Pathogenesis, prevention and treatment of corticosteroid-resistant gut GVHD

皮质类固醇耐药性肠道GVHD的发病机制及防治

• 批准号: 10585851
• 负责人: Defu Zeng
• 金额: $ 85.67万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585851
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Adrenal Cortex Hormones; Affect; Allogenic; Anti-Inflammatory Agents; Apoptosis; Bacterial Translocation; Biopsy Specimen; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Colon; Compensation; Cytometry; Development; Disease; EP300 gene; Enzymes; Epithelial Cells; Equilibrium; FOXP3 gene; Functional disorder; Generations; Goals; Hematologic Neoplasms; Histone Acetylation; Human; IL18 gene; Immune response; Inflammation; Inflammatory; Interruption; Intestines; Macrophage; Mediating; Metabolic; Monoclonal Antibodies; Mononuclear; Motion; Mus; Ornithine Decarboxylase; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagocytes; Pharmaceutical Preparations; Play; Polyamines; Prevention; Putrescine; Regulatory T-Lymphocyte; Research Personnel; Resistance; Role; Specific qualifier value; Spermidine; Steroid Resistance; Steroids; T-Lymphocyte; Testing; Therapeutic; Tissues; curative treatments; cytokine; deoxyhypusine monooxygenase; deoxyhypusine synthase; dysbiosis; epigenetic regulation; graft vs host disease; hematopoietic cell transplantation; histone acetyltransferase; hypusine; inhibitor; insight; interleukin-22; intestinal epithelium; microorganism; mortality; mouse model; novel; novel strategies; prevent; response; restoration; transcytosis; transdifferentiation; translational approach

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.

项目摘要：同种异体造血细胞移植（Allo-HCT）可以治愈血液学 恶性肿瘤，但这种治疗会导致移植物抗宿主病（GVHD），供体细胞的免疫反应 反对接收者。抗炎皮质类固醇药物通常可以控制GVHD，但在某些情况下， GVHD对这种治疗具有抵抗力，尤其是当它影响肠道时。这个项目的目标是 了解引起类固醇（SR）肠道GVHD的机制，并开发有效的方法 预防或治疗SR-GUT-GVHD。具有新建立的鼠模型的结果表明，SR-Gut- GVHD是由长期给药的皮质类固醇引起的。皮质类固醇治疗诱导 IL-22产生的Th/Tc22样细胞，肠道微生物中IL-22依赖性异常，数量减少 调节T细胞膨胀和对照的抗炎CX3CR1HI单核吞噬细胞（MNP） 细菌易位。我们的初步研究和其他研究人员的信息表明 皮质类固醇治疗抑制T和MNP细胞中的多胺 - 夏普汀途径，并调节保真度 T细胞谱系分化以及促炎和抗炎MNP细胞的扩展。我们的研究也是如此 表明类固醇治疗会增加肠上皮细胞的CEACAM-1表达，从而增加 细菌转胞病，不利地改变了促炎的CX3CR1LO MNP和抗 - 炎性CX3CR1HI MNP细胞。这些变化触发了一个由 扩展IL-22产生的Th/Tc22样细胞，IL-22依赖性营养不良，数量增加 促炎CX3CR1LO MNP，调节性CX3CR1HI MNP数量减少，导致成熟 sr-gut-gvhd。为了检验这一假设，该应用程序提出了3个目标。 AIM 1将确定是否 皮质类固醇抑制T细胞中多胺 - 夏季途径的抑制导致Th/Tc22样细胞的膨胀 血统不忠。 AIM 2将确定皮质类固醇激素是否抑制多胺 - 夏季途径 CX3CR1+ MNP细胞增强促炎的CX3CR1LO MNP的膨胀，抗抗菌数量减少 炎症性CX3CR1HI MNP响应营养不良的挑战。 AIM 3将决定是否观察 在鼠模型中，反映了人类SR-GUT-GVHD的发病机理，以及是否逆转异常 多胺 - 夏季途径以及在肠上阻塞与CECAM-1的细菌相互作用是否阻塞 抗CEACAM-1 MAB上皮细胞可防止并逆转SR-GUT-GVHD。 相关性：通过阐明对导致SR-GUT-GVHD的发病机理的深入机理理解 一个表征良好的鼠模型，并通过评估结肠组织中实验结果的相关性 从患有SR-GUT-GVHD患者的患者中，该项目的结果可以确定潜在的有效方法 人类的翻译测试。