T细胞亚群失衡在抗精神病药源性肥胖中的影响及机制

Recent studies have shown that abnormalities in the immune reaction exist in schizophrenia. While atypical antipsychotics are effective in treating certain types of schizophrenia, obesity and its associated metabolic side effects are the hurdles for patients complying with the treatment. These patients appear to have a low grade of inflammation. Our previous studies have shown that there was an increased proportion of Th17 cells in schizophrenia patients. Abnormal levels of cytokines are dynamic changed after antipsychotics treatment. Therefore, we hypothesise that: the increased levels of pro-inflammatory Th cell subsets may promote the progression of metabolic inflammation in antipsychotic-induced obesity. TNF-α and other proinflammatory cytokines would promote and maintain the polarization direction of proinflammatory Th cells in the manner of positive feedback. This positive feedback differentiation regulation could contribute to chronic inflammation. We shall examine the number and proportion of peripheral Thl / Th2, Thl7 / Treg and Th22 T cell subsets in association with psychiatric symptoms, the relevant levels of cytokines and metabolic indicators at different time points of antipsychotics treatment in schizophrenia patients. Obese and healthy individuals with normal weight will be studied. TNF-α antagonist will be used to correct the altered pathways of T cell subsets which are imbalanced in the animal model. The purpose of this study is to explore the impact and possible mechanisms of T cell subsets which are imbalanced in antipsychotic-induced obesity and metabolic disorders.

目前研究认为精神分裂症(SZ)患者存在免疫异常，应用抗精神病药物（AP）常可导致药源性肥胖，而肥胖也被认为是一种轻度慢性炎症。本课题组既往研究显示SZ患者AP治疗前Th17细胞比例增高，相关细胞因子水平异常，应用AP治疗后脂肪细胞因子呈现动态变化。因此我们提出假说：SZ患者存在促炎性Th细胞亚群比例升高，能促进用药后药源性肥胖代谢性炎症的起始和进展，TNF-α等促炎因子又能以正反馈的方式推动和维持Th细胞的促炎极化方向，这种正反馈的分化调节方式至少部分导致了慢性炎症持续迁延状态。本研究拟选取首发SZ患者、肥胖和体重正常的健康志愿者，比较并动态观察应用AP治疗后不同时间点外周血Thl／Th2，Thl7／Treg及Th22等T细胞亚群数目及比例、相关细胞因子水平及代谢指标的变化，并利用动物模型应用TNF-α拮抗剂干扰相关的通路，旨在探讨T细胞亚群失衡在AP药源性肥胖中产生的影响及可能机制。

精神分裂症(SCH)患者存在免疫异常，应用抗精神病药物常可导致药源性肥胖，而肥胖也被认为是一种轻度慢性炎症，可能存在促炎性的CD4+T 细胞如Thl、Thl7 与抗炎性的Th2、Treg 之间的比例功能失衡。本研究提出假说：SCH存在促炎性Th细胞亚群比例升高，能促进用药后抗精神病药源性肥胖代谢性炎症的起始和进展，TNF-α 等促炎因子又能以正反馈的方式推动和维持Th 细胞的促炎极化方向，这种正反馈的分化调节方式至少部分导致了慢性炎症持续迁延状态。基于此假说，课题组从T细胞亚群的角度出发探讨抗精神病药源性肥胖的机制。研究发现首发未用药SCH患者在基线期已经出现Th1/Th2，Th17/Treg失衡，Th1、Th2、Th17以及T细胞相关促炎因子IL-1β、TNF-α和IL-6水平升高，在接受为期半年的利培酮治疗后，Th1、Th2、Th17下降，IL-1β和IL-6降低，TNF-α进一步升高。以体重增加≥7%定义为体重增加，结果发现：基线期Th17细胞和炎症因子水平较高与抗精神病药源性体重增加的发生有关，治疗后体重增加组Th17细胞和炎症因子水平明显高于体重无明显增加组；控制混杂变量后发现，Th17、TNF-α和IL-1β的变化与BMI的变化明显相关。以上结果说明，T细胞亚群失衡所致的促炎性细胞因子水平升高与抗精神病药源性体重增加的发生有关。进一步制备SCH神经发育动物模型，将模型大鼠分为模型组（无干预），奥氮平组（给予模型大鼠奥氮平干预），依那西普组（给予模型大鼠依那西普干预）以及干预组（给予模型大鼠奥氮平+依那西普干预）。与对照组相比，奥氮平组体重显著增加，于喂饲34天前后体重增加超过20%，达到抗精神病药源性肥胖的标准。模型组，奥氮平组均出现Th1／Th2，Th17／Treg紊乱和炎症因子产生增多，而依那西普组，干预组与对照组比较差异无统计学意义。本研究说明了，SCH存在Th1/Th2，Th17/Treg失衡和促炎性细胞因子水平升高，机体炎症状态增加了用药后抗精神病药源性肥胖的易感性，TNF-α 等促炎因子又能以正反馈的方式推动和维持Th 细胞的促炎极化方向，这种正反馈调节方式与药源性肥胖的慢性炎症持续迁延状态有关。