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）： 每年在美国，20万人被诊断出患有腹部主动脉瘤（AAA），而15,000人不可避免地会因动脉瘤囊的不懈膨胀而死于破裂。因此，每年进行40,000次选举血管内或开放性手术，发病率高达23％，两年成本高达23％，每名在退伍军人管理医疗系统中接受治疗的患者$ 116K。因此，破裂的风险会以AAA直径加速，因此可以抑制AAA扩张的有效疗法会对患者的生存，生活质量和医疗保健成本产生重大影响。具有强力霉素，他汀类药物和β受体阻滞剂的随机对照试验未能降低AAA的扩展率，因此对AAA的药理抑制仍然是未满足的医疗需求。有积极的证据表明AAA是一种自身免疫性疾病，其特征是先天和适应性免疫系统的激活。在AAA患者中，我们和其他患者已经证明，循环CD4+CD25+FOXP3+T调节细胞（Treg）的频率和免疫抑制器功能显着降低，而CD4+/CD8+CD28-T细胞和活性单核细胞的数量和细胞毒性增加。在小鼠模型中，我们已经证明了人间充质基质细胞（MSC）增加Treg频率，通过诱导转录因子Foxp3的表达并抑制AAA扩张来促进其免疫抑制剂功能。我们在此阶段I中的核心目标是通过在AAA形成中隐含的致病免疫反应来确定的随机安慰剂对照临床试验，可以通过对小AAA（35-45。mm。直径）的患者进行MSC来调节。 AIM 1的主要终点是与安慰剂处理的对照组相比，评估同种异体MSC（1或300万MSC/kg）对循环Treg数量和免疫抑制剂功能的剂量作用。次要终点是TR1调节细胞频率的变化，CD4+CD8+/CD28- T细胞，细胞毒性功能（perforin和IFN-γ活性）的变化以及活化的CD45+CD14DIM/-CD16 ++单细胞的频率。 AIM 2的主要终点是表征由于体外和体内患者特定信号而产生的MSC分泌组，专门针对IL-10。 AIM 3将通过测量具有PET/CT的18-荧光脱氧葡萄糖摄取以及基质金属蛋白酶-2和-9活性来评估主动脉炎症的有效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研究所需的样本量，以测试MSC在抑制AAA扩展方面的有效性。同样重要的是，该提案将是对MSC在人类疾病中调节免疫调查的机制的定义，并促进了卧床式实验，这些试验可能会在未来对AAA产生更有效的治疗策略。