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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要异基因造血干细胞移植（HSCT）对于难治性或难治性造血干细胞移植是一种潜在的挽救生命的治疗方法。复发性血液恶性肿瘤，例如急性髓性白血病或多发性骨髓瘤。抗肿瘤 HSCT的效果似乎是由于同种异体的激活和分化（免疫不匹配）供体 T 细胞通过称为移植物抗肿瘤的机制识别并消除肿瘤细胞。虽然造血干细胞移植已被证明比化疗更有效地治疗这些侵袭性恶性肿瘤，大约 35-50% 接受同种异体 HSCT 的患者会出现多器官炎症组织称为急性移植物抗宿主病（aGVHD）的损伤。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作和严重程度是由预治疗的组织损伤作用加剧的移植调理方案，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）促进促炎物质的产生细胞因子和介质以及肠道细菌易位到肠道组织中。这两个事件被认为有助于供体来源的同种异体 CD4+ 和 CD8+ T 细胞的激活和扩增介导肺、肝、皮肤和肠道的炎症组织损伤。然而，最近的初步研究我们实验室的研究表明，aGVHD 的发生可能不需要肠道损伤。我们的初步研究表明，同种异体 CD4+ T 细胞过继转移到健康/未经治疗的体内淋巴细胞减少的受者会诱发 aGVHD 的许多临床和组织学特征，包括体重减轻并减少活动以及皮肤、肺部和肝脏炎症。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疾病发病机制中的作用 aGVHD 在没有肠道损伤的情况下。我们假设同种异体 CD4+ T 细胞都是必要的并且足以在没有肠道损伤的情况下诱导aGVHD。为了检验这个假设，我们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 CD4+ 和/或 CD8+ T 细胞过继转移至健康淋巴细胞减少后的炎症收件人； 2) 我们将定义 T 细胞相关的表观遗传修饰因子 Sirtuin 1 在产生疾病的效应细胞，3) 我们将确定肠道微生物群的作用在健康淋巴细胞减少的小鼠中，aGVHD 的诱导和进展中发挥作用。数据获得自拟议的研究将增进我们对诱导免疫机制的理解在没有肠道损伤的情况下发生aGVHD。此外，这些数据可能对更新的产品具有重要意义。临床研究正在探索在移植前调理中使用降低强度来减少 aGVHD 的严重程度。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

饲养温度和遗传多样性对同种异体 T 细胞诱导的小鼠组织损伤的影响。

DOI：
发表时间：
2023-11-20
期刊：
影响因子：
0
作者：
Enriquez, Josue;McDaniel Mims, Brianyell;Stroever, Stephanie;Dos Santos, Andrea Pires;Jones;Furr, Kathryn L;Grisham, Matthew B
通讯作者：
Grisham, Matthew B

Genomic, microbial and environmental standardization in animal experimentation limiting immunological discovery.

动物实验中的基因组、微生物和环境标准化限制了免疫学发现。

DOI：
发表时间：
2020
期刊：
影响因子：
3
作者：
Enriquez, Josue;Mims, Brianyell Mc Daniel;Trasti, Scott;Furr, Kathryn L;Grisham, Matthew B
通讯作者：
Grisham, Matthew B

The Versatility of Sirtuin-1 in Endocrinology and Immunology.

Sirtuin-1 在内分泌学和免疫学中的多功能性。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Rasha, Fahmida;Mims, Brianyell McDaniel;Castro;Barnes, Betsy J;Grisham, Matthew B;Rahman, Rakhshanda Layeequr;Pruitt, Kevin
通讯作者：
Pruitt, Kevin

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

抗生素给药会加剧淋巴细胞减少小鼠的急性移植物抗宿主病引起的骨髓和脾损伤。

DOI：
发表时间：
2021
期刊：
影响因子：
3.7
作者：
McDaniel Mims, Brianyell;Enriquez, Josue;Pires Dos Santos, Andrea;Jones;Dowd, Scot;Furr, Kathryn L;Grisham, Matthew B
通讯作者：
Grisham, Matthew B