Blockade of IL-23 for the Prevention of Graft Versus Host Disease

阻断 IL-23 用于预防移植物抗宿主病

• 批准号: 10391538
• 负责人: William R. Drobyski
• 金额: $ 55.82万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391538
• 关键词: Acute; Address; Affect; Alloantigen; Allogenic; Antibodies; Antigen-Presenting Cells; Attenuated; Bone Marrow Transplantation; CD8B1 gene; Clinic; Clinical; Colon; Complication; Correlative Study; Critical Pathways; Development; Digestive System Disorders; Disease; Disease Pathway; Environment; Functional disorder; Gastrointestinal tract structure; Genetic; Goals; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Human; Immune system; Incidence; Inflammation; Inflammatory; Intestinal Graft Versus Host Disease; Lead; Mediating; Morbidity - disease rate; Mus; Organ; Pathologic; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Play; Population; Prevention; Prevention approach; Prevention strategy; Production; Regulatory T-Lymphocyte; Relapse; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Site; Source; T cell reconstitution; T-Lymphocyte; Therapeutic Effect; Tissues; Transgenic Mice; Translating; Transplant Recipients; arm; base; chronic graft versus host disease; clinically significant; cytokine; design; disorder prevention; experimental study; gastrointestinal; graft vs host disease; graft vs leukemia effect; immune reconstitution; improved; insight; interleukin-23; microbial; microbiome; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; post-transplant; pre-clinical; preservation; response; stem; transplantation therapy

PROJECT SUMMARY Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). During the acute phase of this disease, a restricted set of organs is affected of which the gastrointestinal (GI) tract is the most clinically significant. 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 pre-clinical murine studies, we have identified interleukin 23 (IL-23) as a key inflammatory cytokine that mediates pathological damage in the GI tract during GVHD. The overall goal of this proposal is therefore to define the mechanistic pathways by which IL-23 induces inflammation in the GI tract, and to directly translate these findings into the clinic to examine whether blockade of this pathway reduces the severity of GVHD in human allogeneic HSCT recipients. Our overall hypothesis is that IL-23 produced by donor antigen presenting cells (APCs) induces a proinflammatory environment in the GI tract and that this pathway is a clinically viable target for the prevention of GVHD in humans. Experiments in Specific Aim 1 will define the cellular mechanism(s) by which IL-23 promotes inflammation in the GI tract during GVHD in murine transplant recipients. To address this question, we will identify the relevant donor APC populations that produce IL-23 and are functionally important for the induction of inflammation in the colon, examine whether donor APC-derived IL-23 promotes indirect alloantigen presentation which is a critical pathway for the propagation of GVHD in the GI tract, and define whether IL-23 production adversely impacts the regulatory arm of the immune system by deleteriously affecting CD4+ and CD8+ regulatory T cell reconstitution. Studies in Specific Aim 2 will consist of a phase 2 clinical trial to determine whether administration of the IL-23p19-specific antibody, tildrakizumab, attenuates the severity of GVHD in human allogeneic HSCT recipients with underlying hematological malignancies. In addition, we will perform correlative studies to define the effect of this therapeutic approach on immune reconstitution and determine whether tildrakizumab is able to mitigate systemic inflammatory cytokine production that occurs during GVHD. We will also serially examine the microbiome to delineate whether administration of tildrakizumab preserves microbial diversity that is otherwise adversely affected during this disease. The overall goal of these studies is to define the mechanisms by which IL-23 facilitates GVHD in the GI tract and to determine whether blockade of this pathway constitutes a clinically viable strategy for the prevention of GVHD in humans.

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）。在这种疾病的急性期， 有限的一组器官受到影响，其中胃肠道 (GI) 临床上受影响最严重 重要的。促炎细胞因子在肠道病理生理学中发挥着重要作用 GVHD 部分是通过激活供体 T 细胞群来引起组织损伤。 在临床前小鼠研究中，我们已确定白细胞介素 23 (IL-23) 是一种关键的炎症因子 GVHD 期间介导胃肠道病理损伤的细胞因子。本次活动的总体目标 因此，建议定义 IL-23 诱导炎症的机制途径 胃肠道，并将这些发现直接转化为临床，以检查封锁是否有效 该途径的作用可降低人类同种异体 HSCT 受者 GVHD 的严重程度。我们的整体 假设 IL-23 由供体抗原呈递细胞 (APC) 产生 在胃肠道中诱导促炎环境，并且该途径是 预防人类 GVHD 的临床可行目标。实验于 具体目标 1 将定义 IL-23 促进炎症的细胞机制 小鼠移植受者 GVHD 期间的胃肠道。为了解决这个问题，我们将确定 产生IL-23并且对于功能重要的相关供体APC群体 诱导结肠炎症，检查供体 APC 衍生的 IL-23 是否促进 间接同种异体抗原呈递是GVHD在体内传播的关键途径 胃肠道，并定义 IL-23 的产生是否对胃肠道的监管部门产生不利影响 通过有害地影响 CD4+ 和 CD8+ 调节性 T 细胞的重建来损害免疫系统。 具体目标 2 的研究将包括一项 2 期临床试验，以确定是否 使用 IL-23p19 特异性抗体 tildrakizumab 可减轻 GVHD 的严重程度 患有潜在血液恶性肿瘤的人类同种异体 HSCT 受者。此外， 我们将进行相关研究来确定这种治疗方法对免疫的影响 重建并确定 tildrakizumab 是否能够减轻全身炎症 GVHD 期间发生细胞因子的产生。我们还将连续检查微生物组，以 描述 tildrakizumab 的给药是否可以保留微生物多样性 在这种疾病期间受到不利影响。这些研究的总体目标是定义 IL-23 促进胃肠道 GVHD 的机制并确定是否阻断 该途径的研究构成了预防人类 GVHD 的临床可行策略。