Mesenchymal stem cells induce regulatory T cells in patients with aortic aneurysm

间充质干细胞诱导主动脉瘤患者调节性T细胞

• 批准号: 9143284
• 负责人: Michael Patrick Murphy
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143284
• 关键词: Abdominal Aortic Aneurysm; Adaptive Immune System; Adrenergic beta-Antagonists; Aftercare; Allogenic; Aneurysm; Animal Model; Aortic Aneurysm; Autoimmune Diseases; Biological Assay; Blood specimen; CD28 gene; CD8B1 gene; Caliber; Cells; Cessation of life; Clinical Research; Control Groups; Controlled Clinical Trials; Cultured Cells; Cytotoxic T-Lymphocytes; Data; Diagnosis; Disease; Dose; Double-blind trial; Doxycycline; Extracellular Matrix Degradation; FCGR3B gene; FOXP3 gene; Flow Cytometry; Frequencies; Future; Gelatinase A; Goals; Health Care Costs; Human; IL2RA gene; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Interferon Type II; Interleukin-10; Measures; Medical; Mesenchymal; Mesenchymal Stem Cells; Morbidity - disease rate; Operative Surgical Procedures; PET/CT scan; PTPRC gene; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phase; Phase II Clinical Trials; Phenotype; Placebo Control; Placebos; Population; Quality of life; Randomized; Randomized Controlled Trials; Regulatory T-Lymphocyte; Risk; Rupture; Sample Size; Sampling; Serum; Severities; Signal Transduction; Stromal Cells; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Treatment Efficacy; United States Department of Veterans Affairs; Veterans; bench to bedside; clinical investigation; cost; cytotoxic; effective therapy; efficacy testing; experimental study; fluorodeoxyglucose; human disease; in vitro Assay; in vivo; monocyte; mouse model; perforin; prevent; public health relevance; response; transcription factor; translational impact; uptake

 DESCRIPTION (provided by applicant): Each year in the U.S. 200,000 people are diagnosed with abdominal aortic aneurysm (AAA) and 15,000 will inevitably die from rupture due to unrelenting expansion of the aneurysm sac. Consequently 40,000 elective endovascular or open surgeries are performed annually with morbidity rates as high as 23% and two-year costs up to $116K per patient treated in the Veterans Administration medical system. The risk of rupture accelerates with AAA diameter thus an effective therapy that could suppress AAA expansion would have a significant impact on patient survival, quality of life, and health care costs. Randomized, controlled trials with doxycycline, statins, and beta-blockers have failed to decrease AAA expansion rates and thus pharmacologic inhibition of AAA remains an unmet medical need. There is accumulating evidence that AAA is an autoimmune disease characterized by activation of the innate and adaptive immune systems. In patients with AAA we and others have demonstrated that circulating CD4+CD25+FoxP3+ T-regulatory cells (Treg) are significantly diminished in frequency and immune suppressor function whereas CD4+/CD8+CD28- T-cells and activated monocytes are increased in number and cytoxicity. In mouse models we have demonstrated that human mesenchymal stromal cells (MSC) increase Treg frequency, promote their immune suppressor function by inducing expression of the transcription factor FoxP3, and inhibit AAA expansion. Our central objective in this Phase I randomized, placebo controlled clinical trial is t determine if the pathogenic immune responses implicated in AAA formation can be favorably modulated by administering MSCs in patients with small AAA (35-45. mm. diameter). The primary endpoint of Aim 1 is to assess the dose effect of allogeneic MSCs (1 or 3 million MSCs/kg) on circulating Treg number and immune suppressor function as compared to a placebo treated control group. The secondary endpoints are changes in frequency of Tr1 regulatory cells, CD4+CD8+/CD28- T-cells, changes in cytotoxic function (perforin and IFN-γ activity), and frequency of activated CD45+CD14dim/-CD16++ monocytes. The primary endpoint of Aim 2 is to characterize the MSC secretome produced in response to patient specific signals in vitro and in vivo, specifically focusing on IL-10. Aim 3 will assess the effectof MSC administration on aortic inflammation by measuring 18-flurodeoxyglucose uptake with PET/CT and serum levels of matrix metalloproteinase-2 and -9 activity. Completion of this proposal will allow us to develop statistical power to calculate the sample sizes needed to execute a larger clinical study that will test the efficacy of MSCs in suppressing AAA expansion. Equally important, this proposal will be plenary in its definition of the mechanisms by which MSCs modulate immune responses in human disease and facilitate bedside to bench experiments that may yield more effective therapeutic strategies for AAA in the future.

 描述（由申请人提供）： 在美国，每年有 200,000 人被诊断患有腹主动脉瘤 (AAA)，其中 15,000 人将不可避免地因动脉瘤囊不断扩张而死亡。每年进行 40,000 例选择性血管内或开放手术，发病率高达 23%。每名患者在退伍军人管理局医疗中心接受治疗的两年费用高达 11.6 万美元破裂的风险随着 AAA 直径的增加而增加，因此抑制 AAA 扩张的有效治疗将对患者的生存、生活质量和医疗费用产生重大影响。未能降低 AAA 扩张率，因此 AAA 的药物抑制仍然是一个未满足的医疗需求。越来越多的证据表明 AAA 是一种自身免疫性疾病，其特征是患者先天性和适应性免疫系统的激活。我们和其他人已经证明，在 AAA 中，循环 CD4+CD25+FoxP3+ T 调节细胞 (Treg) 的频率和免疫抑制功能显着减少，而 CD4+/CD8+CD28- T 细胞和活化的单核细胞的数量和细胞毒性增加。我们已经在小鼠模型中证明，人间充质基质细胞 (MSC) 可以增加 Treg 频率，通过诱导转录因子 FoxP3 的表达来促进其免疫抑制功能，并抑制 AAA我们在这项 I 期随机、安慰剂对照临床试验中的中心目标是确定是否可以通过在小 AAA（直径 35-45 毫米）患者中施用 MSC 来有利地调节与 AAA 形成相关的致病性免疫反应。目标 1 的终点是评估与安慰剂治疗的对照组相比，同种异体 MSC（1 或 300 万 MSC/kg）对循环 Treg 数量和免疫抑制功能的剂量效应。终点是 Tr1 调节细胞、CD4+CD8+/CD28- T 细胞频率的变化、细胞毒功能（穿孔素和 IFN-γ 活性）的变化以及激活的 CD45+CD14dim/-CD16++ 单核细胞的频率。 Aim 的主要终点。图2是表征在体外和体内响应患者特定信号而产生的MSC分泌组，特别关注IL-10，目的3将评估其效果。通过使用 PET/CT 测量 18-氟脱氧葡萄糖摄取以及基质金属蛋白酶-2 和 -9 活性的血清水平来对主动脉炎症进行 MSC 给药，该提案的完成将使我们能够开发统计能力来计算执行更大的临床所需的样本量。这项研究将测试 MSC 抑制 AAA 扩张的功效，同样重要的是，该提案将全面定义 MSC 调节人类疾病中的免疫反应并促进临床治疗的机制。进行实验，可能会在未来产生更有效的 AAA 治疗策略。