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

用鲁索替尼靶向内源性间充质基质细胞治疗干燥综合征的唾液腺炎

• 批准号: 10524424
• 负责人: Sara Mccoy
• 金额: $ 15.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524424
• 关键词: Adipose tissue; Adult; Affect; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antiinflammatory Effect; Autoantibodies; B-Lymphocytes; Biological; Bone Marrow; Cell Therapy; Cells; ChIP-seq; Clinical Trials; Coculture Techniques; Data; Disease; Dryness; Equilibrium; Evaluation; FDA approved; Flow Cytometry; Future; Gene Expression; Generations; Genetic Transcription; Gland; Goals; Health; Histocompatibility; Human; Immune system; Immunobiology; In Vitro; Inflammation; Inflammatory; Innovative Therapy; Interferon-alpha; Interferons; JAK1 gene; JAK2 gene; Janus kinase; Knock-out; Knowledge; Lacrimal gland structure; Lymphocytic Infiltrate; Measures; Mediating; Mission; Modality; Morbidity - disease rate; Mus; National Institute of Dental and Craniofacial Research; Oral; Oral Characters; Oral health; Organ; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Play; Population; Prevalence; Production; Property; Regenerative capacity; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Role; STAT1 gene; Saliva; Salivary; Salivary Gland Diseases; Salivary Glands; Sialadenitis; Signal Transduction; Sjogren' s Syndrome; Sodium Glutamate; Synovitis; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Thinking; Tissues; Tryptophan 2,3 Dioxygenase; United States National Institutes of Health; Up-Regulation; base; cell type; chromatin immunoprecipitation; cost; cytokine; deep sequencing; disorder control; economic cost; effective therapy; experimental study; genome-wide; immunoregulation; improved; in vivo; inhibitor; innovation; insight; interest; kinase inhibitor; mesenchymal stromal cell; mouse model; new therapeutic target; novel; peer; prevent; primary outcome; programmed cell death ligand 1; response; single-cell RNA sequencing; systemic autoimmune disease; tertiary lymphoid organ; therapeutic development; tissue repair; treatment group

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.

项目概要 干燥病（SjD）是一种常见的全身性自身免疫性疾病，其特征是明显的口腔和眼部病变 干燥症，没有可用的疾病缓解治疗方法。我们的长期目标是开发新的有效疗法 对于 SjD。本申请的目的是确定鲁索替尼抑制 IFN-的机制 诱导促炎唾液腺间充质基质细胞 (MSC) 并确定鲁索替尼的作用 SjD 小鼠模型中疾病活动的影响。拟议研究的中心假设是 IFN- 通过 STAT1 信号传导刺激的 SG-MSC 具有促炎作用，而鲁索替尼可抑制这种促炎作用。 炎症表型，最终减少 SjD 小鼠的 SG 炎症并恢复唾液产生 模型。这一假设的基本原理是基于我们的新数据，显示鲁索替尼消除了 IFNγ 诱导的 体外通过 STAT1 激活 MSC 并减少 MHCII 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，通过该机制可以改变间充质干细胞的促炎作用。这 将通过追求两个具体目标来检验中心假设：（1）确定鲁索替尼对 SG- MSC 体外免疫生物学和 (2) 定义鲁索替尼对 SG-MSC 和全腺体表型的影响 并在体内发挥作用。根据第一个目标，来自 SjD 和对照患者的 SG-MSC 将接受 IFN-± 治疗 鲁索替尼以及表型和功能差异将在体外进行检查。染色质免疫沉淀- 将进行测序以确定鲁索替尼引起改变的机制 SG-MSC 的免疫调节特性。对于第二个目标，将使用两种 SjD 小鼠模型进行治疗 鲁索替尼或载体。将从每个治疗组中分离并研究 SG-MSC。接下来，全球 将进行唾液腺和系统评估。本申请中提出的研究是 创新是因为传统上 IFN- 处理的 MSC 的抗炎特性一直是研究的焦点 研究。该提案重点关注 IFNα 如何产生可被抑制的促炎 MSC 表型 与鲁索替尼一起使用。此外，SjD 研究重点是 JAK1 抑制，我们建议使用 JAK1 &2 抑制剂治疗 SjD。拟议的研究意义重大，因为鲁索替尼有望成为一种可行的药物 促进抗炎驻留 MSC 和系统性 SjD 治疗的方式。这项试点研究是否应该 确定鲁索替尼产生抗炎 MSC 或鲁索替尼改善 SjD 的机制 在小鼠中，这些发现将被用于基于 MSC 的新型或系统性 SjD 治疗。