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.

项目概述：同种异体造血细胞移植（alloo - hct）可治疗血液病