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

项目总结 移植物抗宿主病(GVHD)是与异基因移植相关的主要并发症。 造血干细胞移植。在这种疾病的急性期， 受限的一组器官受到影响，其中胃肠道(GI)是临床上最常见的 意义重大。促炎性细胞因子在肠道病理生理学中的重要作用 GVHD在一定程度上是通过激活供者T细胞群，从而导致组织损伤。 在临床前的小鼠研究中，我们已经确定白介素23(IL-23)是一种关键的炎症因子 在移植物抗宿主病中介导胃肠道病理损害的细胞因子。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。 并将这些发现直接转化到临床上，以检查是否存在阻断 这一途径的应用可降低人类异基因造血干细胞移植受者GVHD的严重程度。我们的整体 假设IL-23由供体抗原提呈细胞(APC)产生 在胃肠道中诱导促炎环境，这一途径是一种 临床上可行的预防人类移植物抗宿主病的靶点。实验在 具体目标1将定义IL-23促进炎症反应的细胞机制(S) 小鼠移植受者GVHD期间的胃肠道反应。为了解决这个问题，我们将确定 产生IL-23的相关捐赠者APC群体，并且对 诱导结肠炎症，检查供体APC来源的IL-23是否促进 间接同种异体抗原提呈是移植物抗宿主病传播的关键途径 并确定IL-23的产生是否对胃肠道的调节功能产生不利影响。 通过有害地影响免疫系统中的CD4+和CD8+调节性T细胞重建。 针对特定目标2的研究将包括2期临床试验，以确定 给予IL-23p19特异性抗体tildrakizumab可减轻GVHD的严重程度 在患有潜在血液系统恶性肿瘤的异基因造血干细胞移植受者中。此外, 我们将进行相关研究，以确定这种治疗方法对免疫的影响 重建并确定替拉珠单抗是否能够减轻全身炎症 在移植物抗宿主病期间产生的细胞因子。我们还将对微生物群进行连续检查，以 描述给予替德拉吉单抗是否保存了微生物多样性 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促进胃肠道移植物抗宿主病的机制 这一途径构成了临床上可行的预防人类移植物抗宿主病的策略。

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.