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

摘要 移植物抗宿主病(GVHD)是异基因造血术后发病率和死亡率的主要原因。 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者T细胞识别 基因不同的宿主是外来的，并攻击移植接受者的组织。虽然遗传 供者和受者之间的不相容是决定移植程度的主要因素。 同种异体免疫反应、非遗传因素也可影响移植物抗宿主病的发生率和严重程度。近期 免疫学的进展表明，环境因素，包括饮食中的微量营养素，积极 参与改变多种免疫反应，影响实验动物的易感性 和人类的自身免疫性和炎症性疾病。膳食微量营养素在移植物抗宿主病中的作用 发病机制尚不清楚。我们和其他人最近发现了活性代谢物维甲酸(RA) 维生素A是促进肠道移植物抗宿主病发生的关键分子。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异基因造血干细胞移植后GVHD的风险。这些 这一发现促使我们研究了其他膳食微量营养素在调节同种免疫中的潜在作用。 回应。这笔赠款的目的是确定维生素D如何影响GVHD的发展。我们会 测试增强肠道维生素D受体(VDR)信号增强粘膜的新假说 上皮屏障可减轻移植物抗宿主病。这一假设是基于我们令人兴奋的初步数据证明的 选择性地增强肠道VDR信号对实验小鼠的GVHD具有保护作用。我们会 结合遗传学、药理学和饮食方法来检验这一假设。目标1中的研究将 明确肠上皮VDR信号在HSCT后调节同种异体免疫中的作用。目标2将 确定维生素D/VDR途径的治疗靶点如何降低移植物抗宿主病的风险。我们期待着这一结果 这些研究将促进我们对维生素D作为一种环境因子的作用的理解 在移植物抗宿主病发病机制中起重要作用。此外，这些研究将提供临床前数据，支持使用 维生素D及其类似物是治疗GVHD的简单且成本效益高、副作用最小的辅助疗法 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.