新型冠状病毒肺炎免疫治疗药物托珠单抗的作用机制及安全性风险分析

目的分析托珠单抗的安全性风险,为临床合理用药提供参考。方法对世界卫生组织药品不良反应监测数据库、我国药品不良反应监测数据库、国内文献数据库中的不良反应报告情况及国外药监机构风险控制措施等相关资料进行整理与分析。结果应重视托珠单抗临床使用中可能发生的肝功能异常、皮肤损害、过敏反应、胃肠道损害、感染、血液系统损害等不良反应。结论托珠单抗临床使用中,应加强对严重感染及肝功能损害等严重不良反应的安全性监测,促进药品的临床合理使用。     

胡蜂毒提取物对胶原诱导性类风湿性关节炎大鼠的作用研究

目的建立胶原诱导性类风湿关节炎(collagen-induced arthritis,CIA)大鼠模型来探讨胡蜂毒提取物对大鼠类风湿性关节炎(rheumatoid arthritis,RA)的治疗作用。方法将SD大鼠随机分为正常组、模型组、阳性对照组(注射用蜂毒冻干粉,1.25 mg·kg^-1)和胡蜂毒提取物低、中、高剂量(0.125、0.25、0.5 mg·kg^-1)组,除正常组外,其余各组采用多点注射鸡Ⅱ型胶原加完全弗氏佐剂的方法来诱导大鼠RA模型,每7 d一次,共14 d。造模结束后,各给药组于足趾皮下注射对应剂量的药物,连续给药14 d。分别于造模前、造模第14天和给药第14天测量大鼠踝关节直径和周长,并进行AI评分;观察大鼠脏器指数和踝关节组织HE染色的变化;采用酶联免疫吸附测定(ELISA)检测大鼠血清中相关炎症因子白细胞介素(IL)-1β、IL-6、肿瘤坏死因子(TNF)-α、IL-8、前列腺素(PG)E-2、环氧化酶(COX)-2和类风湿因子免疫球蛋白(Ig)G、Ig A、Ig M的含量变化;利用流式细胞术检测大鼠脾脏T细胞亚群的变化。结果与模型组比较,胡蜂毒提取物对CIΑ大鼠的关节肿胀(直径及周长)抑制效果显著(P<0.01),能明显降低其AI评分(P<0.01或P<0.05),能不同程度恢复大鼠的脏器指数(P<0.01或P<0.05),改善踝关节组织病理学结构病变,降低大鼠血清中各炎症因子和类风湿因子的表达(P<0.01或P<0.05),调节和改善T细胞亚群比例的紊乱(P<0.01或P<0.05)。结论胡蜂毒提取物对CIA大鼠具有较好的治疗作用,这与其对炎症细胞因子网络的调控和对免疫的调节有关系。     

Combined IMIG and immune Ig attenuates inflammatory colitis in mice

BackgroundUsing a combination of homologous and heterologous (mouse/human) polyclonal anti-idiotypic Igs and immune Igs in BALB/c mice we have previously reported attenuation of allergic type responses following OVA immunization. We have now investigated attenuation of an inflammatory colitis in C57BL/6 mice receiving dextran sodium sulfate (DSS) in their drinking water, using additional treatment of DSS-exposed mice with combined human Igs, commercial IVIG (given IM, hence hereafter IMIG) as a source of pooled anti-idiotype Ig, and human anti-Tet as immune Ig.MethodsAcute or chronic colitis was induced by DSS in groups of C57BL/6 mice. Mice also received weekly immunotherapy with im injections of polyclonal immune Ig, polyclonal anti-idiotype Ig, or the combined Igs, for a total of 5 injections, beginning with DSS treatment or after 2 cycles of DSS. Weight loss and mortality were monitored daily, and the extent of colitis was determined further using colonic length measurement, and by ELISA measurement of inflammatory cytokines in supernatants from colonic explant cultures.ResultsMice developed colitis in both the acute and chronic models with loss of body weight, shortened colon lengths, and increased expression of inflammatory cytokines in colonic tissue. Loss of body weight, and inflammatory cytokine production, was attenuated only in chronic colitis, and only after combined IMIG and immune Ig treatment, and not in groups receiving only IMIG or immune Ig alone.ConclusionHeterologous combinations of polyclonal IMIG and immune Ig can attenuate inflammatory colitis in mice. Given the described efficacy of this treatment for allergic desensitization, we hypothesize this methodology may have widespread clinic utility.     

婴幼儿肠道菌群的影响因素及其在肠道免疫中的作用

婴幼儿肠道菌群自定植起,随着年龄增长,需历经多次改变才能最终形成微生物稳态。本文主要介绍婴幼儿肠道菌群受分娩阶段、喂养方法、饮食结构、生活环境、疾病因素、药物使用后发生的改变,及其在肠道免疫功能形成中发挥的重要作用。     

淫羊藿治疗类风湿关节炎作用机制的网络药理学分析

目的运用网络药理学方法探讨淫羊藿治疗类风湿关节炎(RA)的作用机制。方法利用中药系统药理学技术平台(TCMSP)数据库收集淫羊藿的主要活性成分及其作用靶点;通过GeneCards、OMIM等数据库获取RA相关疾病靶点。取淫羊藿活性成分靶点与RA疾病靶点的交集基因(共同靶点),作为淫羊藿对RA作用的潜在关键靶点基因。将交集基因上传至String数据库,构建淫羊藿活性成分与RA疾病的共同靶点蛋白互作(PPI)网络,并根据其度值筛选出核心靶点。借助DAVID分析平台对共同靶点进行基因本体(GO)分析和京都基因与基因组百科全书(KEGG)通路富集分析。结果共获得淫羊藿活性成分23个,共同靶蛋白即关键靶标72个。重要活性成分包括槲皮素(Quercetin)、木犀草素(Luteolin)、山萘酚(Kaempferol)等;核心靶点包括白细胞介素6(IL-6)、血管内皮生长因子A(VEGFA)、半胱氨酸蛋白酶3(CASP3)、表皮生长因子受体(EGFR)、丝裂原活化蛋白激酶8(MAPK8)等;KEGG主要通路富集在肿瘤坏死因子(TNF)信号通路、磷脂酰肌醇3激酶/蛋白激酶B(PI3K-Akt)信号通路、促乳素(Prolactin)信号通路、甲状腺激素(Thyroid hormone)信号通路、缺氧诱导因子1(HIF-1)信号通路等。结论淫羊藿可能主要通过多成分、多靶点、多通路,从调节炎症、免疫等多方面发挥对类风湿关节炎的治疗作用。     

人参皂苷抗肝纤维化作用机制研究进展

人参皂苷是一类重要的天然产物,在自然界中分布广泛,是多种药用植物中的主要活性成分,具有多种生理活性。研究发现,人参皂苷在肿瘤疾病治疗中取得很大进展,同时在抗肝纤维化方面也有显著的作用。因此人参皂苷对肝纤维化的治疗具有重要的应用价值。对人参皂苷的抗肝纤维化作用机制进行综述,以便为今后进一步的研究提供理论依据。     

Association between PD-1/PD-L1 and T regulate cells in early recurrent miscarriage

In this study, we try to testify the relationship between the programmed cell death receptor-1 (PD-1)/programmed cell death ligand 1 (PD-L1) passway and Treg cells in maternal-fetal immune regulation through PD-1 blockade on lymphocytes of normal early pregnancy in vitro and investigation of the PD-1 and PD-L1 changes in early recurrent miscarriage patients. CD4+ CD25+ Treg cells and PD-1 (CD279) positive cell were detected in deciduas in early recurrent miscarriage patients by flow cytometry. And the normal early pregnant women were as controls. Meanwhile the mRNA level of PD-1 and molecular expression of PD-L1 in deciduas of early recurrent miscarriage patients were detected by real time RT-PCR test and Immunohistochemical staining respectively. Also through antibody blocking assay to block PD-1 on lymphocytes of normal early pregnancy in vitro further testify the relationship between PD-1/PD-L1 and Treg cells, the results were analyzed by flow cytometry. CD4+ CD25+ Treg cells decreased both in deciduas in RM (P < 0.05), and for all almost 100% Treg cells (CD4+ CD25+) expressed PD-1, but there was no difference between the PD-1 positive cells in decidual lymphocytes in RM and that in normal pregnancy women (P > 0.05). PD-L1 mRNA in deciduas decreased in RM (P < 0.001), but PD-1 mRNA no difference (P > 0.1). After PD-1 blockade there was no change in CD4+ CD25+ Treg cells percentage, while the CD4+ T cell percentage increased (P < 0.01), as well as the level of IFN-gamma in cells supernatant (P < 0.01). PD-1 blockade has a little influence on the number of Treg cells, and may lead to impaired Treg cells function, the decrease of PD-L1 may closely relates to the occurrence of early recurrent miscarriage and implies that Treg cells may through PD-1/PD-L1 pathway play a role of immunosuppression regulation, and the impairment of Treg cells function in recurrent early abortion cases may be due to PD-L1 decrease in deciduas or trophoblast cells rather than PD-1 change.     

轴突导向蛋白4D 在肿瘤进展中的作用*

轴突导向蛋白4D（SEMAPHORIN 4D,SEMA 4D）又称CD100,是轴突导向蛋白Ⅳ亚族（SEMAs Ⅳ）的重要成员之一,其最初作为影响神经发育的轴突导向分子被发现。近来越来越多的研究表明,SEMA 4D 在免疫调节、血管发生及肿瘤生长转移等方面也有重要的生物学功能,尤其作为新的促血管生成分子,SEMA 4D 的相关研究引起广泛关注。本文旨在对SEMA 4D 的结构、受体特点、促血管生成及肿瘤侵袭转移等方面的最新研究进展进行综述。      

Mesenchymal stem cells are enriched in head neck squamous cell carcinoma,correlates with tumour size and inhibit T-cell proliferation

Background:

Cancer is a multifactorial disease not only restricted to transformed epithelium, but also involving cells of the immune system and cells of mesenchymal origin, particularly mesenchymal stem cells (MSCs). Mesenchymal stem cells contribute to blood- and lymph- neoangiogenesis, generate myofibroblasts, with pro-invasive activity and may suppress anti-tumour immunity.

Methods:

In this paper, we evaluated the presence and features of MSCs isolated from human head neck squamous cell carcinoma (HNSCC).

Results:

Fresh specimens of HNSCC showed higher proportions of CD90+ cells compared with normal tissue; these cells co-expressed CD29, CD105, and CD73, but not CD31, CD45, CD133, and human epithelial antigen similarly to bone marrow-derived MSCs (BM-MSCs). Adherent stromal cells isolated from tumour shared also differentiation potential with BM-MSCs, thus we named them as tumour-MSCs. Interestingly, tumour-MSCs showed a clear immunosuppressive activity on in vitro stimulated T lymphocytes, mainly mediated by indoelamine 2,3 dioxygenase activity, like BM-MSCs. To evaluate their possible role in tumour growth in vivo, we correlated tumour-MSC proportions with neoplasm size. Tumour-MSCs frequency directly correlated with tumour volume and inversely with the frequency of tumour-infiltrating leukocytes.

Conclusions:

These data support the concept that tumour-MSCs may favour tumour growth not only through their effect on stromal development, but also by inhibiting the anti-tumour immune response.