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。GVHD对胃肠道（GI）的损害是导致显著发病率和死亡率的特别严重的事件。促炎细胞因子在肠道GVHD的病理生理学中起关键作用，部分通过激活供体T细胞群，随后诱导直接组织损伤。在初步研究中，我们已经确定白细胞介素23（IL-23）是位于该细胞因子级联反应顶点的关键细胞因子，其次级激活表达β2整联蛋白（CD 11 c）的独特CD 4 + IL-23受体（IL-23 R）阳性T细胞群。该提案的总体目标是确定该CD 4 + T细胞亚群诱导病理性损伤的机制途径，并确定平衡胃肠道内IL-23 R介导的炎症的调节途径。我们的总体假设是，β2整合素，CD 11 c，定义了一种新的，致病性的CD 4 + IL-23 R + T细胞群体，在GVHD期间诱导结肠炎症，并由Stat 3依赖性细胞因子，白细胞介素-10和白细胞介素-27调节。将进行特定目标1的研究，以确认CD 11 c共表达定义了致大肠杆菌性CD 4 + IL-23 R + T细胞群，确定GVHD期间产生的Stat 3依赖性细胞因子是否增强了IL-23 R和CD 11 c的协调表达，并检查表达β2整联蛋白的CD 4 + T细胞的致病性是否归因于该T细胞亚群上增强的肠道归巢分子表达。我们还将确定表达β2整合素的CD 4 + T细胞群是否能够诱导结肠微环境中的内皮损伤和新血管形成。Specific Aim 2的研究将定义GVHD期间调节CD 4 + IL-23 R + T细胞的机制。我们将检验以下假设：IL-10和IL- 27（也是Stat 3依赖性细胞因子）在调节IL-23 R介导的结肠炎症中发挥关键作用。提出的实验将鉴定和表征对调节CD 4 + IL-23 R + T细胞最关键的特异性IL-10产生供体T细胞群。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-23 R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，这将使我们能够表征和定义这些细胞因子中的每一种在胃肠道GVHD的病理生理学中的作用。该提案的总体目标是对胃肠道内GVHD的病理生理学和调节形成新的见解，这将促进临床相关策略的发展，以减轻同种异体造血干细胞移植受者的这种并发症。

 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.