Role of Interleukin 23 in Gastrointestinal GVHD

 描述(申请人提供)：移植物抗宿主病(GVHD)是异基因造血干细胞移植的主要并发症。移植物抗宿主病(GVHD)对胃肠道(GI)的损害是一种特别严重的事件，导致显著的发病率和死亡率。促炎细胞因子在肠道移植物抗宿主病的病理生理学中起关键作用，部分是通过激活供体T细胞群，从而导致直接的组织损伤。在初步研究中，我们发现白细胞介素23(IL-23)是一种关键的细胞因子，位于这种细胞因子级联反应的顶端，继而激活独特的CD4IL-23受体(IL-23R)阳性T细胞群，表达β2整合素CD11c。这项建议的总体目标是确定这种CD4T细胞亚群导致病理损害的机制途径，并确定在胃肠道内抵消IL-23R介导的炎症的调节途径。我们的总体假设是β2整合素CD11c定义了一种新的致病的CD4IL-23RT细胞群，它在移植物抗宿主病中诱导结肠炎症，并受STAT3依赖的细胞因子IL-10和IL-27的调节。针对特定目的1的研究将确认CD11c共表达定义了一个结肠性CD4IL-23R T细胞群，确定在移植物抗宿主病过程中产生的STAT3依赖细胞因子是否增强了IL-23R和CD11c的协同表达，并检查表达β2整合素的CD4T细胞的致病性是否归因于该T细胞亚群上肠道归巢分子表达的增强。我们还将确定这种表达β-2整合素的CD4T细胞群体是否能够在结肠微环境中诱导内皮损伤和新生血管。在特定目标2中的研究将确定在GVHD期间调节CD4IL-23R T细胞的机制。我们将测试IL-10和IL-27的假设，它们也是STAT3依赖的细胞因子，在调节IL-23R介导的结肠炎症中发挥关键作用。拟议的实验将确定和表征特定的产生IL-10的捐赠者T细胞群，这些T细胞群对调节CD4IL-23R T细胞最为关键。我们还将确定IL-27如何通过对常规和调节性T细胞群的影响来调节IL-23R介导的胃肠道炎症。这些研究将利用独特的试剂和转基因小鼠模型，使我们能够表征和定义这些细胞因子在胃肠道移植物抗宿主病的病理生理学中的作用。这项建议的总体目标是发展对胃肠道内移植物抗宿主病的病理生理学和调控的新见解，这将促进临床相关策略的发展，以减轻异基因造血干细胞移植受者的这一并发症。

 DESCRIPTION (provided by applicant): Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation. Damage to the gastrointestinal (GI) tract from GVHD is a particularly serious event leading to significant morbidity and mortality. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD, in part, by activating donor T cell populations which subsequently induce direct tissue damage. In preliminary studies, we have identified interleukin 23 (IL-23) as a pivotal cytokine positioned at the apex of this cytokine cascade that secondarily activates a unique CD4+ IL-23 receptor (IL-23R)-positive T cell population that expresses the β2 integrin, CD11c. The overall goal of this proposal is to define the mechanistic pathways by which this CD4+ T cell subset induces pathological damage and determine the regulatory pathways that counter balance IL-23R-mediated inflammation within the GI tract. Our overall hypothesis is that the β2 integrin, CD11c, defines a novel, pathogenic CD4+ IL-23R+ T cell population that induces colonic inflammation during GVHD, and that is regulated by the Stat3-dependent cytokines, interleukin-10 and interleukin-27. Studies in Specific Aim 1 will be conducted to confirm that CD11c co-expression defines a colitogenic CD4+ IL-23R+ T cell population, determine whether Stat3 dependent cytokines produced during GVHD augment coordinate expression of the IL-23R and CD11c, and examine whether the pathogenicity of β2 integrin-expressing CD4+ T cells is attributable to augmented gut-homing molecule expression on this T cell subset. We will also determine whether this β2 integrin-expressing CD4+ T cell population is able to induce endothelial damage and neovascularization in the colon microenvironment. Studies in Specific Aim 2 will define mechanisms by which CD4+ IL-23R+ T cells are regulated during GVHD. We will test the hypotheses that IL-10 and IL- 27, which are also Stat3 dependent cytokines, play critical roles in the regulation of IL-23R-mediated inflammation in the colon. Proposed experiments will identify and characterize the specific IL-10- producing donor T cell populations most critical for regulating CD4+ IL-23R+ T cells. We will also determine how IL-27 modulates IL-23R-mediated inflammation in the GI tract through effects on both conventional and regulatory T cell populations. These studies will take advantage of unique reagents and transgenic mouse models which will allow us to characterize and define the effects of each of these cytokines in the pathophysiology of gastrointestinal GVHD. The overall objective of this proposal is to develop new insights into the pathophysiology and regulation of GVHD within the GI tract that will foster the development of clinically relevant strategies to mitigate this complication in allogeneic hematopoietic stem cell transplant recipients.