Immunotoxicity of poly (lactic-co-glycolic acid) nanoparticles: influence of surface properties on dendritic cell activation

Abstract

Modified nanoparticles (NPs) can interact with the immune system by causing its activation to fight tumors or for vaccination. During this activation, dendritic cells (DCs) are effective in generating robust immune response. However, the effect of nanomaterials on dendritic cell (DC) maturation, and the associated adjuvant effect, should be assessed as a novel biocompatibility criteria for biomaterials since immune consequences may constitute potential complications in nanomedicine. Among emerging biomaterials, poly(lactic-co-glycolic acid) NPs (PLGA NPs) are widely explored for various applications in which the degree of desired adjuvant effect may vary. As contradictory results are reported regarding their effects on DCs, we aimed at clarifying this point with particular emphasis on the relative impact of particle surface properties. To that end, NP uptake and effects on the viability, phenotype, and secretory activity of DC primary cultures. Intracellular signaling pathways were explored and evaluated. Immature human and murine DCs were exposed to cationic, neutral, or anionic PLGA NPs. Particle uptake was assessed by both confocal microscopy and flow cytometry. Cell viability was then evaluated prior to the study of maturation by examination of both surface marker expression and cytokine release. Our results demonstrate that PLGA NPs are rapidly engulfed by DCs and do not exert cytotoxic effects. However, upon exposure to PLGA NPs, DCs showed phenotypes and cytokine secretion profiles consistent with maturation which resulted, at least in part, from the transient intracellular activation of mitogen-activated protein kinases (MAPKs). Interestingly, NP-specific stimulation patterns were observed since NP surface properties had a sensible influence on the various parameters measured.     

Developmental immunotoxicity in male rats after juvenile exposure to di-n-octyltin dichloride (DOTC)

To determine relevant endpoints for evaluating developmental immunotoxicity due to juvenile exposure and optimal age of the animals at assessment, a wide range of immunological parameters were assessed in a juvenile toxicity study. Rats were exposed to di-n-octyltin dichloride (DOTC) by gavage from postnatal day (PND) 10 through PND 21 and via the diet after weaning using a benchmark dose (BMD) approach. Immune assessments were performed in male rats on PNDs 21, 42, and 70 and a subset of animals was used to evaluate the T-cell dependent antibody response (TDAR) to Keyhole limpet hemocyanin. Immune effects were more pronounced on PND 21 and 42 and observed at lower doses than developmental effects. The most sensitive immune parameters affected included TDAR parameters and thymocyte subpopulations with lower confidence limits of the benchmark doses (BMDLs) below the overall no-observed-adverse-effect-level (NOAEL) for DOTC reported so far in literature. These findings illustrate the relative sensitivity of the developing immune system for DOTC, the additional value of assessing functional immune parameters, and underscore the relevance of juvenile immunotoxicity testing in view of the risk assessment of chemicals.     

T细胞依赖性抗体反应检测方法研究进展

T细胞依赖性抗体反应(TDAR)是检测免疫功能的主要试验技术。根据使用抗原及抗原特异性抗体检测方法的不同,TDAR方法包括绵羊红细胞(SRBC)作为抗原的空斑形成细胞(PFC)方法、SRBC作为抗原的ELISA方法和钥孔戚血蓝素(KLH)作为抗原的ELISA方法。KLH作为抗原比SRBC稳定、易标准化且容易获得,ELISA检测方法操作简便、样本可保存,便于整合到临床前毒理学研究中。本文综述了TDAR检测方法对免疫毒性的预测作用及其研究进展。     

Allergy and Sensitization during Childhood Associated with Prenatal and Lactational Exposure to Marine Pollutants

Background

Breast-feeding may affect the risk of developing allergy during childhood and may also cause exposure to immunotoxicants, such as polychlorinated biphenyls (PCBs), which are of concern as marine pollutants in the Faroe Islands and the Arctic region.

Objectives

The objective was to assess whether sensitization and development of allergic disease is associated with duration of breast-feeding and prenatal or postnatal exposures to PCBs and methylmercury.

Methods

A cohort of 656 singleton births was formed in the Faroe Islands during 1999–2001. Duration of breast-feeding and history of asthma and atopic dermatitis were recorded at clinical examinations at 5 and 7 years of age. PCB and mercury concentrations were determined in blood samples obtained at parturition and at follow-up. Serum from 464 children (71%) at 7 years of age was analyzed for total immunoglobulin E (IgE) and grass-specific IgE.

Results

The total IgE concentration in serum at 7 years of age was positively associated both with the concomitant serum PCB concentration and with the duration of breast-feeding. However, the effect only of the latter was substantially attenuated in a multivariate analysis. A raised grass-specific IgE concentration compatible with sensitization was positively associated with the duration of breast-feeding and inversely associated with prenatal methylmercury exposure. However, a history of asthma or atopic dermatitis was not associated with the duration of breast-feeding, although children with atopic dermatitis had lower prenatal PCB exposures than did nonallergic children.

Conclusions

These findings suggest that developmental exposure to immunotoxicants may both increase and decrease the risk of allergic disease and that associations between breast-feeding and subsequent allergic disease in children may, at least in part, reflect lactational exposure to immunotoxic food contaminants.     

Inhibition of cytochrome P-450 with 2-diethylaminoethyl-2,2-diphenylpropylacetate (SKF-525A) reduces immunotoxicity of chlorinated carbohydrates

Experiments on outbred albino rats showed that single intraperitoneal injection of cytochrome P-450 inhibitor 2-diethylaminoethyl-2,2-diphenylpropylacetate (SKF-525A) in a dose of 50 mg/kg before acute poisoning with 1,2-dichloroethane and trichloroethane in a dose of 1.0 LD₅₀, metabolized in the body to compounds with higher toxicity (the phenomenon of “lethal synthesis”) reduced their immunotoxicity by decreasing the formation of their biotransformation products. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 9, pp. 294–296, September, 2006     

Serum Concentrations of Antibodies Against Vaccine Toxoids in Children Exposed Perinatally to Immunotoxicants

Background

Polychlorinated biphenyls (PCBs) may cause immunotoxic effects, but the detailed dose–response relationship and possible vulnerable time windows of exposure are uncertain. In this study we applied serum concentrations of specific antibodies against childhood vaccines as sentinels of immunotoxicity.

Objectives

The main objective was to assess the possible dependence of antibody concentrations against diphtheria and tetanus toxoids in children with regard to prenatal and postnatal PCB exposures.

Methods

From a cohort of 656 singleton births formed in the Faroe Islands during 1999–2001, children were invited for examination with assessment of serum antibody concentrations at 5 years (before and after a booster vaccination) and at 7 years of age. Total PCB concentrations were determined in serum from ages 5 and 7 years, and data were also available on PCB concentrations in maternal pregnancy serum, maternal milk, and, for a subgroup, the child’s serum at 18 months of age.

Results

A total of 587 children participated in the examinations at ages 5 and/or 7 years. At age 5 years, before the booster vaccination, the antidiphtheria antibody concentration was inversely associated with PCB concentrations in milk and 18-month serum. Results obtained 2 years later showed an inverse association of concentrations of antibodies against both toxoids with PCB concentrations at 18 months of age. The strongest associations suggested a decrease in the antibody concentration by about 20% for each doubling in PCB exposure. At age 5 years, the odds of an antidiphtheria antibody concentration below a clinically protective level of 0.1 IU/L increased by about 30% for a doubling in PCB in milk and 18-month serum.

Conclusions

Developmental PCB exposure is associated with immunotoxic effects on serum concentrations of specific antibodies against diphtheria and tetanus vaccinations. The immune system development during the first years of life appears to be particularly vulnerable to this exposure.     

纳米TiO2对子代大鼠免疫系统的毒性研究

目的：研究纳米二氧化钛（nano-TiO₂）对子代大鼠免疫系统的毒性。方法：实验分为nano-TiO₂组和对照组,每组45只SD大鼠（雌鼠30只、雄鼠15只）。染毒组每天给予250 mg/kg的nano-TiO₂混悬液,对照组每天灌胃给予等体积生理盐水,灌胃2周后进行交配,各组雌鼠在交配期、妊娠期、哺乳期继续灌胃染毒。F1代子鼠从离乳到处死持续灌胃染毒。在子鼠出生后第56天进行免疫毒性评价,指标包括免疫器官（肝、脾和胸腺）脏器系数、脾和潘氏淋巴结淋巴细胞分型、脾抗体生成细胞检测。结果：与对照组比较,nano-TiO₂组F1代雌鼠脾脏系数升高,而雄鼠肝脏系数降低,差异均有统计学意义（P均 < 0.05）,但病理学检查未发现异常;淋巴细胞分型和抗体生成细胞试验结果的差异均无统计学意义（P均 > 0.05）。结论：在本试验条件下,Nano-TiO₂对F1代子鼠免疫系统功能未见明显不良影响。     

铅镉砷混合毒物对机体免疫功能的影响

目的　探讨金属毒物对机体免疫损伤的敏感指标。方法　选择 2 8名重金属中毒的矿工作为毒物组 ,另选择 2 8名同期住院患者作为对照组 ,分别检测患者血、尿铅、镉、砷含量 ,及血免疫球蛋白含量。结果　毒物组血、尿铅、镉、砷含量较对照组显著升高 (P <0 .0 1 )。与对照组比较 ,IgG下降了 1 .1 6倍 ,IgM下降了 0 .51倍 ,而IgA升高了 0 .2 9倍 ,差异有统计学意义 (P <0 .0 1 )。 结论　检测患者血液中免疫球蛋白含量可能作为铅镉砷混合物中毒的灵敏的早期诊断指标     

亚硒酸钠染毒对小鼠免疫功能的影响

[目的]观察实验性硒染毒对小鼠免疫功能的影响,为进一步揭示硒免疫损伤过程和机制提供科学依据。[方法]取昆明种健康成年小鼠72只,分为阴性对照组和亚硒酸钠0.28mg/kg(1/100LD50)、1.40mg/kg(1/20LD50)2个剂量组,每组雌雄各半,腹腔注射染毒,每周一次,共56d,分别于染毒后第7、28、56d采用断头断尾取血法采血,测定α-醋酸萘脂酶(acidα-naphthylacetateesterase,α-ANAE)阳性率、淋巴细胞转化率、脾胸腺系数、半数血清溶血素(hemolysin,HC50)数值。[结果]0.28、1.40mg/kg剂量组,α-ANAE阳性率、淋巴细胞转化率、脾脏系数和胸腺系数、半数血清溶血素值均有降低,呈免疫抑制现象,且与硒离子剂量及作用时间均具有相关性。[结论]染毒剂量亚硒酸钠对小鼠具有免疫毒性作用,且呈明显剂量-效应关系。     

The effects of chronic carbamazepine treatment on haem biosynthesis in man and rat

Summary Recently, there has been a variety of reports of adverse drug reactions during therapy with the flavonoid Cianidanol (Ci), a cytoprotective radical scavenger, especially involving haemolytic anaemia and drug fever.To elucidate whether the fever was due to a direct, antigen-independent interaction of Ci with immune competent cells, its effect on macrophage (M) function and early biochemical events during lymphocyte activation has been examined.A direct interaction of Ci with M was demonstrated, resulting in increased secretion of interleukin-1 (IL-1). The influence of Ci on lymphocyte activation was assessed by measuring levels of cyclic AMP and GMP. At high concentrations of Ci, cAMP levels were increased, and at low Ci concentrations cGMP levels were elevated. Both findings are correlated with lymphocyte proliferation and function, which is increased at low and decreased at high concentrations of Ci. The synthesis of prostaglandin E₂ by M, an important factor in M-mediated suppression, was reduced by increasing doses of Ci, which inhibited M-cyclooxygenase. Ci did not affect phospholipase A₂ activity.These findings indicate that flavonoid-induced fever may be due to allergic as well as pseudo-allergic mechanisms, the latter probably caused by increased antigen-independent release of IL-1, the endogeneous mediator of fever.