Role of Interleukin 23 in the Pathophysiology of GVH and GVL Reactivity

描述(申请人提供)：移植物抗宿主病(GVHD)是异基因干细胞移植的主要并发症。GVHD是一系列促炎事件的结果，这些事件可归因于预处理方案与供者T细胞对宿主同种异体抗原的识别。这引发了炎症级联反应，其特征是同种异体反应性供者T细胞的扩张，次级效应细胞群的募集和致炎细胞因子的产生。尤其是胃肠道，已被证明是移植物抗宿主病病理生理学的关键靶器官。研究表明，脂多糖(LPS)跨胃肠道粘膜表面的移位可诱导全身性促炎细胞因子的产生，在局部和全身病理损伤的传播中发挥重要作用。然而，粘膜损伤和内毒素渗漏是如何导致GVHD期间广泛的促炎效应的，目前还不完全清楚。在初步研究中，我们发现白细胞介素23(IL-23)是连接预适应诱导的粘膜损伤和内毒素移位到随后的促炎细胞因子产生和GVHD相关病理损伤的关键介质。我们还做了新的观察，在缺乏供体APC来源的IL-23分泌的情况下，结肠被选择性地保护，不会发生急性移植物抗宿主病。因此，在多系统、炎症性疾病的背景下，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。这项建议的目的是确定IL-23如何调节促炎事件，并测试抑制IL-23的新策略，该策略可能允许在不损失同种异体移植物所赋予的抗白血病作用的情况下减少GVHD。为了解决这些问题，已经设计了实验来解决以下特定目标：特定目标1的研究将确定IL-23介导结肠病理损害的机制。这些研究还将确定抑制IL-23预防移植物抗宿主病的最佳时机。具体目标2将检查IL-23对免疫系统调节臂的影响。通过在体内精确识别调节性T细胞的独特模型，我们将确定IL-23在调节性T细胞(Tregs)移植后的功能和重建中的作用。具体目标3将确定选择性靶向IL-23是否可以在减轻GVHD严重程度的同时保留移植物抗白血病效应。这些研究的总体目标是确定IL-23的生物学效应，因为它们与异基因干细胞移植后的GVH和GVL反应有关。 公共卫生相关性：该项目与公共卫生的相关性源于移植物抗宿主病是异基因干细胞移植的主要并发症这一事实。更好地了解如何减少这种并发症，同时保留移植所产生的有益的抗白血病作用，将为患者带来新的治疗方法和更好的结果。

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.