Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents

Toll-like receptor (TLR) agonists are being developed for use as vaccine adjuvants and as stand-alone immunomodulators because of their ability to stimulate innate and adaptive immune responses. Among the most thoroughly studied TLR agonists are the lipid A molecules that target the TLR4 complex. One promising candidate, monophosphoryl lipid A, which is a derivative of lipid A from Salmonella minnesota, has proven to be safe and effective as a vaccine adjuvant in > 120,000 human doses. A new class of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates (AGPs), have been engineered specifically to target human TLR4 and are showing promise as vaccine adjuvants and as monotherapeutic agents capable of eliciting nonspecific protection against a wide range of infectious pathogens. In this review, the authors provide an update of the preclinical and clinical experiences with the TLR4 agonists, MPL (Corixa Corporation) adjuvant and the AGPs.     

Monophosphoryl lipid A is an lipopolysaccharide-derived Toll-like receptor 4 agonist which may improve Alzheimer's disease pathology

Introduction: Alzheimer's disease (AD) is partly characterized by the formation of plaques composed of β-amyloid (Aβ) as a result of excessive accumulation of Aβ. Monophosphoryl lipid A (MPL) is a Toll-like receptor 4 agonist commonly used as a nontoxic, FDA-approved adjuvant in viral vaccines.

Areas covered: Previous reports had shown MPL as an effective adjuvant for Aβ vaccinations to decrease Aβ deposition. Recently, it was discovered that MPL monotherapy in APP/PS1 transgenic AD mice had beneficial effects, such as decreasing the number and size of deposits, decreasing soluble Aβ monomers and improving cognition through phagocytic activation of microglia. Unlike the parental endotoxin lipopolysaccharide (LPS), MPL stimulated microglial phagocytosis of Aβ, while only minimally increasing a proinflammatory response.

Expert opinion: MPL is a promising therapeutic option for AD treatment due to its ability to promote Aβ clearance without eliciting a strong adverse inflammatory response. Since MPL is already FDA-approved in humans, clinical application can be accelerated. Further analysis of how MPL affects other hallmarks of AD pathology such as dystrophic neurites and hyperphosphorylated tau aggregates, as well as its mechanism of action, will facilitate the understanding of the therapeutic benefits that MPL can produce.     

Role of Toll-like receptor 4 in the initiation and progression of atherosclerotic disease

The family of Toll-like receptors (TLRs) initiates an innate immune response after recognition of pathogen-associated molecular patterns (PAMPs). Evidence is accumulating that TLRs, and particularly TLR4, are important players in the initiation and progression of atherosclerotic disease. Not only exogenous ligands but also endogenous ligands that are expressed during arterial injury are recognized by TLR4. Mouse knockout studies and epidemiological studies of human TLR4 polymorphisms have demonstrated that the TLR4 might play a role in the initiation and progression of atherosclerosis. This review will summarize the latest progression in research on the role of TLR4 in arterial occlusive disease In addition, the potential of intervention in TLR4 signalling to influence progression of atherosclerotic disease is discussed.     

IgA肾病患者外周血单个核细胞Toll样受体4的表达及血清炎症趋化因子的水平

目的研究Ig A肾病(IgAN)患者外周血单个核细胞Toll样受体4(TLR4)的表达及血清中趋化因子MCP-1和炎症因子IL-6的水平,探讨TLR4在IgAN发病中可能的作用。方法将在本科经肾组织活检确诊为IgAN的60例患者(排除继发性和遗传性IgAN)根据蛋白尿程度进行分组,分为轻度蛋白尿组(24 h尿蛋白定量≤1.0 g),中度蛋白尿组(24 h尿蛋白定量1.0~3.0 g)和重度蛋白尿组(24 h尿蛋白定量≥3.0 g)。另取年龄性别相匹配的健康志愿者20例作为健康对照组。分别使用流式细胞仪和Realtime-PCR方法检测外周血单个核细胞(PBMC)中TLR4蛋白和基因的表达,ELISA法检测血清中趋化因子MCP-1和炎症因子IL-6的水平。结果 IgAN组患者PBMC中TLR4的蛋白和基因表达水平以及血清中MCP-1和IL-6的浓度均较健康对照组显著增加(P均0.05)。PBMC中TLR4的蛋白和基因表达水平随着蛋白尿的严重程度而逐渐增高。直线相关分析提示PBMC中TLR4 mRNA的表达水平与24 h尿蛋白定量呈显著正相关(r=0.855,P0.05),而与GFR呈负相关(r=-0.735,P0.05)。MCP-1和IL-6的水平与PBMC中TLR4 mRNA的表达水平呈显著正相关(r=0.746、0.821,P0.05)。结论 IgAN患者PBMC中存在TLR4的表达水平上调,与蛋白尿程度和肾功能水平密切相关。血清中趋化因子MCP-1和炎症因子IL-6的水平也随着PBMC中TLR4的表达水平升高而升高。TLR4可能通过调节机体趋化因子和炎症因子的释放介导了Ig A肾病中的炎症损伤。     

Toll样受体4与肾纤维化的关系研究进展

肾纤维化是大多数慢性肾脏疾病进展至终末期肾病的基本病理改变,其发病过程受到多种信号通路的调节。肾纤维化过程以持续炎症为特征,包括炎性细胞浸润和细胞因子分泌。Toll样受体4(Toll-likereceptor-4,TLR4)信号分子是介导肾脏炎症及纤维化的重要桥梁,可通过核因子-κB(nuclear factor-kappa B,NF-κB)激活炎性因子大量释放而造成肾纤维化。TLR4在肾纤维化中发挥重要作用。     

类风湿性关节炎患者早期外周血单个核细胞Toll样受体2、4表达及意义

目的探讨类风湿性关节炎(RA)早期患者外周血单个核细胞(PBMC)Toll样受体(TLR)2、TLR4对其配体双糖链蛋白多糖(BGN)、脂多糖(LPS)的刺激反应性,阐明PBMC TLR2、TLR4在RA疾病早期中的作用。方法采用流式细胞术、实时荧光定量逆转录(RT)-聚合酶链反应(PCR)、酶联免疫吸附试验(ELISA)分别检测BGN和LPS刺激前后,RA组和健康对照组外周血CD14+单核细胞TLR4+细胞频率、PBMC TLR2 mRNA和TLR4mRNA及上清液白细胞介素6(IL-6)和肿瘤坏死因子α(TNFα)的含量变化。结果 RA早期患者TLR2 mRNA明显升高、TLR4 mRNA下降(P<0.01);经LPS刺激后,RA患者TLR4 mRNA升高3.50倍,而健康对照组下降到0.11倍;LPS和BGN促进了各组PBMC产生IL-6、TNFα,但RA早期患者组上升的倍数明显高于健康对照组。结论 PBMC TLR2、TLR4参与早期RA的发生、发展。     

Innate immune defenses in HIV-1 infection: prospects for a novel immune therapy

HIV-1 infection leads to a severe decrease of CD4⁺ T lymphocytes, dysregulation of several leukocyte subpopulations and generalized immune activation, with the subsequent development of opportunistic infections and malignancies. Administration of highly active antiretroviral therapy (HAART) has been successful in reducing HIV-1 plasma viremia; however, the ability of HAART to restore immunocompetence appears incomplete, particularly in patients with chronic and advanced disease. Several components of the innate immune system have direct anti-HIV-1 effects, and studies to analyze the benefits of enhancing the function of the innate response during HIV-1 infection are increasing. Development of any complementary therapeutic approaches to HIV-1 infection, particularly those able to compensate for the limitations of HAART, and enhance the anti-HIV-1 innate immune activity would be of interest. The stimulation of innate immune responses using Toll-like receptor agonists, such as monophosphoryl lipid A and oligodeoxynucleotides with CpG motifs, are currently being investigated and their benefit in HIV-1-infected patients are under evaluation.     

脓毒症患者血小板参数与Toll样受体4表达的关系及中西医结合治疗研究

目的 观察西药联合加味凉膈散对脓毒症患者血小板参数变化及活化状态与血小板Toll样受体4(TLR4)表达、炎症反应变化的影响.方法 64例脓毒症患者依据“不平衡指数最小的分配原则”随机分为西医常规治疗组(X组,32例)和西医联合加味凉隔散组(L组,32例),比较两组患者入院时及治疗3、5、9d的血小板计数(PLT)、平均血小板体积(MPV)、血小板分布宽度(PDW)、血小板TLR4阳性表达率、血小板膜糖蛋白GPⅡb/Ⅲa的半胱天冬酶原活化复合物-1(PAC-1)表位阳性表达率及血浆可溶性CD40配体(sCD40L)、肿瘤坏死因子-α(TNF-α)浓度变化,以及急性生理学与慢性健康状况评分系统Ⅱ(APACHE Ⅱ)评分、重症监护病房(ICU)住院时间、出血事件及28d病死率.以同期15例健康体检者作为对照组(C组).结果 与C组比较,脓毒症患者PLT(×109/L)显著降低(211.37±77.84比272.33±34.23,P＜0.01),MPV(fL)、PDW (fL)均显著增大(MPV:10.24土0.81比9.64±0.66;PDW:17.79±1.68比15.61±1.54,P＜0.05和P＜0.01),伴有血小板TLR4及PAC-1表达上调[TLR4:(39.93±9.07)%比(23.50±4.68)%,PAC-1:(42.21±8.74)%比(21.02±3.49)%,均P＜0.01],血浆中sCD40L (μg/L)和TNF-α(ng/L)浓度显著上升(sCD40L:6.94±1.05比3.27±0.41;TNF-α:60.10±9.77比4.08±3.08,均P＜0.01).治疗后9d,L组肝肾功能、TLR4和PAC-1表达及血浆sCD40L、TNF-α浓度较X组显著降低[肌酐(μmol/L):106.2±34.4比127.5±43.7;丙氨酸转氨酶(U/L):31.7±12.5比41.9±19.9;天冬氨酸转氨酶(U/L):54.1±21.6比68.5土24.1;TLR4:(27.14±6.08)%比(30.92±5.47)%;PAC-1:(27.52±6.51)%比(31.24±5.77)%;sCD40L:3.86±0.69比4.38土0.73; TNF-α:22.06±7.19比28.25±8.99,P＜0.05或P＜0.01],PLT(×109/L)较X组显著升高(261.93±55.32比231.37土63.58,P＜0.05).相关性分析显示:脓毒症患者血小板PAC-1表达与PLT呈负相关(r=-0.409,P＜0.01),与MPV、PDW、血小板TLR4表达、血浆sCD40L水平呈正相关(r1=0.262,r2=0.318,r3=0.341,r4=0.519,均P＜0.01);sCD40L与TNF-α呈正相关(r=0.542,P＜0.01).L组ICU住院时间(d)明显短于X组(8.06±2.86比9.31±2.48,P＜0.05),出血发生率低于X组(12.5%比21.9%,P＜0.05),9 d APACHEⅡ评分(分)显著低于X组(12.75±4.56比14.59±3.97,P＜0.05).L组与X组28 d病死率差异无统计学意义(15.63%比18.75%,P＞0.05).结论 脓毒症炎症反应常伴有血小板TLR4表达上调、血小板活化及PLT减少;西医联合加味凉膈散可通过下调血小板TLR4表达、减少血小板活化及炎症介质的释放,从而改善脓毒症患者血小板减少状态.