Stem Cell Therapy, Inflammation and Treatement Response in Alcholoism-Depression Comobidity

摘要 酒精使用障碍（AUD）与抑郁症（MD）共病是最常见和最严重的 临床实践中遇到的疾病，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炎症反应中的关键病理生理因素。 酗酒和抑郁症的病因尽管免疫和炎症机制已经被 在相当大的程度上研究了酒精中毒和抑郁症， 酒精中毒和严重抑郁症最有可能表现出严重的炎症。促炎 机制似乎在抑郁症和酒精中毒中发挥双向作用，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 干预方式和不同的治疗目标，针对机制，这种合并症。我们 假设这些患者的炎症增加代表了促进减少的主要因素， 治疗反应。 因此，患有AUD和MD共病的患者代表了测试 有效的抗炎干预我们建议使用同种异体人间充质干细胞（ahMSC） 治疗，一个高度新颖的治疗开创了迈阿密大学米勒医学院，以治疗各种 炎症的症状这种治疗已被证明是安全和良好的耐受性，在各种医疗 并发挥强大和持续的抗炎作用。我们计划测试ahMSCs对 炎症和酒精和抑郁症的结果在合并AUD和复发性MD（AUD- MD）预先选择高炎症标志物（hsCRP>3 mg/L）的存在。我们的研究有以下几点 具体目标：目标1。为了检查单次ahMSC输注对炎症的影响，如通过C- 一项在80例MD-AUD患者中开展的12周随机、安慰剂对照试验中的反应蛋白（CRP）浓度 (40活性输注，40安慰剂），所有这些都是预先选择的炎症的存在。目标2.为了检验 CRP和其他炎症标志物的减少与临床医生的ahMSC治疗相关- 酒精使用严重程度（TLFB-重度饮酒天数%）和抑郁症（MADRS）的管理措施 全球临床功能（CGI）目标3。检查直接（CRP和其他炎性 生物标志物）和间接（酒精使用和抑郁症的减少）对二次研究的影响 结果包括，渴望，认知，日常功能和感知生活质量。目标4。我们的探索 目的包括评估童年创伤的中介作用和评估持续存在的 治疗效果随诊一年以上，配合采集血样，探讨其作用 炎症相关的多态性和治疗反应的表观遗传学。如果成功，这种治疗方法将 代表治疗AUD-MD合并症的范式转变，并将对 用于其它复杂病症的治疗剂，其中改变的炎症机制在 其发病机制。

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.