Pathogenesis, prevention and treatment of corticosteroid-resistant gut GVHD

异基因造血细胞移植(Allo-HCT)可治愈血液病 恶性肿瘤，但这种治疗会引起移植物抗宿主病(GVHD)，这是供体细胞的一种免疫反应 对接受者不利。抗炎皮质类固醇药物通常可以控制GVHD，但在某些情况下， GVHD对这种治疗有抵抗力，特别是当它影响肠道时。这个项目的目标是 了解引起类固醇抵抗(SR)肠道移植物抗宿主病的机制，并开发有效的方法来治疗 预防或治疗SR-Gut-GVHD。新建立的小鼠模型的结果表明，SR-Gut- GVHD是由于长期服用皮质类固醇引起的。皮质类固醇治疗导致血管扩张 产生IL-22的Th/Tc22样细胞，肠道微生物中依赖IL-22的异常，以及数量减少 单核巨噬细胞(MNP)中抗炎CX3CR1调节T细胞增殖和控制的研究 细菌易位。我们的初步研究和其他调查人员提供的信息表明 糖皮质激素治疗抑制T细胞和MNP细胞的多胺-亚硫氨酸途径并调节其保真度 T细胞谱系分化以及促炎和抗炎的MNP细胞的扩张。我们的研究也 提示类固醇治疗可增加肠上皮细胞CEACAM-1的表达，从而增加 细菌跨细胞和不利改变促炎因子CX3CR1lo-MNP和抗炎因子之间的平衡 炎性CX3CR1在MNP细胞中的表达。这些变化触发了前馈致病循环，包括 扩增产生IL-22的Th/Tc22样细胞，依赖IL-22的生物失调，并增加 促炎症CX3CR1lo MNP与调节CX3CR1hi MNP的数量减少，导致完全成熟 SR-GUT-GVHD。为了验证这一假设，该应用程序提出了三个目标。目标1将决定是否 糖皮质激素抑制T细胞中多胺-亚硫氨酸途径导致Th/Tc22样细胞的扩张 血统不忠的人。目的2确定皮质类固醇对多胺-亚精氨酸通路的抑制作用 CX3CR1+MNP细胞增强前炎症细胞CX3CR1lo-MNP的扩增 炎症性CX3CR1hi MNP应对生物失调的挑战。目标3将决定观察结果是否 在小鼠模型中反映了人类SR-Gut-GVHD的发病机制，以及是否逆转了 多胺-亚硫氨酸途径及CEACAM-1能否阻断肠道细菌相互作用 上皮细胞通过抗CEACAM-1单抗预防和逆转SR-Gut-GVHD。 相关性：通过深入阐明导致SR-Gut-GVHD的发病机制 一种具有良好特征的小鼠模型，并通过评估实验结果与结肠组织的相关性 从SR-GUT-GVHD患者中，该项目的结果可以确定潜在的有效方法 在人类身上进行的翻译测试。

Project Summary: Allogeneic hematopoietic cell transplantation (Allo-HCT) can cure hematological malignancies, but this treatment causes graft-versus-host disease (GVHD), an immune response of donor cells against the recipient. Anti-inflammatory corticosteroid medications can often control GVHD, but in some cases, GVHD is resistant to this treatment, especially when it affects the intestinal tract. The goal of this project is to understand the mechanisms that cause steroid-resistant (SR) gut GVHD and to develop effective approaches to prevent or treat SR-Gut-GVHD. Results with a newly established murine model have demonstrated that SR-Gut- GVHD is induced by prolonged administration of corticosteroids. Corticosteroid treatment induces expansion of IL-22-producing Th/Tc22-like cells, IL-22-dependent abnormalities in gut microorganisms, and reduced numbers of anti-inflammatory CX3CR1hi mononuclear phagocytes (MNP) that regulate T cell expansion and control bacterial translocation. Information from our preliminary studies and other investigators suggests that corticosteroid treatment inhibits the polyamine-hypusine pathway in T and MNP cells and regulates the fidelity of T cell lineage differentiation and the expansion of pro- and anti-inflammatory MNP cells. Our studies also suggest that steroid treatment increases Ceacam-1 expression by intestinal epithelial cells, thereby increasing bacterial transcytosis and unfavorably altering the balance between proinflammatory CX3CR1lo MNP and anti- inflammatory CX3CR1hi MNP cells. These changes trigger a feedforward pathogenic loop consisting of expanding IL-22-producing Th/Tc22-like cells, IL-22-dependent dysbiosis, and increased numbers of proinflammatory CX3CR1lo MNP with decreased numbers of regulatory CX3CR1hi MNP, leading to full-blown SR-Gut-GVHD. To test this hypothesis, this application proposes 3 aims. Aim 1 will determine whether corticosteroid inhibition of the polyamine-hypusine pathway in T cells leads to expansion of Th/Tc22-like cells with lineage infidelity. Aim 2 will determine whether corticosteroid inhibition of polyamine-hypusine pathway in CX3CR1+ MNP cells augment expansion of proinflammatory CX3CR1lo MNP with reduced numbers of anti- inflammatory CX3CR1hi MNP in response to challenge by dysbiosis. Aim 3 will determine whether observations in murine models reflect the pathogenesis of SR-Gut-GVHD in humans and whether reversal of abnormalities in the polyamine-hypusine pathway and whether blocking bacterial interaction with Ceacam-1 on intestinal epithelial cells by anti-Ceacam-1 mAb prevents and reverses SR-Gut-GVHD. Relevance: By elucidating in-depth mechanistic understanding of the pathogenesis leading to SR-Gut-GVHD in a well characterized murine model and by assessing the relevance of the experimental results in colon tissue from patients with SR-Gut-GVHD, results of this project could identify potentially effective approaches for translational testing in humans.