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

项目摘要 移植物抗宿主病（GVHD）是同种异体移植的主要并发症， 造血干细胞移植（HSCT）。在这种疾病的急性期， 受影响的器官有限，其中胃肠道（GI）是临床上最常见的 显著促炎性细胞因子在肠道炎症的病理生理学中起着关键作用， GVHD部分通过激活供体T细胞群，随后诱导组织损伤。 在临床前小鼠研究中，我们已经确定白细胞介素23（IL-23）是一种关键的炎症因子， 在GVHD期间介导胃肠道病理损伤的细胞因子。这个项目的总体目标是 因此，建议定义IL-23诱导炎症的机制途径。 胃肠道，并直接将这些发现转化为临床，以检查是否封锁 这一途径降低了人类同种异体HSCT受者中GVHD的严重程度。我们的整体 假设供体抗原呈递细胞（APC）产生的IL-23 诱导胃肠道中的促炎环境，并且该途径是一种 用于预防人类GVHD的临床上可行的靶标。实验 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并对免疫应答功能重要的相关供体APC群体， 诱导结肠中的炎症，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移植物抗宿主病（GVHD）在骨髓中传播的关键途径， 胃肠道，并确定IL-23的产生是否对胃肠道的调节臂产生不利影响。 免疫系统通过有害地影响CD 4+和CD 8+调节性T细胞重建。 具体目标2的研究将包括一项2期临床试验，以确定是否 IL-23 p19特异性抗体tildrakizumab的给药减轻了GVHD的严重程度 在患有潜在恶性血液病的人类同种异体HSCT受者中。此外，本发明还提供了一种方法， 我们将进行相关研究，以确定这种治疗方法对免疫功能的影响。 重建并确定tildrakizumab是否能够减轻全身性炎症 在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给药是否能保护微生物多样性， 在这种疾病中受到不利影响。这些研究的总体目标是确定 IL-23促进胃肠道中GVHD的机制，并确定阻断是否 这一途径的研究构成了预防人类GVHD的临床可行策略。

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.