Role of the retinoic acid pathway during graft-versus-host disease

移植物抗宿主病（GVHD）仍然是广泛应用的最大障碍， 异基因造血干细胞移植（HSCT）是一种挽救许多恶性肿瘤和 非恶性疾病它主要由供体T细胞介导，导致多器官损伤，包括 HSCT受者的皮肤、肝脏和胃肠道。在这些靶器官中，胃肠道是 具有特殊的临床和免疫学意义。事实上，严重的肠道损伤是导致 患者和实验动物中GVHD相关的死亡。然而，细胞和分子 GVHD期间胃肠道炎症反应的潜在机制仍不清楚。我们长久以来- 长期目标是开发基于临床的策略来预防或减轻GVHD期间的肠道损伤， 从而改善同种异体HSCT的结果。我们最近发现维甲酸（RA），活性 维生素A的代谢产物，作为促进肠道GVHD发展的关键分子。具体地说， 外源性RA的给药加重了受体小鼠的肠道损伤，并显著增加了GVHD。 相关死亡率。重要的是，来自视黄酸受体（RAR）-α缺陷小鼠的供体T细胞显示， 导致致命GVHD，更具体地，肠损伤的能力显著降低。这些新颖 研究结果确定了RA在GVHD中的器官特异性作用，并提供了RA途径在GVHD中至关重要的证据。 参与肠道GVHD的发病机制。本提案的目的是解决临床相关的 关于RA途径如何控制肠道GVHD发展以及是否 操纵这一途径可以降低疾病的严重程度。我们假设RA通路对于宿主的免疫应答是至关重要的。 和供体树突状细胞来启动和维持肠道GVHD，并且该途径可以被操纵用于 治疗目的。我们将结合联合收割机遗传学、营养学和药理学的方法来研究 假设在目标1中，我们将确定RA的产生和RAR信号是如何在同种异体移植后改变的。 HSCT。然后，我们将研究这些变化如何影响宿主和供体树突状细胞的功能， 肠道GVHD。目的2将确定操纵RA通路是否是预防和/或 治疗肠道GVHD。我们将研究是否使用新的小分子药物阻断RA通路。 分子抑制剂可以预防肠道GVHD。我们还将探索RA编程的调节性T细胞是否可以 用于治疗已建立的肠道GVHD。最后，我们将确定关键移植物是否与- 使用这些方法保留了白血病效应。我们希望从这些研究中获得的见解将 有助于更好地理解RA通路在疾病病理生理学中的基本作用。 肠道GVHD，并提供临床前数据，以开发新的策略，以预防或治疗这种破坏性的 异基因造血干细胞移植后并发症。

Graft-versus-host disease (GVHD) remains the most significant obstacle to the broader application of allogeneic hematopoietic stem cell transplantation (HSCT), a life-saving treatment for many malignant and nonmalignant diseases. It is mediated primarily by donor T cells that cause multi-organ damage, including the skin, liver, and gastrointestinal tract in HSCT recipients. Of these target organs, the gastrointestinal tract is of particular clinical and immunological significance. Indeed, severe intestinal damage is largely responsible for the GVHD-associated deaths in patients and experimental animals. However, the cellular and molecular mechanisms underlying the inflammatory responses in the GI tract during GVHD remain unclear. Our long- term goal is to develop clinically based strategies to prevent or mitigate intestinal damage during GVHD, thereby improving the outcomes of allogeneic HSCT. We recently identify retinoic acid (RA), the active metabolite of vitamin A, as a key molecule in facilitating the development of intestinal GVHD. Specifically, administration of exogenous RA exacerbates gut damage in recipient mice and significantly increases GVHD- associated mortality. Importantly, donor T cells from the retinoic acid receptor (RAR)-α deficient mice show markedly diminished ability to cause lethal GVHD and, more specifically, intestinal damage. These novel findings identify an organ-specific role of RA in GVHD and provide evidence that the RA pathway is critically involved in the pathogenesis of intestinal GVHD. The objective of this proposal is to address clinically relevant questions with respect to how the RA pathway controls intestinal GVHD development and whether manipulating this pathway can reduce disease severity. We hypothesize that the RA pathway is critical for host and donor dendritic cells to initiate and perpetuate intestinal GVHD and this pathway can be manipulated for therapeutic purposes. We will combine genetic, nutritional, and pharmacological approaches to examine the hypotheses. In Aim 1, we will determine how RA production and RAR signaling are altered after allogeneic HSCT. We will then examine how these changes affect the function of host and donor dendritic cells to cause intestinal GVHD. Aim 2 will determine if manipulating the RA pathway is a novel approach to prevent and/or treat intestinal GVHD. We will examine if pharmacological blockade of the RA pathway using novel small molecule inhibitors can prevent intestinal GVHD. We will also explore if RA-programmed regulatory T cells can be used to treat established intestinal GVHD. Finally, we will determine whether the critical graft-versus- leukemia effect is preserved using these approaches. We expect that insights gained from these studies will contribute to a better understanding of the fundamental role of the RA pathway in the pathophysiology of intestinal GVHD and provide preclinical data to develop novel strategies to prevent or treat this devastating complication after allogeneic HSCT.