Lrg1 as a therapeutic target in Graft-versus-Host Disease

移植物抗宿主病（GVHD）是异基因造血干细胞移植（allo-HSCT）的主要并发症，导致相当高的死亡率。存在对新疗法的医学需求，因为使用免疫抑制药物的标准GVHD治疗具有严重的不希望的作用，包括致命感染和肿瘤复发。在我们以前的工作中，我们发现血管生成在GVHD期间启动器官炎症，使得治疗性抑制血管生成成为一种有吸引力的新方法，以减少GVHD期间的炎症，而不会严重损害免疫。然而，这种方法的主要障碍是缺乏合适的分子靶点，这些靶点在病理性血管生成和生理性血管生成期间差异上调。富含亮氨酸的α-2-糖蛋白1（Lrg 1）可能是这样一个合适的目标，因为它已被证明是参与病理性血管生成，而它似乎是一种生理性血管生成。缺乏Lrg 1的小鼠发育正常，但病理性血管生成显著减少。Lrg 1与转化生长因子-β1（TGF-β1）辅助受体endoglin结合并促进内皮细胞中促血管生成的Smad 1/5/8信号通路。lrg 1抗体阻断抑制这种促血管生成开关并减弱血管生成。我们的初步研究结果表明：1）Lrg 1在GVHD过程中靶器官表达上调。2)实验性GVHD和结肠炎在Lrg 1缺陷小鼠中减弱。因此，我们假设Lrg 1可以用作GVHD的治疗靶点。我们提出在小鼠allo-HSCT模型和临床样本中进行研究，具体目标如下：目的1。实验性GVHD中的遗传学和药理学Lrg 1耗竭以及Lrg 1产生的机制目的2。在不同的体外研究中Lrg 1耗竭的功能和机制分析目的3. Lrg 1在人GVHD中的表达以及细胞、分子和临床变化的分析从计划的实验结果将有助于：-更好地理解病理性血管生成在GVHD中的作用及其由Lrg 1的调节。- 靶向Lrg 1的治疗策略在GVHD和其他炎症性疾病中的翻译发展。

Graft-versus-host disease (GVHD) is the main complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) causing considerable mortality. There is a medical need for novel therapies because standard GVHD treatments with immunosuppressive drugs have severe unwanted effects including fatal infection and tumor relapse. In our previous work, we found that angiogenesis initiates organ inflammation during GVHD, making therapeutic inhibition of angiogenesis an attractive novel approach to reduce inflammation during GVHD without severely impairing immunity. The main obstacle to this approach, however, has been the lack of suitable molecular targets, which are differentially upregulated during pathological angiogenesis and physiological angiogenesis. Leucine-rich alpha-2-glycoprotein 1 (Lrg1) could be such a suitable target, as it has been demonstrated to be involved in pathological angiogenesis, whereas it appears to be dispensable for physiological angiogenesis. Mice lacking Lrg1 develop normally, but exhibit a significant reduction in pathological angiogenesis. Lrg1 binds to transforming growth factor-β1 (TGF-β1) accessory receptor endoglin and promotes the pro-angiogenic Smad1/5/8 signaling pathway in endothelial cells. Lrg1 antibody blockade inhibits this pro-angiogenic switch and attenuates angiogenesis. Results from our preliminary studies suggest that:1) Lrg1 is upregulated in target organs during GVHD. 2) Experimental GVHD and colitis are attenuated in Lrg1-deficient mice.We therefore hypothesize that Lrg1 can be used as a therapeutic target in GVHD.We propose studies in murine allo-HSCT models and in clinical samples with the following specific aims:Aim 1. Genetic as well as pharmacologic Lrg1 depletion in experimental GVHD and mechanisms of Lrg1 production Aim 2. Functional and mechanistic analyses of Lrg1 depletion in different in vitro studiesAim 3. Lrg1 expression in human GVHD and analyses of cellular, molecular and clinical alterationsThe results from the planned experiments will contribute to: - A better understanding of the role of pathological angiogenesis during GVHD and its regulation by Lrg1. - The translational development of therapeutic strategies targeting Lrg1 in GVHD and possibly in other inflammatory diseases.