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

项目摘要/摘要 异基因造血干细胞移植(HSCT)是治疗难治性或非霍奇金淋巴瘤的一种潜在的挽救生命的方法 复发的血液系统恶性肿瘤，如急性髓系白血病或多发性骨髓瘤。抗肿瘤药物 HSCT的作用似乎是由于同种异体(免疫不匹配)的激活和分化所致 捐赠者T细胞通过一种名为移植物抗肿瘤的机制识别和消除肿瘤细胞。虽然HSCT 已经被证明比化疗更有效地治疗这些侵袭性的恶性肿瘤， 大约35-50%接受异基因造血干细胞移植的患者会出现多器官炎症组织 损伤称为急性移植物抗宿主病(AGVHD)。确切的免疫致病机制 对于aGVHD还没有明确的定义；然而，绝大多数临床前和临床研究 提示这种疾病的发病和严重程度是由于前病毒对组织的破坏作用而增强的 移植调节方案，如全身照射和/或化疗。这是对 肠道和其他靶组织(如皮肤、肝脏和肺)促进促炎因子的产生 细胞因子和介质以及肠道细菌在肠道组织中的移位。这两件事 被认为有助于激活和扩增供者来源的同种异体CD4+和CD8+T细胞 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 来自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/未治疗中 淋巴细胞减少受体可导致aGVHD的许多临床和组织学特征，包括体重减轻 减少活动以及皮肤、肺和肝脏的炎症。基于这些发现，我们总体上 目的是为了更好地了解T细胞和肠道微生物区系在病毒性肝炎发病机制中的作用。 AGVHD在无肠道损伤的情况下。我们假设同种异体的CD4+T细胞 在没有肠道损伤的情况下足以诱发aGVHD。为了检验这一假设，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 将同种异体CD4+和/或CD8+T细胞过继转移到健康淋巴细胞减少者体内后的炎症反应 2)我们将定义T细胞相关的表观遗传修饰物sirtuin 1在 产生致病效应细胞和3)我们将确定肠道微生物区系的作用 在健康淋巴细胞减少症小鼠的aGVHD的诱导和进展中起作用。数据获取自 拟议的研究将促进我们对诱导的免疫学机制的理解。 在无肠道损伤的情况下发生aGVHD。此外，这些数据可能会对较新的 正在探索在移植前条件反射中使用降低强度的临床研究 AGVHD的严重程度。

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.