A Phase II Controlled Trial of Allogeneic Mesenchymal Stem Cells for the Treatment of Refractory Lupus

项目摘要/摘要 骨髓间充质干细胞(MSCs)临床疗效及其作用机制的研究 难治性狼疮的治疗具有重要意义。我们和其他人已经报告了在 健康小鼠或人的异基因骨髓间充质干细胞输注后的狼疮小鼠模型。输注间充质干细胞， 来自骨髓或脐带，在100多名难治性狼疮患者中得到了治疗 在接受治疗的患者中，有65%-75%的患者临床受益。然而，骨髓间充质干细胞在狼疮中的安慰剂对照试验已经 并不是为了明确地表明MSCs比标准护理更有效。一个明确的结果 到目前为止，对MSCs的多次试验表明，它们可以安全地给予，几乎没有严重的不良反应。这个 临床前数据、非对照试验和安全性简介创建了一项受控试验的授权，以测试 骨髓间充质干细胞治疗狼疮的疗效观察这项试验的关键是机械研究，以定义MSCs如何 冲击性疾病。之前对狼疮和类风湿性关节炎的研究报告说，循环中的Treg细胞增加， MSC术后患者Th17细胞减少，TFH细胞减少，活化B细胞和浆细胞减少 输液。这些细胞效应发生的机制尚不清楚。我们发现狼疮患者 降低循环中以糖蛋白A重复序列为主(GARP)/转化生长因子复合体的水平。MSCs 表达GARP，GARP是转化生长因子生物活性的主要决定因素，并具有重要的促进作用 对Treg数和功能的影响。我们假设，异基因骨髓间充质干细胞输注，加上标准的护理，将 事实证明，在治疗患有活动期疾病的狼疮患者时，明显比单纯的标准护理有效。我们 进一步假设MSCs在狼疮中的作用是通过调节和致病的T和B来实现的 通过上调GARP表达，导致转化生长因子生物活性增强和Treg增加 数字和活跃度。为了检验这些假设，我们的具体目标是： 1.确定骨髓间充质干细胞治疗的安全性和有效性。 多中心盲法安慰剂对照试验治疗中重度狼疮患者 与正在进行的护理标准相比，疾病活动对标准护理治疗反应迟钝。 2.从机制上定义MSCs如何调节狼疮患者的调节性和致病性T细胞和B细胞 以及GARP介导的转铁蛋白生物活性在这一过程中的作用。 拟议的试验将在六个学术中心进行，这些中心都是熟练的、成功的和有经验的 进行狼疮试验。如果我们证实MSC治疗如报道的那样有效，那么MSC输注可能会 成为狼疮的替代疗法。详细的机理分析将为我们提供对 狼疮中复杂的细胞基质以及间充质干细胞对这些细胞相互作用的影响。有一个定义好的 FDA许可细胞疗法的途径，如果有效，允许该疗法转化为临床。

PROJECT SUMMARY/ABSTRACT Determining the clinical effectiveness of mesenchymal stem cells (MSCs) and their mechanism of action in treating refractory lupus is of significant importance. We and others have reported reproducible improvement in murine models of lupus following allogeneic MSC infusions from healthy mice or humans. Infusion of MSCs, derived from bone marrow or umbilical cords, in more than 100 treatment-refractory lupus patients has resulted in positive clinical benefit in 65-75% of those treated. However, a placebo-controlled trial of MSCs in lupus has not been performed to show definitively that MSCs are more effective than standard of care. One clear result from multiple trials of MSCs to date is that they can be given safely with almost no serious adverse events. The preclinical data, the uncontrolled trials and the safety profile create a mandate for a controlled trial to test the efficacy of MSCs as a therapeutic for lupus. Critical to this trial are mechanistic studies to define how MSCs impact disease. Prior studies in lupus and rheumatoid arthritis reported increased circulating Treg cells, decreased Th17 cells, decreased TFH cells and fewer activated B and plasma cells in patients after MSC infusion. The mechanism by which these cellular effects occur is unknown. We have found that lupus patients have decreased circulating levels of glycoprotein A repetitions predominant (GARP)/TGF complexes. MSCs express GARP, and GARP is a major determinant of TGF bioactivity and also has important enhancing effects on Treg number and function. We hypothesize that allogeneic MSC infusion, plus standard of care, will prove significantly more effective in treating lupus patients with active disease than standard of care alone. We further hypothesize that effects of MSCs in lupus occur via modulation of regulatory and pathogenic T and B cells through upregulation of GARP expression, resulting in enhanced TGF bioactivity and increased Treg numbers and activity. To test these hypotheses, our specific aims are to: 1. Determine the safety and efficacy of mesenchymal stem cell therapy in a two-dose escalation double- blind placebo-controlled multi-center trial as a treatment for lupus patients with moderate to severe disease activity unresponsive to standard of care therapy compared to ongoing standard of care. 2. Define mechanistically how MSCs modulate regulatory and pathogenic T and B cells in lupus patients and the role of GARP-mediated TFG bioactivity in this process. The proposed trial will be performed in six academic centers that are all skilled, successful and experienced in performing lupus trials. If we confirm that MSC therapy is as effective as reported, then MSC infusions may become an alternative therapy for lupus. The detailed mechanistic analysis will provide novel insight into the complex cellular matrix in lupus and the impact MSCs have on these cellular interactions. There is a defined FDA pathway for licensing cellular therapies allowing this therapy, if effective, to be translated to the clinic.