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）：移植与宿主疾病（GVHD）是与同种异体干细胞移植有关的主要并发症。 GVHD是一系列促炎事件的结果，这些事件与供体T细胞对宿主同种抗菌素的识别归因于调节方案。这引发了一种炎症性级联反应，其特征是同种反应性供体T细胞的扩展，次要效应细胞群的募集和促炎细胞因子的产生。尤其是胃肠道已被证明是GVHD病理生理学中的关键靶心器官。已证明，胃肠道和供体T细胞损坏的胃肠道中脂多糖（LPS）跨粘膜表面的易位，已证明均已损坏，均被证明会诱导全身性促炎细胞因子的产生，在局部和系统地造成病理损害的传播中起着重要作用。然而，粘膜损伤和LP泄漏如何引起GVHD期间发生的广泛促炎作用。在初步研究中，我们现在确定白介素（IL-23）是关键的调解人，将调节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相关病理损害联系起来。我们还做出了新的观察结果，即在没有供体APC衍生的IL-23分泌的情况下，结肠有选择地保护了急性GVHD。因此，在多系统的背景下，炎症性疾病我们的研究表明，单个细胞因子可以负责指导组织特异性病理学。该提案的目的是定义IL-23如何介导促炎事件并测试抑制IL-23的新型策略，这可能允许降低GVHD而不会损失抗血清症的效应，从而允许同种异体移植物赋予。为了解决这些问题，已经设计了实验来解决以下特定目的：特定目标1中的研究将定义IL-23介导结肠病理损害的机制。这些研究还将定义抑制IL-23在GVHD预防方面的最佳时机。具体目标2将检查IL-23对免疫系统调节部门的影响。使用一个独特的模型，可以在体内准确鉴定调节T细胞，我们将定义IL-23在移植后调节和重构调节性T细胞（TREG）的作用。特定的目标3将确定IL-23的选择性靶向是否可以保留移植物与白血病效应，同时降低GVHD的严重程度。这些研究的总体目的是定义IL-23的生物学作用，因为它们与同种异体干细胞移植后与GVH和GVL反应性相关。 公共卫生相关性：该项目与公共卫生的相关性来自以下事实：移植与宿主疾病是同种异体干细胞移植的主要并发症。更好地理解如何减少这种并发症，同时保留由移植引起的有益的抗白血病作用，将导致新的疗法和更好的患者结局。