褪黑素对幽门螺杆菌相关胃疾病的免疫调节作用

Helicobacter pylori (Hp) colonizes the gastric mucosa of more than 50% of the world's population. The analysis of data showed that infection rate reaches highly from 50 to 80% in china, which increased day after day. WHO considers Hp-induced gastritis is the strongest singular risk factors for gastric carcinogenesis.CD4+CD25+regulatory T cells(Treg) take part in inflammation immunologic suppression, which at high expression in the microenvironment of gastritis and gastric cancer.Melatonin is a neuroendocrine hormone,which is a immunomodulator also.Both gastric mucosa and lymphocyte synthetize endogenous melatonin and express melatonin receptors. Ligand-receptor binding can adjust immunity,protect gastric mucosa.The correlative reports showed many functional relativities among melatonin,Treg and Hp-associate gastric diseases.On the basis of the early study, and for the immune anergy after Hp infection, this project will try to discuss changes of melatonin concentration in serum with Hp infection and mealtonin receptors MT1,MT2and ROR in host, and discover the regulatory effect of melatonin on number change and function of Treg during the course of Hp infection, through detection of clinic speciments,the animal models in vivo and cell models in vitro. Furthermore try to illuminate the influence of melatonin on Hp-associated gastric diseases and the possible immunoregulation mechanism. The purpose of the study is to find a new idea for the prevention and therapy of Hp-associate gastric diseases, and to offer some theoretical foundation for the relationship of neuro-endocrine-immune network and tumor occurrence and development.

幽门螺杆菌（Hp）在我国感染率高达50～80%，且呈不断上升趋势，WHO认为Hp引起的胃炎是导致胃癌的最强单一危险因素。CD4+CD25+Treg细胞参与炎症免疫抑制，在胃炎及胃癌微环境均高表达。褪黑素是神经内分泌激素，也是免疫调节剂，胃黏膜及淋巴细胞也可合成内源性褪黑素，且表达褪黑素受体，二者结合调节免疫，保护胃黏膜。相关研究资料显示，褪黑素，Treg细胞及Hp相关胃疾病三者之间存在一定的功能联系。本项目在前期研究基础上，试图针对Hp感染后免疫反应的无能性，通过临床标本检测和体内外研究实验，探讨Hp感染宿主血清褪黑素浓度变化和褪黑素受体MT1、MT2、ROR表达变化，及褪黑素对Hp感染过程中Treg细胞数量及功能的调控作用和相关性，进一步阐明褪黑素对Hp相关胃疾病的影响及可能免疫调节机制，为Hp相关胃疾病预防与治疗寻找新的思路，也为神经内分泌免疫网络与肿瘤发生发展的关系提供理论依椐。

本课题组长期从事褪黑素免疫调节和抗肿瘤两大功能的研究，已发表论文四十余篇，承担各类课题十余项。以往研究结果表明，褪黑素体内外能够抑制胃癌细胞增殖，且能影响CD4+CD25+Foxp3+ Treg细胞的产生和功能，并通过Treg细胞进而影响胃癌的发生发展。本项目在前期研究的基础上，继续以Treg细胞为切入点，探讨褪黑素对H.pylori相关胃疾病的影响及可能的免疫调节作用机制。.首先通过建立H.pylori感染胃炎小鼠模型，造模验证成功后小鼠经过不同浓度褪黑素及褪黑素拮抗剂干预2，4，6周后，发现褪黑素对Hp感染小鼠的胃疾病严重程度有改善作用，而拮抗剂加重了小鼠的病情，使其存活率大大降低，其机制可能与褪黑素下调机体CD4+CD25+Foxp3+ Treg 细胞数量及Foxp3 的表达量相关，同时伴有褪黑素核受体RORβ表达上调及外周血和肝的TGFβ1表达上调。其次已收集部分Hp感染相关胃炎及胃癌临床标本，整理分析病例，着手检测标本中Treg细胞相关指标与褪黑素受体的表达。该项目不仅有助于进一步揭示Hp介导的机体免疫应答及调节作用，同时也为包括胃炎以及胃癌在内的Hp感染性胃疾病的预防和治疗寻找新的思路，为神经内分泌免疫网络与肿瘤发生发展的关系提供理论依椐。