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

描述（由申请人提供）：移植物抗宿主病（GVHD）是与异基因干细胞移植相关的主要并发症。GVHD是一系列促炎事件的结果，这些促炎事件可归因于预处理方案连同供体T细胞对宿主同种异体抗原的识别。这引发了一个炎症级联反应，其特征在于同种异体反应性供体T细胞的扩增，次级效应细胞群的募集和促炎细胞因子的产生。特别是胃肠道，已被证明是GVHD病理生理学中的关键靶器官。脂多糖（LPS）在已经被预处理方案和供体T细胞损伤的胃肠道中穿过粘膜表面的易位已经显示诱导全身性促炎细胞因子产生，其在局部和全身病理损伤的传播中起重要作用。然而，粘膜损伤和LPS渗漏如何诱导GVHD期间发生的广谱促炎作用尚不完全清楚。在初步研究中，我们现在已经确定白细胞介素（IL-23）作为关键介质连接调节方案诱导的粘膜损伤和LPS易位，随后的促炎细胞因子的产生和GVHD相关的病理损伤。我们还进行了新的观察，即在不存在供体APC来源的IL-23分泌的情况下，结肠被选择性地保护免于发生急性GVHD。因此，在多系统的情况下，炎症性疾病，我们的研究表明，一个单一的细胞因子可以负责指导组织特异性病理。该提案的目标是确定IL-23如何介导促炎事件，并测试抑制IL-23的新策略，该策略可以减少GVHD而不损失同种异体移植物所赋予的抗白血病作用。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中的研究将定义IL-23介导结肠病理损伤的机制。这些研究还将确定抑制IL-23预防GVHD的最佳时机。具体目标2将检查IL-23对免疫系统的调节臂的作用。使用一个独特的模型，其中调节性T细胞可以在体内精确识别，我们将定义IL-23在移植后调节性T细胞（TCFs）的功能和重建中的作用。具体目标3将确定IL-23的选择性靶向是否可以保持移植物抗白血病效应，同时降低GVHD的严重程度。这些研究的总体目标是确定IL-23的生物学效应，因为它们与同种异体干细胞移植后的GVH和GVL反应性相关。 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.