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; 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.

项目摘要 移植与宿主疾病（GVHD）是与同种异体有关的主要并发症 造血干细胞移植（HSCT）。在这种疾病的急性阶段， 受限的器官集受到胃肠道（GI）的影响最多 重要的。促炎细胞因子在肠道生理学中起关键作用 GVHD部分通过激活供体T细胞种群，后来诱导组织损伤。 在临床前的鼠研究中，我们已经将白介素23（IL-23）确定为关键炎症 GVHD期间介导GI道中病理损害的细胞因子。总体目标 因此，建议是定义IL-23诱导炎症的机械途径 胃肠道，并将这些发现直接转化为诊所，以检查是否封锁 该途径降低了人类同种异体HSCT受体中GVHD的严重程度。我们的整体 假设是由供体抗原呈递细胞（APC）产生的IL-23 在胃肠道中诱导促炎环境，该途径是 预防人类GVHD的临床可行目标。实验 具体目标1将定义IL-23促进炎症的细胞机制 鼠类移植受者GVHD期间的GI道。为了解决这个问题，我们将确定 产生IL-23的相关供体APC群体在功能上对 诱导结肠炎症，检查供体APC衍生的IL-23是否促进 间接同种抗原表现，这是GVHD传播中的关键途径 胃肠道，并定义IL-23的生产是否不利影响 免疫系统通过有害影响CD4+和CD8+调节T细胞重建。 特定目标2中的研究将由2期临床试验组成，以确定是否是否 IL-23P19特异性抗体Tildrakizumab的给药减弱了GVHD的严重程度 在人类同种异体HSCT接受者中，具有潜在的血液学恶性肿瘤。此外， 我们将进行相关研究以定义这种治疗方法对免疫的影响 重建并确定tildrakizumab是否能够减轻系统性炎症 GVHD期间发生的细胞因子产生。我们还将连续检查微生物组 描述tildrakizumab的给药是否保留微生物多样性 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GI道中的GVHD并确定是否封锁的机制 该途径构成了预防人类GVHD的临床可行策略。