肝脏固有免疫系统对肠源性感染的免疫应答与免疫耐受机制

肝特殊的解剖结构及生理特征使其成为暴露肠源性抗原的主要器官。由于肝具有独特的固有免疫系统,在正常情况下,肝分布多种致耐受的抗原提呈细胞,对持续性表达或递呈于肝的肠源性抗原物质,诱发针对该抗原的系统性免疫耐受,避免肝受到不必要的免疫损伤。当炎症发生及肝脏固有免疫系统活化时,则通过免疫效应细胞及免疫效应因子对肠源性病原体发挥强烈地免疫应答以控制感染。该过程形成机制的研究对肝功能的理解及肝性疾病的预防与治疗至关重要。本文就肝固有免疫系统对肠源性感染的免疫应答与免疫耐受形成机制作一综述。     

细胞自噬在病毒感染与免疫调节中的作用机制

细胞自噬(autophagy)是一种主要由溶酶体介导的降解通路,作为细胞维持内环境稳态的一种保护性机制,不仅通过将长寿命蛋白和衰老细胞器降解为小肽或氨基酸为细胞提供再生资源,而且也可作为防御机制抵抗病原微生物感染和寄生. 自噬缺失与许多疾病如癌症、心血管疾病等的发生关系密切,在机体生理、病理过程中发挥重要作用. 本文拟就细胞自噬与病毒感染、机体免疫的关系加以综述,以期为研究细胞自噬的发生、参与机体免疫、发挥抗病毒感染作用及其分子机制提供参考,也为进一步研究抗病毒治疗的靶标提供新思路.     

外泌体在肿瘤免疫逃逸和耐受中的作用

肿瘤细胞能够通过多种机制抵御免疫防御或药物的抗肿瘤作用.近年研究发现,外泌体能够直接介导癌症的进展和远端转移灶的形成.更为重要的是,在肿瘤免疫微环境中,肿瘤来源外泌体不仅能够抑制树突状细胞(DC)、巨噬细胞、T细胞、NK细胞等免疫细胞功能,还能促进骨髓来源的抑制性细胞(MDSC)、调节性T细胞(Treg)等的免疫抑制功能,进而降低抗肿瘤免疫应答过程,帮助肿瘤细胞逃避机体免疫细胞识别.本文将概述肿瘤外泌体及其携带的关键介质分子在介导肿瘤免疫逃逸和耐受过程中扮演的角色,并对这一研究领域的最新进展作一综述.     

Immune implication of an autophagy-related prognostic signature in uveal melanoma

Uveal Melanoma (UM) is a rare cancer deriving from melanocytes within the uvea. It has a high rate of metastasis, especially to the liver, and a poor prognosis thereafter. Autophagy, an intracellular programmed digestive process, has been associated with the development and progression of cancers, with controversial pro- and anti-tumour roles. Although previous studies have been conducted on autophagy-related genes (ARGs) in various cancer types, its role in UM requires a deeper understanding for improved diagnosis and development of novel therapeutics. In the present study, Zheng et al. used univariate Cox regression followed by least absolute shrinkage and selection operator (Lasso) regression to identify a robust 9-ARG signature prognostic of survival in a total of 230 patients with UM. The authors used the Cancer Genome Atlas (TCGA) UM cohort as a training cohort (n=80) to identify the signature and validated it in another four independent cohorts of 150 UM patients from the Gene Expression Omnibus (GEO) repository ({"type":"entrez-geo","attrs":{"text":"GSE22138","term_id":"22138"}}GSE22138, {"type":"entrez-geo","attrs":{"text":"GSE27831","term_id":"27831"}}GSE27831, {"type":"entrez-geo","attrs":{"text":"GSE44295","term_id":"44295"}}GSE44295 and {"type":"entrez-geo","attrs":{"text":"GSE84976","term_id":"84976"}}GSE84976). This 9-ARG signature was also significantly associated with the enrichment of cancer hallmarks, including angiogenesis, IL6-KJAK-STAT3 signalling, reactive oxygen species pathway and oxidative phosphorylation. More importantly, this signature is associated with immune-related functional pathways and immune cell infiltration. Thus, this 9-ARG signature predicts prognosis and provides deeper insights into the immune mechanisms in UM, with potential implications for future immunotherapy.     

免疫系统防御强，遇到缺氧HIF帮

缺氧诱导因子（hypoxia-inducible factor,HIF）是一类受氧调控的转录因子。其α亚基是氧敏感性亚基,包括HIF-1α、HIF-2α和HIF-3α,与β亚基形成异源二聚体,活化目标基因的表达以调节细胞对低氧的反应。HIF本身受到精细调节,包括转录组水平的调节,以及通过蛋白质翻译后修饰所进行的蛋白质水平的调节,以确保细胞对低氧压力产生适当反应。免疫应答常伴随局部组织的低氧状况,HIF是低氧环境中先天免疫和适应性免疫应答的重要调节因子。在天然免疫系统,HIF激活一系列与代谢相关的基因表达,调节中性粒细胞、巨噬细胞和树突状细胞的发育、极化和功能。对于适应性免疫,近年来的研究确立了HIF在CD4⁺T细胞分化和功能中的重要作用。本综述将重点讨论近年来有关HIF调节机制,及其在免疫细胞功能研究的进展。     

石香薷挥发油抑菌和免疫应答作用

对石香薷挥发油(简称香薷油)的抑菌和对机体免疫功能影响进行了初步的研究。结果表明:香薷油具有广谱的抑菌作用,能增强机体特异性和非特异性免疫应答,提高机体的防御机制。     

酵母多糖对中华条颈龟非特异性免疫机能的影响

本研究旨在探讨饲料中添加不同水平的酵母多糖对中华条颈龟(Mauremys sinensis)非特异性免疫机能的影响。选取体重为134.7±19.1 g的中华条颈龟,随机分成Ⅰ、Ⅱ、Ⅲ、Ⅳ四个组,各组饲料中酵母多糖的添加量分别为每千克龟重0 mg、800 mg、1200 mg和1600mg,并在第15d、30d检测各组免疫器官指数、白细胞数目、血清中溶菌酶及补体C3、C4活性等免疫指标。结果表明,各实验组脾脏指数和肝脏指数与对照组之间差异均不显著(p>0.05);各实验组白细胞数目相比对照组显著增多(p<0.05);在第15d血清中溶菌酶和C3、C4活性均显著高于对照组(p <0.05),在添加量为1200 mg/kg时活性最高,在第30d 各实验组溶菌酶和补体C4活性与同剂量组相比显著下降,补体C4活性与对照组差异不显著(p>0.05)。由此得出,饲料中添加酵母多糖可提升中华条颈龟的非特异性免疫机能,以1200 mg/kg添加水平的效果最佳,且投喂时间不宜过长。     

Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

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果寡糖和甘露寡糖对断奶仔猪免疫机能的影响

研究探讨了果寡糖和甘露寡糖对断奶仔猪免疫机能的影响。实验采用随机区组设计法将48头健康、体重一致的35日龄断奶杜洛克仔猪分为4组,每组3次重复,每个重复4头进行为期28天的饲养实验。4个处理组分别为:基础日粮 0.5%果寡糖(FOS组)、基础日粮 0.3%甘露寡糖(MOS组)、基础日粮 0.45%果寡糖 0.25%甘露寡糖(F M组)、基础日粮 75 mg/kg金霉素 40 mg/kg洛克沙生(ABT组)。实验结果表明:(1)寡糖组免疫器官指数较ABT组大(P>0.05)。(2)在断奶后第7天,FOS组(0.32±0.49)、MOS组(0.32±0.04)和F M组(0.32±0.07)均较ABT组(0.20±0.01)显著提高了血清免疫球蛋白A(IgA)的浓度(P<0.05),同时FOS组(3.50±0.49)较ABT组(2.68±0.47)显著提高了IgG浓度(P<0.05);F M组显著提高了断奶后第21天IgG浓度(P<0.05);MOS组显著提高了断奶后第21天IgM浓度(P<0.05)。(3)与ABT组相比,FOS显著提高了断奶后第7天胸腺(21.33±6.03对37.33±4.04)、脾脏(19.67±2.08对30.33±8.73)、淋巴结(24.67±4.16对37.67±2.52)CD4 T淋巴细胞百分数(P<0.05);FOS组(21.33±4.04对32.00±5.29)、MOS组(21.33±4.04对37.33±3.21)、F M组(21.33±4.04对32.00±3.60)显著提高了断奶后第28天胸腺CD4 T淋巴细胞百分数(P<0.05);MOS组(20.67±3.51对29.67±5.51)显著提高了断奶后第7天胸腺CD8 T淋巴细胞百分数;F M组(17.00±1.00对22.67±3.06)显著提高了断奶后第7天脾脏CD8 T淋巴细胞百分数(P<0.05);各寡糖组对断奶后第28天CD4 、CD8 T淋巴细胞百分数影响不显著(P>0.05);ABT组(34.33±5.03)在断奶后第7天较F M组(20.67±6.43)显著提高了淋巴结CD8 T淋巴细胞百分数(P<0.05);在断奶后第7天,FOS组(1.42±0.32)、MOS组(1.52±0.46)、F M组(1.51±0.30)淋巴结CD4 与CD8 比值显著(P<0.05)大于ABT组(0.71±0.03);在断奶后第28天,FOS组(1.36±0.21)和MOS组(1.34±0.16)脾脏CD4 与CD8 比值显著(P=0.01)大于ABT组(0.94±0.29),除此之外,各寡糖组CD4 与CD8 比值较寡糖组大(P>0.05),寡糖组间差异不显著。     

Immune modulation and apoptosis induction: Two sides of the antitumoral activity of imiquimod

Imiquimod, the first member of the imidazoquinoline family of immune response modifiers, has proven good clinical efficacy against basal cell carcinomas and actinic keratoses in several independent studies. In addition, there is recent evidence that imiquimod is also efficacious against other tumors such as cutaneous metastases of malignant melanoma or vascular tumors. Imiquimod exerts its antitumoral effect, at least in part, through binding to TLR-7 and TLR-8 on dendritic cells followed by secretion of a multitude of proinflammatory cytokines. The net result of this proinflammatory activity is a profound tumor-directed cellular immune response. However, recent experimental and clinical data indicate that imiquimod also possesses considerable direct pro-apoptotic activity against tumor cells both in vitro and in vivo. This novel mode of action appears to be independent of membrane bound death receptors, but involves caspase activation. Induction of apoptosis by imiquimod is, at least in part, presumably mediated through Bcl-2-dependent release of mitochondrial cytochrome c and subsequent activation of caspase-9. The structural analogue, resiquimod, exhibited very limited, if any, such pro-apoptotic activity, possibly due to its lacking ability to enter the cell. Bypassing molecular mechanisms of apoptosis deficiency by a topical compound may be of great utility for treating certain cutaneous tumors.     

Flt3配体增强HCV核心-包膜E2融合基因DNA疫苗诱导的细胞免疫应答

建立一种可高效诱导细胞免疫应答 ,对丙型肝炎病毒 (HCV)感染可能起预防和治疗作用的DNA疫苗。将小鼠Flt3配体 (FL)信号肽和胞外段cDNA插入结构优化的HCV核心 包膜E2融合抗原DNA疫苗pST CE2t,构建成pST CE2t FL。将pST CE2t FL转染COS7细胞 ,Westernblot和ELISA检测表明该重组质粒能表达HCV核心 包膜E2融合抗原和可溶性小鼠FL。分别将pST CE2t、pST CE2t FL和空载体pCI neo肌肉注射接种BALB c小鼠 ,检测小鼠的体液和细胞免疫应答。结果表明两种DNA结构均能在小鼠体内诱生细胞和体液免疫应答 ,但pST CE2t诱导的体液免疫应答强于pST CE2t FL ,而后者诱导的细胞免疫应答明显强于前者。FL能明显增强HCV核心 包膜E2融合抗原DNA疫苗诱导的细胞免疫应答 ,对于发展HCV预防和治疗性疫苗有潜在的应用价值。     

CpG ODN增强rHBsAg疫苗对小鼠免疫应答影响的研究

通过CpG寡核苷酸(CpG ODN)与重组HBsAg蛋白疫苗(rHBsAg)联合免疫C57BL/6BL/6小鼠,观察CpG ODN对小鼠免疫状况的影响。试验分对照、乙肝疫苗以及用乙肝疫苗加CpG三组,MTT法分别进行HBsAg特异性刺激淋巴细胞转化试验、HBsAg特异性刺激细胞毒性T细胞杀伤试验、自然杀伤细胞非特异性杀伤试验,以及ConA刺激淋巴细胞转化试验;ELISA测定HBsAb、INF-γ、IL-12和IL-4结果中,疫苗加CpG组抗原特异性转化试验指数为4.05±0.31;疫苗加CpG组抗原特异性CTL率为82.27±22.64,在统计学上差异显著(P<0.05);而HBsAb、INF-γ、IL-12的结果分别为51.85±14.41、802.25±104.25和373.62±66.58,与对照组及疫苗组比较,差异显著(P<0.05)。CpG ODN能作为一种新的免疫佐剂更好地增强重组乙肝表面抗原蛋白疫苗诱导小鼠产生高效的体液和细胞免疫应答。     

Immune responses of mice to influenza subunit vaccine in combination with CIA07 as an adjuvant

CIA07 is an immunostimulatory agent composed of E. coli DNA fragments and modified LPS lacking the lipid A moiety. In this study, we investigated whether CIA07 promotes immune responses as an adjuvant to the influenza subunit vaccine. Balb/c mice were immunized intramuscularly once or twice at a 4-week interval with the trivalent influenza subunit vaccine antigen alone or in combination with CIA07 as adjuvant. Antigen-specific serum antibody titers and hemagglutination-inhibition (HI) antibody titers were assessed. At 4 weeks after each immunization, the antigen-specific total serum IgG antibody titer in mice receiving CIA07 was 2 to 3 times higher than that in animals administered antigen alone (P<0.05). The CIA07-treated group additionally displayed higher HI antibody titers against each of the 3 vaccine strains, compared to the antigen group. Animals receiving antigen alone displayed barely detectable antigen-specific serum IgG2a antibody titers. In contrast, coadministration of CIA07 with antigen led to significantly enhanced IgG2a antibody responses, suggesting that CIA07 stimulates a Th1-type immune response. Moreover, the CIA07-treated group displayed a marked increase in the number of interferon gamma-producing CD8(+) T cells in splenocytes. These data collectively demonstrate that CIA07 has the ability to induce both Th1-type cellular and Th2-type humoral immune responses to the influenza subunit vaccine, and support its potential as an effective adjuvant to the influenza vaccine.     

IL-12增强HBV融合抗原DNA疫苗在小鼠诱导的细胞免疫应答

乙型肝炎病毒(hepatitis B virus,HBV)极易形成慢性感染,主要机制在于感染者不能产生强有力的细胞免疫应答以清除病毒[1].慢性HBV感染者体内虽然存在HBV抗原特异性T淋巴细胞,但对HBV抗原的反应性较低.研究发现,增强这类T淋巴细胞的反应性,可以促进HBV的清除[2].     

Pattern recognition by primary and secondary response of an Artificial Immune System

Summary In this paper we show how an Artificial Immune System can be used to study pattern recognition processes and learning. In particular we show the ability of the model to discover and maintain coverage of the diverse patterns through mechanism of evolution and mutation.     

西咪替丁对坏死性小肠结肠炎小鼠炎症免疫反应、肠道微生物的影响

摘要 目的：探讨与分析西咪替丁对坏死性小肠结肠炎（NEC）小鼠炎症免疫反应、肠道微生物的影响。方法：将建模成功的坏死性小肠结肠炎小鼠36只随机平分为三组-模型组、西咪替丁1组、西咪替丁2组,每组12只,每组每日分别灌胃生理盐水0.1mL、胃西咪替丁0.1 mL、胃西咪替丁0.2 mL,持续应用14 d,观察小鼠炎症免疫反应、肠道微生物变化情况。结果：西咪替丁1组、西咪替丁2组治疗第7 d、第14 d的体重都显著高于模型组（P<0.05）,西咪替丁2组与西咪替丁1组对比有显著提高（P<0.05）。西咪替丁1组、西咪替丁2组治疗第14 d的肠组织白介素-2含量低于模型组（P<0.05）,白介素-10含量高于模型组（P<0.05）,西咪替丁2组与西咪替丁1组对比有显著差异（P<0.05）。西咪替丁1组、西咪替丁2组治疗第14 d的粪便双歧杆菌、乳酸杆菌相对表达水平显著高于模型组（P<0.05）,大肠埃希菌相对表达水平显著低于模型组（P<0.05）,西咪替丁2组与西咪替丁1组对比有显著差异（P<0.05）。西咪替丁1组、西咪替丁2组治疗第14 d的肠组织CaMKIV、CREM蛋白相对表达水平都显著低于模型组（P<0.05）,西咪替丁2组与西咪替丁1组对比也显著降低（P<0.05）。结论：西咪替丁在坏死性小肠结肠炎小鼠的应用能调节炎症免疫反应平衡,促进小鼠体重恢复正常,还可降低肠组织CaMKIV、CREM蛋白相对表达水平,从而改善小鼠肠道微生物状况,且具有剂量依赖性。     

不同毒力疟原虫感染早期根治性治疗对再感染体液免疫应答的影响

为探讨不同毒力疟原虫感染早期根治性治疗对再感染体液免疫应答的影响,用致死型和非致死型约氏疟原虫感染DBA/2小鼠,感染后3 d进行根治性治疗,并于初次感染后90 d进行再感染。计数红细胞感染率和检测再感染前（0 d）和再感染后（1、3、5 d）不同时间点脾细胞中活化性B细胞百分率以及血清中IgG、IgG1和IgG2 a水平,结果显示,再感染后2组小鼠均出现短暂的低水平虫体血症,再感染后第3天活化性B细胞、IgG、IgG1和IgG2 a均出现有意义的升高,但在每一相同检测时间点,2组小鼠的虫体血症、活化性B细胞百分率、IgG、IgG1和IgG2 a水平均没有显著差异。这些结果表明,不同毒力疟原虫感染早期的根治性治疗并不影响宿主在再感染时产生有效的体液免疫应答,强毒株原虫感染也能获得与弱毒株相同的可抵御再感染的能力。     

The Immune Response of the Tasmanian Devil (Sarcophilus harrisii) and Devil Facial Tumour Disease

One of the most remarkable aspects of Devil Facial Tumour Disease (DFTD) is its infectious nature, and for successful transmission it must avoid detection by the devil’s immune system. For this to occur, the devil either is severely immunosuppressed or factors produced by the tumor contribute to its avoidance of immune detection. An analysis of the devil’s immune system revealed the presence of normal-looking lymphoid organs and lymphoid cells. At a functional level the lymphocytes proliferated in response to mitogen stimulation. Subcutaneous injection of a cellular antigen produced a strong antibody response, providing compelling evidence that the devil has a competent immune system. Tumor cell analysis demonstrated that the tumor expresses the genes of the major histocompatibility complex; however, there was a limited diversity. Therefore, the most likely explanation for devil-to-devil transmission of DFTD is that the tumor is not recognized by the devil as “non-self” because of the limited genetic diversity. With its consistent morphology and relatively stable genome, this tumor would provide a reasonable target for a vaccine approach, provided the immune system can be coaxed into recognizing the tumor as “non-self.”