Targeting intestinal vitamin D receptor signaling to mitigate graft-versus-host disease

摘要 移植物抗宿主病（GVHD）是异基因造血干细胞移植后发病和死亡的主要原因。 干细胞移植（HSCT）。它的发生是因为同种异体移植物中具有免疫活性的供体T细胞 将基因完全不同的宿主视为外来物并攻击移植受体的组织。而遗传 捐赠者和接受者之间的不相容性是决定捐赠程度的主要因素。 非遗传因素也可影响GVHD的发生率和严重程度。最近 免疫学的进展表明，环境因素，包括膳食微量营养素， 参与改变各种免疫反应并影响实验动物的易感性 以及人类自身免疫性疾病和炎症性疾病。膳食微量营养素在GVHD中的作用 发病机制知之甚少。我们和其他人最近发现了维甲酸（RA），活性代谢物 维生素A是促进肠道GVHD发展的关键分子。这些研究揭示了 一种常见维生素的代谢产物可以深刻地影响同种异体造血干细胞移植后GVHD的风险。这些 这些发现促使我们研究其他膳食微量营养素在调节同种免疫中的潜在作用。 反应这项资助的目的是确定维生素D如何影响GVHD的发展。我们将 测试新的假设，即增强肠道维生素D受体（VDR）信号转导增强粘膜 上皮屏障以减轻GVHD。这个假设是基于我们令人兴奋的初步数据， 选择性增强肠道VDR信号可以保护实验小鼠免受GVHD。我们将 联合收割机遗传学、药理学和饮食方法来检验这一假说。目标1中的研究将 确定肠上皮VDR信号传导在HSCT后调节同种免疫中的作用。目标2将 确定维生素D/VDR通路的治疗靶向如何减轻GVHD风险。我们希望结果 从这些研究将促进我们对维生素D的作用的理解，作为一种环境保护剂， 因子，在GVHD发病机制中的作用。此外，这些研究将提供支持使用 维生素D及其类似物作为GVHD的简单且具有成本效益的辅助疗法，副作用最小 预防和/或治疗。

Abstract Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). It occurs because immunocompetent donor T cells in the allograft recognize the genetically disparate host as foreign and attack the transplant recipient's tissues. While genetic incompatibility between the donor and the recipient is the primary factor that determines the extent of the alloimmune response, non-genetic factors can also influence the incidence and severity of GVHD. Recent advances in immunology establish that environmental factors, including dietary micronutrients, actively participate in modifying a variety of immune responses and influence the susceptibility of experimental animals and humans to autoimmune and inflammatory diseases. The role of dietary micronutrients in GVHD pathogenesis is poorly understood. We and others recently identified retinoic acid (RA), the active metabolite of vitamin A, as a key molecule in facilitating the development of intestinal GVHD. These studies reveal how the metabolite of a single common vitamin can profoundly influence GVHD risk after allogeneic HSCT. These findings prompted us to examine the potential role of other dietary micronutrients in modulating the alloimmune response. The objective of this grant is to define how vitamin D influences the development of GVHD. We will test the novel hypothesis that enhancing intestinal vitamin D receptor (VDR) signaling strengthens mucosal epithelial barrier to mitigate GVHD. This hypothesis is based on our exciting preliminary data demonstrating that selectively enhancing intestinal VDR signaling protects against GVHD in experimental mice. We will combine genetic, pharmacologic, and dietary approaches to examine this hypothesis. Studies in Aim 1 will define the role of intestinal epithelial VDR signaling in modulating alloimmunity after HSCT. Aim 2 will determine how therapeutic targeting of vitamin D/VDR pathway mitigates GVHD risk. We expect that results from these studies will advance our understanding with respect to the role of vitamin D, as an environmental factor, in GVHD pathogenesis. Furthermore, these studies will provide preclinical data that support the use of vitamin D and its analogs as simple and cost-effective adjunct therapies with minimal side effects for GVHD prevention and/or treatment.