Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease

胃肠道移植物抗宿主病中的炎症细胞因子网络

基本信息

批准号：
10159292
负责人：
William R. Drobyski
金额：
$ 50.42万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159292
关键词：
Acute Acute Graft Versus Host Disease Address Affect Affinity Alloantigen Allogenic Animals Antibodies Bone Marrow Transplantation CD4 Positive T Lymphocytes CD8B1 gene Cell Compartmentation Cell Lineage Cells Clinical Colon Complication Cytokine Network Pathway Development Digestive System Disorders Disease Environment Event Fostering Functional disorder Gastrointestinal tract structure Gene Expression Gene Expression Profile Genetic Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Receptors Hematopoietic Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation IL7 gene ITGAX gene Immune Immune system Inflammation Inflammatory Intestinal Graft Versus Host Disease Maps Mediating Morbidity - disease rate Mus Myeloid Cells Organ Pathogenicity Pathologic Pathway interactions Patients Phase Play Population Positioning Attribute Production Regulation Regulatory T-Lymphocyte Reporter Reporting Role Severities Severity of illness Signal Transduction Site Stem cell transplant T cell response T-Lymphocyte Testing Tissues Transplant Recipients arm base cell type clinical development clinically relevant clinically significant cytokine design experimental study graft vs host disease improved outcome insight interleukin-23 mortality novel preclinical study receptor reconstitution recruit response stem

项目摘要

PROJECT SUMMARY Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). Damage to the gastrointestinal (GI) tract from acute GVHD is a particularly serious event leading to significant morbidity and mortality. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD, in part, by activating donor T cell populations which subsequently induce tissue damage. In preliminary studies, we have identified GM-CSF as a pivotal cytokine which plays an important role in the pathophysiology of acute GVHD in the GI tract. The goal of this proposal is to define the mechanistic pathways by which GM-CSF affects the innate and adaptive arms of the immune system to induce inflammation in this tissue site during GVHD. Our overall hypothesis is that GM-CSF induces a proinflammatory environment in the GI tract, and that this effect is attributable to the recruitment of pathogenic myeloid cell populations and the augmentation of alloreactive donor T cell responses. Studies in Specific Aim 1 will characterize the innate cell populations that are responsive to GM-CSF signaling and define the functional role of specific GM-CSF-responsive cells in mediating damage in the GI tract during acute GVHD. To address this question, we will employ novel Csf2rbfl/fl mice in which the high affinity beta chain of the GM-CSF receptor has flanking lox p sites, which will allow for myeloid cell-specific deletion when bred with appropriate lineage-specific Cre animals. Experiments in Specific Aim 2 will define mechanistic pathways by which GM-CSF affects T cell-mediated inflammatory and regulatory functions in the immune system, and thereby modulates the severity of GVHD in the GI tract. Specifically, we will determine whether GM-CSF elicits IL-23 production by donor-derived APCs in the GI tract, examine whether CD4+ T cell-derived GM-CSF promotes indirect alloantigen presentation by donor-derived APCs in the colon, and define the role of GM- CSF in the reconstitution of the regulatory T cell compartment during GVHD. Studies in Specific Aim 3 will determine whether CD4+ GM-CSF+ T cells represent a stable T cell lineage that is regulated by interleukin 7 (IL-7) signaling. To address this question, we will construct a novel GM-CSF fate reporter mouse that will allow us to fate map immune cell populations that produce GM-CSF and define their response to IL-7. The overall objective of this proposal is to develop new insights into the pathophysiology and regulation of GVHD within the GI tract that will foster the development of clinically relevant strategies to mitigate this complication in allogeneic HSCT recipients and improve outcomes in patients with blood cancers.

项目概要移植物抗宿主病（GVHD）是同种异体移植相关的主要并发症造血干细胞移植（HSCT）。对胃肠道 (GI) 的损害急性 GVHD 是一种特别严重的事件，会导致显着的发病率和死亡率。促炎细胞因子在肠道 GVHD 的病理生理学中发挥着关键作用，部分原因是通过激活供体 T 细胞群，随后诱导组织损伤。在初步研究表明，GM-CSF 是一种关键细胞因子，在胃肠道急性 GVHD 的病理生理学。该提案的目标是定义 GM-CSF影响先天性和适应性免疫臂的机制途径 GVHD 期间诱导该组织部位炎症的系统。我们的总体假设是 GM-CSF 在胃肠道中诱导促炎环境，并且这效应归因于致病性骨髓细胞群的募集和同种异体反应性供体 T 细胞反应的增强。具体目标 1 的研究将描述对 GM-CSF 信号敏感的先天细胞群，并定义特定 GM-CSF 反应细胞在介导胃肠道损伤中的功能作用急性GVHD。为了解决这个问题，我们将使用新型 Csf2rbfl/fl 小鼠，其中高 GM-CSF 受体的亲和力 β 链具有侧翼 lox p 位点，这将允许骨髓细胞当与适当的谱系特异性 Cre 动物繁殖时，细胞特异性缺失。实验于具体目标 2 将定义 GM-CSF 影响 T 细胞介导的机制途径免疫系统中的炎症和调节功能，从而调节严重程度胃肠道中的 GVHD。具体来说，我们将确定 GM-CSF 是否引发 IL-23 产生通过胃肠道中供体来源的 APC，检查 CD4+ T 细胞来源的 GM-CSF 是否促进结肠中供体来源的 APC 间接呈递同种异体抗原，并定义了 GM-的作用 GVHD 期间调节性 T 细胞区室重建中的 CSF。具体研究目标 3 将确定 CD4+ GM-CSF+ T 细胞是否代表稳定的 T 细胞谱系受白细胞介素 7 (IL-7) 信号传导调节。为了解决这个问题，我们将构建一部小说 GM-CSF命运报告小鼠将使我们能够绘制产生免疫细胞群的命运图谱 GM-CSF 并定义其对 IL-7 的反应。该提案的总体目标是发展对胃肠道内 GVHD 的病理生理学和调节的新见解将促进制定临床相关策略以减轻同种异体 HSCT 中的这种并发症接受者并改善血癌患者的治疗结果。