Targeting Endogenous Mesenchymal Stromal Cells with Ruxolitinib to Treat Sialadenitis in Sjogren's Syndrome

项目总结 Sjӧ-gren‘s病是一种常见的全身性自身免疫性疾病，以口腔和眼部症状为特征 Sicca，没有可用的疾病修改治疗方法。我们的长期目标是开发新的有效疗法 为SJD。本应用的目的是确定Ruxolitinib抑制干扰素的机制。 诱导炎性唾液腺间充质基质细胞及鲁索利替尼的作用 对SJD小鼠模型疾病活动性的影响。拟议研究的中心假设是干扰素- 刺激的SG-MSCs，通过STAT1信号，是促炎的，而鲁索利替尼抑制这种促炎- SJD小鼠炎症表型并最终减轻SG炎症并恢复唾液产生 模特们。这一假设的理论基础是基于我们的新数据，即鲁索利替尼取消干扰素诱导的 通过STAT1在体外激活MSC，减少MHCII的上调。这些新数据至关重要，因为 他们确定了一种可能的机制，通过这种机制可以修改MSCs的促炎方面。这个 中心假说将通过追求两个具体目标来检验：(1)确定鲁索利替尼对SG-2的影响。 MSC的体外免疫生物学研究及(2)Ruxolitinib对SG-MSC和全腺表型的影响 并在体内发挥作用。在第一个目标下，SJD患者和对照组的SG-MSCs将被±干扰素处理。 Ruxolitinib与表型和功能的差异将在体外进行检测。染色质免疫沉淀- 将进行测序以确定Ruxolitinib在 SG-MSCs的免疫调节特性。对于第二个目的，将对两个SJD小鼠模型进行治疗 鲁索利替尼或赋形剂。从各治疗组分离、传代SG-MSCs。接下来，全球 将进行唾液腺和系统评估。这项申请中提出的研究是 创新是因为传统上干扰素治疗的骨髓间充质干细胞的抗炎特性一直是 研究。本研究的重点是干扰素如何产生一种可被抑制的促炎性间充质干细胞表型。 使用鲁索利替尼。此外，SJD的研究集中在JAK1抑制上，我们建议使用JAK1 &2抑制剂治疗SJD。这项拟议的研究意义重大，因为鲁索利替尼有望成为一种可行的 促进抗炎常驻MSCs和全身性SJD治疗的模式。这项试点研究是否应该 确定Ruxolitinib产生抗炎MSCs的机制或Ruxolitinib改善SJD的机制 在小鼠身上，这些发现将被用于SJD的基于MSC的或系统的新治疗。

PROJECT SUMMARY Sjӧgren’s disease (SjD), a common systemic autoimmune disease characterized by marked oral and ocular sicca, has no disease modifying treatments available. Our long-term goal is to develop new effective therapies for SjD. The objective of this application is to determine the mechanism through which ruxolitinib inhibits IFN- induced pro-inflammatory salivary gland mesenchymal stromal cells (MSCs) and define the effects of ruxolitinib on disease activity in SjD mouse models. The central hypothesis of the proposed studies is that IFN- stimulated SG-MSCs, through STAT1 signaling, are pro-inflammatory and that ruxolitinib inhibits this pro- inflammatory phenotype and ultimately reduces SG inflammation and restores saliva production in SjD mouse models. The rationale for this hypothesis is based on our new data showing ruxolitinib abolishes IFN-induced MSC activation and reduces MHCII upregulation in vitro through STAT1. These new data are pivotal because they identify a possible mechanism by which the pro-inflammatory aspect of MSCs can be modified. The central hypothesis will be tested by pursuing two specific aims: (1) Determine the effect of ruxolitinib on SG- MSC immunobiology in vitro and (2) define the effects of ruxolitinib on SG-MSC and whole gland phenotype and function in vivo. Under the first aim, SG-MSCs from SjD and control patients will be treated with IFN ± ruxolitinib and phenotype and functional differences will be examined in vitro. Chromatin immunoprecipitation- sequencing will be performed to determine the mechanism by which ruxolitinib imparts change in the immunomodulatory profile of SG-MSCs. For the second aim, two SjD mouse models will be treated with ruxolitinib or vehicle. SG-MSCs will be isolated and interrogated from each treatment group. Next, a global salivary gland and systemic evaluation will be performed. The research proposed in this application is innovative because traditionally the anti-inflammatory profile of IFN-treated MSCs has been the focus of research. This proposal focuses on how IFN creates a pro-inflammatory MSC phenotype that can be inhibited with ruxolitinib. Furthermore, SjD research has focused on JAK1 inhibition and we propose the use of a JAK1 & 2 inhibitor to treat SjD. The proposed research is significant because ruxolitinib holds promise as a feasible modality to promote anti-inflammatory resident MSCs and for systemic SjD treatment. Should this pilot study determine the mechanism by which ruxolitinib creates anti-inflammatory MSCs or that ruxolitinib improves SjD in mice, these finding will be harnessed toward novel MSC-based or systemic treatment of SjD.