Role of Interleukin 23 in the Pathophysiology of GVH and GVL Reactivity

白细胞介素 23 在 GVH 和 GVL 反应性病理生理学中的作用

• 批准号: 8053836
• 负责人: William R. Drobyski
• 金额: $ 31.22万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053836
• 关键词: Acute; Acute Graft Versus Host Disease; Address; Affect; Alloantigen; Allogenic; Antibodies; Antigen-Presenting Cells; Biological; Biological Preservation; Cells; Chronic; Chronic Myeloid Leukemia; Colon; Complication; Coupled; Data; Disease; Effector Cell; Environment; Event; Extravasation; Functional disorder; Gastrointestinal tract structure; Genetic; Goals; Immune; Immune response; Immune system; Inflammation; Inflammatory; Injury; Interferons; Interleukin-17; Interleukins; Lead; Link; Lipopolysaccharides; Liver; Mediating; Mediator of activation protein; Modeling; Mus; Organ; Outcome; Pathology; Patients; Phase; Play; Population; Production; Public Health; Regimen; Regulatory T-Lymphocyte; Role; Series; Severities; Severity of illness; Site; Skin; Stem cell transplant; Surface; Syndrome; System; T-Lymphocyte; Testing; Tetracyclines; Time; Tissues; Transgenic Mice; Transplantation; Withdrawal; abl Oncogene; arm; base; chronic graft versus host disease; clinically relevant; conditioning; cytokine; design; disorder prevention; enhanced green fluorescent protein; graft versus host disease induction; graft vs host disease; in vivo; interleukin-22; interleukin-23; leukemia; novel; novel strategies; public health relevance; receptor; reconstitution; research study; transcription factor

DESCRIPTION (provided by applicant): Graft versus host disease (GVHD) is the major complication associated with allogeneic stem cell transplantation. GVHD is the result of a series of proinflammatory events that are attributable to the conditioning regimen in conjunction with the recognition of host alloantigens by donor T cells. This initiates an inflammatory cascade that is characterized by the expansion of alloreactive donor T cells, recruitment of secondary effector cell populations and production of proinflammatory cytokines. The gastrointestinal tract, in particular, has been demonstrated to be a critical target organ in GVHD pathophysiology. Translocation of lipopolysaccharide (LPS) across mucosal surfaces in the gastrointestinal tract that have been damaged by both the conditioning regimen and donor T cells has been shown to induce systemic proinflammatory cytokine production that plays a significant role in the propagation of pathological damage both locally and systemically. How mucosal damage and LPS leakage induces the wide spectrum of proinflammatory effects that occur during GVHD, however, is not completely understood. In preliminary studies, we have now identified interleukin (IL-23) as the critical mediator linking conditioning regimen-induced mucosal injury and LPS translocation to subsequent proinflammatory cytokine production and GVHD-associated pathological damage. We have also made the novel observation that, in the absence of donor APC-derived secretion of IL-23, the colon is selectively protected from developing acute GVHD. Thus, within the context of a multi system, inflammatory disorder our studies demonstrate that a single cytokine can be responsible for directing tissue-specific pathology. The goal of this proposal is to define how IL-23 mediates proinflammatory events and test novel strategies for the inhibition of IL-23 that may allow for a reduction in GVHD without loss of antileukemia effects conferred by the allogeneic graft. To address these questions, experiments have been designed to address the following specific aims: Studies in Specific Aim 1 will define the mechanism by which IL-23 mediates pathological damage in the colon. These studies will also define the optimal timing for the inhibition of IL-23 with respect to GVHD prevention. Specific Aim 2 will examine the effect of IL-23 on the regulatory arm of the immune system. Using a unique model in which regulatory T cells can be precisely identified in vivo, we will define the role of IL-23 in the function and reconstitution of regulatory T cells (Tregs) after transplantation. Specific Aim 3 will determine if the selective targeting of IL-23 can preserve the graft versus leukemia effect while at the same time reducing the severity of GVHD. The overall goal of these studies is to define the biological effects of IL-23 as they relate to both GVH and GVL reactivity after allogeneic stem cell transplantation. PUBLIC HEALTH RELEVANCE: The relevance of this project to public health derives from the fact that graft versus host disease is the major complication of allogeneic stem cell transplantation. Better understanding of how to reduce this complication while at the same time preserving the beneficial antileukemic effects that result from the transplant will lead to new therapies and better outcomes for patients.

描述（由申请人提供）：移植物抗宿主病（GVHD）是与同种异体干细胞移植相关的主要并发症。 GVHD 是一系列促炎事件的结果，这些促炎事件可归因于预处理方案以及供体 T 细胞对宿主同种抗原的识别。这引发了炎症级联反应，其特征是同种异体反应性供体 T 细胞的扩增、次级效应细胞群的募集以及促炎细胞因子的产生。特别是胃肠道已被证明是 GVHD 病理生理学中的关键靶器官。脂多糖 (LPS) 在已被预处理方案和供体 T 细胞损伤的胃肠道粘膜表面易位，已被证明可诱导全身促炎细胞因子的产生，这在局部和全身病理损伤的传播中发挥重要作用。然而，粘膜损伤和 LPS 渗漏如何引起 GVHD 期间发生的广泛促炎作用尚不完全清楚。在初步研究中，我们现已确定白细胞介素 (IL-23) 是连接调理方案诱导的粘膜损伤和 LPS 易位与随后的促炎细胞因子产生和 GVHD 相关病理损伤之间的关键介质。我们还进行了新的观察，即在缺乏供体 APC 衍生的 IL-23 分泌的情况下，结肠受到选择性保护，免于发生急性 GVHD。因此，在多系统炎症性疾病的背景下，我们的研究表明，单一细胞因子可以负责指导组织特异性病理学。该提案的目标是确定 IL-23 如何介导促炎事件，并测试抑制 IL-23 的新策略，该策略可能会减少 GVHD，而不损失同种异体移植物所赋予的抗白血病作用。为了解决这些问题，我们设计了实验来解决以下具体目标：具体目标 1 的研究将确定 IL-23 介导结肠病理损伤的机制。这些研究还将确定抑制 IL-23 预防 GVHD 的最佳时机。具体目标 2 将检查 IL-23 对免疫系统调节臂的影响。使用可以在体内精确识别调节性 T 细胞的独特模型，我们将定义 IL-23 在移植后调节性 T 细胞 (Treg) 的功能和重建中的作用。具体目标 3 将确定选择性靶向 IL-23 是否可以保留移植物抗白血病效应，同时降低 GVHD 的严重程度。这些研究的总体目标是确定 IL-23 的生物学效应，因为它们与同种异体干细胞移植后的 GVH 和 GVL 反应性相关。 公共健康相关性：该项目与公共健康的相关性源于移植物抗宿主病是同种异体干细胞移植的主要并发症这一事实。更好地了解如何减少这种并发症，同时保留移植带来的有益的抗白血病作用，将为患者带来新的疗法和更好的结果。