Role of T cells and the Intestinal Microbiota in the Pathogenesis of Acute Graft- versus- Host Disease

T 细胞和肠道微生物群在急性移植物抗宿主病发病机制中的作用

• 批准号: 9754362
• 负责人: Brianyell McDaniel
• 金额: $ 3.05万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754362
• 关键词: Acute Graft Versus Host Disease; Acute Myelocytic Leukemia; Adoptive Transfer; Allogenic; Antigen-Presenting Cells; Bacteria; Bacterial Translocation; Blood Circulation; Body Weight decreased; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Clinical; Clinical Research; Data; Development; Disease; Effector Cell; Epigenetic Process; Event; Generations; HDAC4 gene; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histologic; Home environment; Immune; Immunologics; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-1 beta; Interleukin-6; Intestines; Laboratories; Life; Liver; Lung; Lung Inflammation; Malignant Neoplasms; Mediating; Mediator of activation protein; Multiple Myeloma; Mus; Pathogenesis; Pathogenicity; Patients; Play; Protocols documentation; Refractory; Relapse; Residual Tumors; Role; SIRT1 gene; Savings; Sensitivity Training Groups; Severities; Severity of illness; Skin; Spleen; T cell differentiation; T-Lymphocyte; TNF gene; Testing; Tissues; Transplantation Conditioning; Whole-Body Irradiation; antitumor effect; base; chemotherapy; cytokine; effector T cell; epigenetic regulation; experimental study; gut microbiota; irradiation; liver inflammation; lymph nodes; mouse model; neoplastic cell; novel; preclinical study; trafficking; tumor

PROJECT SUMMARY/ABSTRACT Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially life-saving treatment for refractory or relapsing hematological malignancies such as acute myeloid leukemia or multiple myeloma. The antitumor effects of HSCT appear to be due to the activation and differentiation of allogeneic (immune mismatched) donor T cells that recognize and eliminate tumor cells via a mechanism called graft vs. tumor. Although HSCT has been shown to be more effective than chemotherapy for treating these aggressive malignancies, approximately 35-50% of patients undergoing allogeneic HSCT will develop multi-organ, inflammatory tissue injury called acute graft vs. host disease (aGVHD). The precise immuno-pathogenic mechanisms responsible for aGVHD have not been definitively defined; however, the vast majority of preclinical and clinical studies suggest that the onset and severity of this disease is potentiated by the tissue-damaging effects of pre- transplant conditioning protocols such as total body irradiation and/or chemotherapy. This initial damage to the gut as well as other target tissues (e.g. skin, liver and lungs) promotes the generation of pro-inflammatory cytokines and mediators as well as translocation of intestinal bacteria into the gut tissue. Both of these events are thought to contribute to the activation and expansion of donor-derived, allogeneic CD4+ and CD8+ T cells that mediate inflammatory tissue injury in the lungs, liver, skin and gut. However, recent preliminary studies from our laboratory, suggest that intestinal injury may not be required for the development of aGVHD. Our preliminary studies demonstrate that adoptive transfer of allogeneic CD4+ T cells into healthy/untreated lymphopenic recipients induces many of the clinical and histological features of aGVHD including weight loss and reduced activity as well skin, lung and liver inflammation. Based upon these findings, our overall objective is to better understand the role that T cells and the intestinal microbiota play in the pathogenesis of aGVHD in the absence of intestinal injury. We hypothesize that allogeneic CD4+ T cells are both necessary and sufficient to induce aGVHD in the absence of intestinal damage. In order to test this hypothesis, we propose the following three specific aims: 1) We will quantify and compare the onset and severity of tissue inflammation following adoptive transfer of allogeneic CD4+ and/or CD8+ T cells into healthy lymphopenic recipients; 2) We will define the role that the T cell-associated epigenetic modifier sirtuin 1 plays in the generation of disease-producing effector cells and 3) We will determine the role that the intestinal microbiota plays in the induction and progression of aGVHD in healthy lymphopenic mice. Data obtained from the proposed studies will advance our understanding of the immunological mechanisms responsible for induction of aGVHD in the absence of intestinal injury. In addition, these data may have important implications for newer clinical studies that are exploring the use of reduced intensity in pre-transplant conditioning to decrease severity of aGVHD.

项目总结/摘要 异基因造血干细胞移植（HSCT）是一种潜在的挽救生命的治疗方法， 复发性恶性血液病，如急性髓性白血病或多发性骨髓瘤。抗肿瘤 HSCT的作用似乎是由于同种异体（免疫错配） 供体T细胞通过一种称为移植物对抗肿瘤的机制识别和消除肿瘤细胞。虽然HSCT 已经证明对于治疗这些侵袭性恶性肿瘤比化疗更有效， 大约35-50%的接受同种异体HSCT的患者将发展多器官炎性组织 急性移植物抗宿主病（aGVHD）。精确的免疫致病机制 aGVHD尚未明确定义;然而，绝大多数临床前和临床研究 表明，这种疾病的发病和严重程度是由预处理的组织损伤作用增强的， 移植调节方案，例如全身照射和/或化疗。这种最初的损害， 肠道以及其他靶组织（例如皮肤、肝脏和肺）促进促炎性细胞因子的产生。 细胞因子和介质以及肠道细菌移位到肠道组织中。这两个事件 被认为有助于供体来源的同种异体CD 4+和CD 8 + T细胞的活化和扩增 介导肺、肝、皮肤和肠道的炎症组织损伤。然而，最近的初步研究表明， 提示肠道损伤可能不是aGVHD发展所必需的。我们 初步研究表明，将同种异体CD 4 + T细胞过继转移到健康/未治疗的 淋巴细胞减少的受体诱导了aGVHD的许多临床和组织学特征， 减少活动以及皮肤、肺和肝脏炎症。根据这些发现，我们的总体 目的是更好地了解T细胞和肠道微生物群在肠道疾病发病机制中的作用。 在没有肠损伤的情况下的aGVHD。我们假设同种异体CD 4 + T细胞是必要的， 并且在没有肠损伤的情况下足以诱导aGVHD。为了验证这个假设，我们 我提出以下三个具体目标：1）我们将量化和比较组织的发病和严重程度 同种异体CD 4+和/或CD 8 + T细胞过继转移到健康淋巴细胞减少症患者中后的炎症 2）我们将定义T细胞相关的表观遗传修饰因子sirtuin 1在受体中的作用。 产生致病效应细胞和3）我们将确定肠道微生物群的作用， 在健康淋巴细胞减少小鼠中aGVHD的诱导和进展中起作用。获得的数据 拟议的研究将促进我们对诱导的免疫机制的理解， 在没有肠损伤的情况下的aGVHD。此外，这些数据可能对新的 正在探索在移植前预处理中使用降低强度以减少 aGVHD的严重程度。

项目成果

The Versatility of Sirtuin-1 in Endocrinology and Immunology.

• DOI: 10.3389/fcell.2020.589016
• 发表时间: 2020
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Rasha F;Mims BM;Castro-Piedras I;Barnes BJ;Grisham MB;Rahman RL;Pruitt K
• 通讯作者: Pruitt K

Antibiotic administration exacerbates acute graft vs. host disease-induced bone marrow and spleen damage in lymphopenic mice.

• DOI: 10.1371/journal.pone.0254845
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: McDaniel Mims B;Enriquez J;Pires Dos Santos A;Jones-Hall Y;Dowd S;Furr KL;Grisham MB
• 通讯作者: Grisham MB

Influence of Housing Temperature and Genetic Diversity on Allogeneic T Cell-Induced Tissue Damage in Mice.

• DOI: 10.3390/pathophysiology30040039
• 发表时间: 2023-11-20
• 期刊: Pathophysiology : the official journal of the International Society for Pathophysiology
• 作者: Enriquez J;McDaniel Mims B;Stroever S;Dos Santos AP;Jones-Hall Y;Furr KL;Grisham MB
• 通讯作者: Grisham MB