The Role of Donor T Cell-Derived GM-CSF in the Pathogenesis of Gastrointestinal Acute GVHD

供体 T 细胞衍生的 GM-CSF 在胃肠道急性 GVHD 发病机制中的作用

• 批准号: 9768151
• 负责人: Clinton T Piper
• 金额: $ 4.7万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768151
• 关键词: Acute; Acute Graft Versus Host Disease; Address; Affect; Alloantigen; Allogenic; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Autoimmunity; Biology; Blocking Antibodies; CD4 Positive T Lymphocytes; Calcineurin; Cell Compartmentation; Cells; Clinical; Colon; Complication; Cytokine Network Pathway; Development; Disease; Effectiveness; Environment; Equilibrium; Event; Experimental Autoimmune Encephalomyelitis; Fostering; Functional disorder; Gastrointestinal tract structure; Genetic; Glycoproteins; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Immune; Immune system; Inflammation; Inflammatory; Intestinal Graft Versus Host Disease; Liver; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Organ; Pathogenesis; Pathologic; Pathway interactions; Pattern; Phase; Physicians; Play; Population; Prevention approach; Production; Prophylactic treatment; Regimen; Regulation; Regulatory T-Lymphocyte; Role; Scientist; Severity of illness; Signal Transduction; Site; Skin; Stem cell transplant; T cell response; T-Lymphocyte; Testing; Therapeutic antibodies; Time; Tissues; Training; Transplant Recipients; Transplantation; arm; base; clinical development; clinically relevant; conditioning; curative treatments; cytokine; design; experimental study; gastrointestinal; graft vs host disease; insight; interleukin-23; man; mortality; mouse model; novel; novel therapeutic intervention; pathogen; post-transplant; preclinical study; prophylactic; receptor; reconstitution; recruit

PROJECT SUMMARY Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic stem cell transplantation (HSCT) and occurs in approximately 50% of all HSCT recipients despite routine immune prophylaxis. GVHD is mediated by mature alloreactive donor-derived T cells, which are present in the graft at the time of transplant and ultimately cause tissue damage. During the acute phase of GVHD, which typically occurs in the first 100 days post-transplantation, inflammation is restricted to a limited number of target organs, specifically the skin, liver, and gastrointestinal (GI) tract. Damage to the GI tract from GVHD is a particularly serious event leading to significant morbidity and mortality. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD by activating both the innate and adaptive arms of the immune system. While T cells are the proximate drivers of GVHD, disease induction and amplification rely on this crosstalk between innate and adaptive immune cells. However, the cellular and cytokine networks which mediate this interplay are incompletely understood. Preliminary studies using well-characterized murine models of GVHD have identified GM-CSF as a cytokine which is produced at high levels by donor-derived CD4+ T cells in the GI tract during GVHD. Moreover, disruption of GM-CSF signaling in CD4+ T cells significantly prolongs survival in murine recipients undergoing GVHD and reduces inflammatory damage to the colon, indicating that this cytokine plays an important role in GVHD biology. Based on these studies, the overall hypothesis of this proposal is that GM-CSF promotes inflammation in the GI tract via the downstream activation of innate immune populations that potentiate T cell alloreactivity. Studies in Specific Aim 1 will determine the GM-CSF responsive myeloid cell populations that mediate inflammation in the GI tract during GVHD. This aim will employ novel genetic and antibody-based approaches to identify the relevant GM-CSF- dependent innate immune populations and will determine how these cellular mediators are able to directly contribute to the proinflammatory milieu. Studies in Specific Aim 2 will define the mechanistic pathways by which GM-CSF modulates T cell alloreactivity in GVHD. These experiments will examine how GM-CSF affects the production of interleukin-23 by donor-derived antigen presenting cells (APCs), a cytokine that has previously been shown to be crucial for the induction of gastrointestinal inflammation during GVHD, determine how GM- CSF signaling in APCs affects indirect alloantigen presentation in the GI tract, and characterize how GM-CSF modulates reconstitution of the regulatory T cell compartment. The overall objective of this proposal is to provide 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.

项目摘要 移植物抗宿主病（GVHD）是同种异体造血干细胞最严重的并发症 尽管常规免疫 预防。 GVHD是由成熟的同种反应性供体衍生的T细胞介导的，该细胞存在于移植物中 移植时间并最终导致组织损伤。在GVHD的急性阶段，通常 在移植后的头100天内发生，炎症仅限于有限数量的目标器官， 特别是皮肤，肝脏和胃肠道（GI）。 GVHD对GI道的损害特别是 严重的事件导致了明显的发病率和死亡率。促炎细胞因子在 通过激活免疫系统的先天和适应性臂，肠道GVHD的病理生理学。 尽管T细胞是GVHD的近端驱动因素，但疾病诱导和扩增依赖于此串扰 在先天和适应性免疫细胞之间。但是，介导此的细胞和细胞因子网络 相互作用是不完全理解的。使用良好特征的GVHD鼠模型的初步研究 已将GM-CSF鉴定为细胞因子，在GI中由供体衍生的CD4+ T细胞在高水平下产生的细胞因子 GVHD期间的道。此外，CD4+ T细胞中GM-CSF信号传导的破坏可显着延长 接受GVHD的鼠接收者并减少了对结肠的炎症损害，表明这是 细胞因子在GVHD生物学中起重要作用。基于这些研究，总体假设 建议是GM-CSF通过下游激活促进胃肠道的炎症 具有增强T细胞同质性的先天免疫群体。在特定目标1中的研究将 确定GM-CSF反应性的髓样细胞群，这些细胞介导了胃肠道的炎症 GVHD。该目标将采用新颖的遗传和抗体方法来识别相关的GM-CSF- 依赖的先天免疫种群，并将确定这些细胞介质如何直接 为促炎的环境做出贡献。特定目标2中的研究将通过 GM-CSF调节T细胞在GVHD中的同种异体反应性。这些实验将检查GM-CSF如何影响 由供体衍生的抗原呈现细胞（APC）生产白介素23，这是一种先前具有的细胞因子 事实证明，GVHD期间胃肠道炎症至关重要，确定GM- APC中的CSF信号传导会影响GI道中的间接同种抗原表现，并表征GM-CSF的方式 调节调节T细胞室的重构。该提议的总体目的是 提供有关GI区内GVHD的病理生理学和调节的新见解，这将促进 制定与同种异体HSCT接受者中这种并发症的临床相关策略。