI) tract from acute GVHD is a particularly serious event leading to significant morbidity and mortality. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD, in part, by activating donor T cell populations which subsequently induce tissue damage. In preliminary studies, we have identified GM-CSF as a pivotal cytokine which plays an important role in the pathophysiology of acute GVHD in the GI tract. The goal of this proposal is to define the mechanistic pathways by which GM-CSF affects the innate and adaptive arms of the immune system to induce inflammation in this tissue site during GVHD. Our overall hypothesis is that GM-CSF induces a proinflammatory environment in the GI tract, and that this effect is attributable to the recruitment of pathogenic myeloid cell populations and the augmentation of alloreactive donor T cell responses. Studies in Specific Aim 1 will characterize the innate cell populations that are responsive to GM-CSF signaling and define the functional role of specific GM-CSF-responsive cells in mediating damage in the GI tract during acute GVHD. To address this question, we will employ novel Csf2rbfl/fl mice in which the high affinity beta chain of the GM-CSF receptor has flanking lox p sites, which will allow for myeloid cell-specific deletion when bred with appropriate lineage-specific Cre animals. Experiments in Specific Aim 2 will define mechanistic pathways by which GM-CSF affects T cell-mediated inflammatory and regulatory functions in the immune system, and thereby modulates the severity of GVHD in the GI tract. Specifically, we will determine whether GM-CSF elicits IL-23 production by donor-derived APCs in the GI tract, examine whether CD4+ T cell-derived GM-CSF promotes indirect alloantigen presentation by donor-derived APCs in the colon, and define the role of GM- CSF in the reconstitution of the regulatory T cell compartment during GVHD. Studies in Specific Aim 3 will determine whether CD4+ GM-CSF+ T cells represent a stable T cell lineage that is regulated by interleukin 7 (IL-7) signaling. To address this question, we will construct a novel GM-CSF fate reporter mouse that will allow us to fate map immune cell populations that produce GM-CSF and define their response to IL-7. The overall objective of this proposal is to develop 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 and improve outcomes in patients with blood cancers.