Stem Cell Therapy, Inflammation and Treatment Response inAlcoholism-Depression Comorbidity

摘要 酒精使用障碍(AUD)合并重度抑郁症(MD)是最常见和最严重的 在临床实践中遇到的情况，目前有效的治疗干预措施有限。 促炎细胞因子和途径的激活正在成为血管内皮细胞瘤的关键病理生理因素。 酒精中毒和严重抑郁症的病因。尽管免疫和炎症机制一直是 在相当大的程度上分别研究了酗酒和抑郁症患者的并存情况 酒精中毒和重度抑郁症最有可能表现出严重的炎症。促炎因子 机制似乎在抑郁症和酒精中毒中都起着双向作用，并可能是有限的 临床试验中报告的治疗反应。缺乏以前有效的治疗方法需要新的 干预模式和不同的治疗目标，靶向是导致这种合并症的机制。我们 假设这些患者的炎症增加是导致下降的主要因素 治疗反应。 因此，患有AUD和MD的患者是测试AUD和MD疗效的理想群体 有效的抗炎干预。我们建议使用异基因人间充质干细胞(AhMSC) 疗法是迈阿密大学米勒医学院首创的一种非常新颖的疗法，用于治疗各种 炎症性疾病。这种疗法已被证明是安全的，耐受性良好，在各种医学 并能产生强健持久的抗炎作用。我们计划测试AHMSCs对 并发AUD和复发MD患者的炎症、酒精和抑郁结局(AUD- MD)预选高炎症标志物(hsCRP&GT；3 mg/L)。我们的研究有以下几点 具体目的：目的：目的1.检测单次输注ahMSC对炎症的影响，根据C- 一项为期12周的随机、安慰剂对照试验中80例MD-AUD患者的反应蛋白(CRP)浓度 (40例主动输液，40例安慰剂)均因存在炎症而预先选择。目标2.检查效果 与ahMSC治疗相关的CRP和其他炎症标志物的降低对临床医生- 酒精使用严重程度(TLFB-重度饮酒天数百分比)和抑郁症(MADRS)的管理措施 和全球临床功能(CGI)。目的3.检查直接(降低C反应蛋白和其他炎症反应 生物标志物)和间接(减少酒精使用和抑郁)对二次研究的影响 结果包括渴望、认知、日常功能和感知的生活质量。目标4.我们的探索 目的包括评估儿童创伤的中介作用和评估儿童创伤的持续性 随访一年以上的治疗效果，配合采集血样探讨其作用 治疗反应中的炎症相关基因多态和表观遗传学。如果成功，这种治疗方法将 代表着治疗AUD-MD共病的范式转变，并将对 对炎症机制改变起重要作用的其他复杂情况的治疗 它们的发病机制。

Abstract Alcohol use disorder (AUD) with comorbid major depression (MD) is among the most frequent and serious conditions encountered in clinical practice, for which effective treatment interventions are currently limited. Activation of pro-inflammatory cytokines and pathways are emerging as key pathophysiological factors in the etiology of both alcoholism and major depression. Although immune and inflammatory mechanisms have been studied to a considerable extent in alcoholism and major depression separately, patients with co-occurring alcoholism and major depression are most likely to exhibit substantial inflammation. Pro-inflammatory mechanisms appear to play a bidirectional role in both depression and alcoholism and may underlie the limited treatment response reported in clinical trials. The lack of previously effective treatments demands new intervention modalities and different treatment targets targeting mechanisms underlying such comorbidity. We hypothesize that increased inflammation in these patients represents a major factor fostering decreased treatment response. Thus, patients with comorbid AUD and MD represent an ideal group to test the effect of a potent anti-inflammatory intervention. We propose to use allogeneic human mesenchymal stem cell (ahMSC) therapy, a highly novel treatment pioneered at the University of Miami Miller School of Medicine, to treat a variety of inflammatory conditions. This treatment has been shown to be safe and well-tolerated in a variety of medical disorders and exerts a robust and sustained anti-inflammatory effect. We plan to test the effects of ahMSCs on inflammation and on alcohol and depression outcomes in patients with comorbid AUD and recurrent MD (AUD- MD) preselected for the presence of high inflammatory markers (hsCRP>3 mg/L). Our study has the following Specific Aims: Aim 1. To examine the effects of a single ahMSC infusion on inflammation, as assessed by C- Reactive Protein (CRP) concentrations in a 12-week randomized, placebo-controlled trial in 80 MD-AUD patients (40 active infusion, 40 placebo) all preselected for the presence of inflammation. Aim 2. To examine the effects of the reduction in CRP and other inflammatory markers associated with ahMSC therapy on clinician- administered measures of the severity of alcohol use (TLFB-% heavy drinking days) and depression (MADRS) and global clinical functioning (CGI). Aim 3. To examine the direct (reduction in CRP and other inflammatory biomarkers) and indirect (reduction in alcohol use and depression) effects of ahMSC therapy on secondary study outcomes including, craving, cognition, everyday functioning and perceived quality of life. Aim 4. Our exploratory aim includes assessment of the mediating role of childhood trauma and assessment of the persistence of treatment effects over the one year follow-up period, with collection of blood samples to explore the role of inflammation related-polymorphisms and epigenetics in treatment response. If successful, this treatment would represent a paradigm shift in treating AUD-MD comorbidity and will have a significant impact on the field of therapeutics for other complex conditions in which altered inflammatory mechanisms play a substantial role in their pathogenesis.