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Vanadium pentoxide increased PTEN and decreased SHP1 expression in NK-92MI cells, affecting PI3K-AKT-mTOR and Ras-MAPK pathways. 五氧化二钒增加NK-92MI细胞PTEN表达,降低SHP1表达,影响PI3K-AKT-mTOR和Ras-MAPK通路。
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2018-12-01 DOI: 10.1080/1547691X.2017.1404662
Francisco Gallardo-Vera, Miguel Tapia-Rodriguez, Daniel Diaz, Teresa Fortoul van der Goes, Luis F Montaño, Erika P Rendón-Huerta

Vanadium is an air pollutant that imparts immunosuppressive effects on NK cell immune responses, in part, by dysregulating interleukin (IL)-2/IL-2R-mediated JAK signaling pathways and inducing apoptosis. The aim of the present study was to evaluate effects of vanadium pentoxide (V2O5) on other IL-2 receptor-mediated signaling pathways, i.e. PI3K-AKT-mTOR and Ras-MAPK. Here, IL-2-independent NK-92MI cells were exposed to different V2O5 doses for 24 h periods. Expression of PI3K, Akt, mTOR, ERK1/2, MEK1, PTEN, SHP1, BAD and phosphorylated forms, as well as caspases-3, -8, -9, BAX and BAK in/on the cells were then determined by flow cytometry. The results show that V2O5 was cytotoxic to NK cells in a dose-related manner. Exposure increased BAD and pBAD expression and decreased that of BAK and BAX, but cell death was not related to caspase activation. At 400 µM V2O5, expression of PI3K-p85 regulatory subunit increased 20% and pPI3K 50%, while that of the non-pPI3K 110α catalytic subunit decreased by 20%. At 200 μM, V2O5 showed significant decrease in non-pAkt expression (p < 0.05); the decrease in pAkt expression was significant at 100 μM. Non-pmTOR expression displayed a significant downward trend beginning at 100 μM. Expressions of pMEK-1/2 and pERK-1/2 increased substantially at 200 μM V2O5. No differences were found with non-phosphorylated ERK-1/2. PTEN expression increased significantly at 100 μM V2O5 exposure whereas pPTEN decreased by 18% at 25 μM V2O5 concentrations, but remained unchanged thereafter. Lastly, V2O5 at all doses decreased SHP1 expression and increased expression of its phosphorylated form. These results indicated a toxic effect of V2O5 on NK cells that was due in part to dysregulation of signaling pathways mediated by IL-2 via increased PTEN and decreased SHP1 expression. These results can help to explain some of the known deleterious effects of this particular form of vanadium on innate immune responses.

钒是一种对NK细胞免疫应答具有免疫抑制作用的空气污染物,其部分途径是通过失调白细胞介素(IL)-2/IL- 2r介导的JAK信号通路并诱导细胞凋亡。本研究的目的是评估五氧化二钒(V2O5)对其他IL-2受体介导的信号通路,即PI3K-AKT-mTOR和Ras-MAPK的影响。在这里,il -2不依赖的NK-92MI细胞暴露于不同剂量的V2O5中24小时。流式细胞术检测细胞中PI3K、Akt、mTOR、ERK1/2、MEK1、PTEN、SHP1、BAD和磷酸化形式以及caspase -3、-8、-9、BAX和BAK的表达。结果表明,V2O5对NK细胞具有剂量相关的细胞毒性。暴露增加了BAD和pBAD的表达,降低了BAK和BAX的表达,但细胞死亡与caspase激活无关。在400µM V2O5下,PI3K-p85调控亚基的表达增加了20%,pPI3K的表达增加了50%,而非pPI3K的110α催化亚基的表达减少了20%。在200 μM时,V2O5的非pakt表达明显降低(p 2O5)。与非磷酸化的ERK-1/2无差异。在100 μM V2O5浓度下,PTEN表达量显著增加,而在25 μM V2O5浓度下,PTEN表达量下降18%,此后保持不变。最后,所有剂量的V2O5都降低了SHP1的表达,并增加了其磷酸化形式的表达。这些结果表明,V2O5对NK细胞的毒性作用部分是由于IL-2通过增加PTEN和降低SHP1表达介导的信号通路失调。这些结果可以帮助解释这种特殊形式的钒对先天免疫反应的一些已知有害影响。
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引用次数: 19
NF-κB signaling pathway-enhanced complement activation mediates renal injury in trichloroethylene-sensitized mice. NF-κB信号通路增强的补体激活介导三氯乙烯致敏小鼠肾损伤。
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2018-12-01 DOI: 10.1080/1547691X.2017.1420712
Min Liu, Hui Wang, Jiaxiang Zhang, Xiaodong Yang, Bodong Li, Changhao Wu, Qixing Zhu

Both NF-κB pathway and complement activation appear to be involved in kidney damage induced by trichloroethylene (TCE). However, any relationship between these two systems has not yet been established. The present study aimed to clarify the role of NF-κB in complement activation and renal injury in TCE-sensitized BALB/c mice. Mice were sensitized by an initial subcutaneous injection and repeated focal applications of TCE to dorsal skin at specified timepoints. NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) was injected (intraperitoneal) before the final two focal TCE challenges. In the experiments, mice had their blood and kidneys collected. Kidney function was evaluated via blood urea nitrogen (BUN) and creatinine (Cr) content; renal histology was examined using transmission electron microscopy (TEM). Kidney levels of phospho-p65 were assessed by Western blot and kidney mRNA levels of interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor (TNF)-α, and p65 by real-time quantitative PCR. Presence of C3 and C5b-9 membrane attack complexes in the kidneys was evaluated via immunohistochemistry. The results showed there was significant swelling, vacuolar degeneration in mitochondria, shrinkage of microvilli, disappearance of brush borders, segmental foot process fusion, and glomerular basement membrane thickening (or disrobing) in kidneys from TCE-sensitized mice. In conjunction with these changes, serum BUN and Cr levels were increased and IL-1β, IL-6, IL-17, and TNFα mRNA levels were elevated. Levels of p65 and phospho-p65 protein were also up-regulated, and there was significant C3 and C5b-9 deposition. PDTC pretreatment attenuated TCE-induced up-regulation of p65 and its phosphorylation, complement deposition, cytokine release, and renal damage. These results provide the first evidence that NF-κB pathway has an important role in TCE-induced renal damage mediated by enhanced complement activation in situ.

NF-κB通路和补体活化似乎都参与了三氯乙烯(TCE)致肾损伤。然而,这两种制度之间还没有建立任何关系。本研究旨在阐明NF-κB在tce致敏BALB/c小鼠补体活化和肾损伤中的作用。小鼠通过初始皮下注射和在指定时间点反复局部应用TCE致敏。在最后两次局灶性TCE挑战之前,注射NF-κB抑制剂吡咯烷二硫代氨基甲酸酯(PDTC)(腹腔内)。在实验中,收集了小鼠的血液和肾脏。通过血尿素氮(BUN)和肌酐(Cr)含量评价肾功能;采用透射电镜(TEM)检查肾脏组织学。Western blot检测肾组织磷酸化p65水平,real-time定量PCR检测肾组织中白细胞介素(IL)-1β、IL-6、IL-17、肿瘤坏死因子(TNF)-α和p65 mRNA水平。通过免疫组化评价肾脏中C3和C5b-9膜攻击复合物的存在。结果显示,tce致敏小鼠肾脏出现明显肿胀、线粒体空泡变性、微绒毛缩小、刷状边界消失、节段性足突融合、肾小球基底膜增厚(或脱膜)。同时,血清BUN和Cr水平升高,IL-1β、IL-6、IL-17和TNFα mRNA水平升高。p65和磷酸化p65蛋白水平也上调,C3和C5b-9显著沉积。PDTC预处理减弱了tce诱导的p65上调及其磷酸化、补体沉积、细胞因子释放和肾损伤。这些结果首次证明了NF-κB通路在tce诱导的补体原位活化增强介导的肾损伤中起重要作用。
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引用次数: 20
Methoxychlor metabolite HPTE alters viability and differentiation of embryonic thymocytes from C57BL/6 mice. 甲氧基氯代谢物HPTE改变C57BL/6小鼠胚胎胸腺细胞的活力和分化。
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2018-12-01 DOI: 10.1080/1547691X.2018.1474978
Lucie Leung-Gurung, Priscilla Escalante Cobb, Faraj Mourad, Cristina Zambrano, Zachary Muscato, Victoria Sanchez, Kanya Godde, Christine Broussard

Endocrine-disrupting chemicals (EDC) are widespread in the built and natural environments. Heightened public awareness of their potential danger has led to concern about whether EDC and their metabolites have significant negative biological effects. Studies have shown that EDC like DDT and other organochlorine pesticides, such as methoxychlor (MXC), have adverse effects on immune cells, but no studies have addressed the impact of HPTE, the primary metabolite of MXC. To elucidate the presence and significance of HPTE adverse effects, this study explored the impact of HPTE on a critical window and component of immune system development, embryonic T-cell development. Lesions at this phase of development can lead to lifelong immune dysfunction and increased incidence of immune disease, such as autoimmunity. Embry-onic thymocytes (GD 16-18) from C57BL/6 mice were subjected to an in vitro differentiation culture that mimicked early steps in thymocyte development in the presence of 0.005, 0.05, 0.5, 5, or 50 μM HPTE, or a model endocrine disruptor, DES. The results indicated that compared to the vehicle control, HPTE- and DES-induced death of thymocytes. Annexin-V staining and Caspase 8, markers of programed cell death, revealed that the loss of cells was due at least in part to induction of apoptosis. Moreover, HPTE-induced cell death not only resulted in selective loss of double positive thymocytes, but also loss of developing CD4 intermediate cells (post-double positive partially differentiated thymocyte population). Phenotypic analysis of thymocyte maturation (T-cell receptor, TCR) and TCR ligation (CD5) surface markers revealed that surviving embryonic thymocytes expressed low levels of both. Taken together these data demonstrate that immature embryonic thymocytes are sensitive to HPTE exposure and that HPTE exposure targets thymocyte populations undergoing critical differentiation steps. These findings suggest HPTE may play a pivotal role in MXC exposure-induced immune dysfunction.

内分泌干扰物(EDC)广泛存在于人造环境和自然环境中。公众对其潜在危险的认识日益提高,人们开始关注EDC及其代谢物是否具有显著的负面生物学效应。研究表明,EDC与滴滴涕和其他有机氯农药,如甲氧基氯(MXC)一样,对免疫细胞有不利影响,但没有研究涉及MXC的主要代谢物HPTE的影响。为了阐明HPTE不良反应的存在及其意义,本研究探讨了HPTE对免疫系统发育的一个关键窗口和组成部分——胚胎t细胞发育的影响。这一发育阶段的病变可导致终身免疫功能障碍,并增加自身免疫等免疫疾病的发病率。将C57BL/6小鼠胚胎胸腺细胞(GD 16-18)分别在0.005、0.05、0.5、5或50 μM HPTE或模型内分泌干扰物DES的作用下进行体外分化培养,模拟胸腺细胞发育的早期阶段。结果表明,与对照相比,HPTE和DES诱导胸腺细胞死亡。Annexin-V染色和程序性细胞死亡标志物Caspase 8显示,细胞的损失至少部分是由于诱导凋亡。此外,hpte诱导的细胞死亡不仅导致双阳性胸腺细胞的选择性丢失,还导致正在发育的CD4中间细胞(双阳性后部分分化胸腺细胞群)的丢失。胸腺细胞成熟(t细胞受体,TCR)和TCR连接(CD5)表面标记的表型分析显示,存活的胚胎胸腺细胞表达低水平的这两种标记。综上所述,这些数据表明,未成熟的胚胎胸腺细胞对HPTE暴露敏感,HPTE暴露的目标胸腺细胞群处于关键的分化步骤。这些发现表明HPTE可能在MXC暴露诱导的免疫功能障碍中起关键作用。
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引用次数: 6
Obituary 讣闻
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2018-01-01 DOI: 10.1080/1547691X.2017.1419443
M. Luster
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引用次数: 0
Obituary 讣告
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2018-01-01 DOI: 10.1080/1547691X.2017.1419429
G. Gerberick
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引用次数: 0
Expression of aryl hydrocarbon receptor, inflammatory cytokines, and incidence of rheumatoid arthritis in Vietnamese dioxin-exposed people. 越南二恶英暴露人群芳烃受体、炎症细胞因子的表达和类风湿关节炎的发病率
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2017-12-01 DOI: 10.1080/1547691X.2017.1377323
Chi Hung Nguyen, Taisuke Nakahama, Truong Tien Dang, Hoang Ha Chu, Luong Van Hoang, Tadamitsu Kishimoto, Nam Trung Nguyen

Many Vietnamese citizens have been and continue to be inadvertently exposed to dioxins and dioxin-like compounds deposited in the country during the Vietnam War. Dioxins may be involved in the pathogenesis of inflammatory diseases in part via by affecting expression of aryl hydrocarbon receptor (Ahr) and inflammatory cytokines in animal models. As the role of the Ahr in dioxin-exposed people is not well defined, a study was conducted to examine gene expression levels of Ahr, inflammatory cytokines, and the incidence of diseases in dioxin-exposed citizens who had/still resided near a heavily dioxin-contaminated area in Vietnam. Whole blood from citizens at/around Da Nang airbase and control individuals living in unsprayed areas was collected. Serum levels of dioxins were analyzed by using a dioxins-responsive chemical-activated luciferase gene expression bioassay. Gene expression of Ahr, interleukin (IL)-1β, TNFα, IL-6, and IL-22 in whole blood was examined by quantitative real-time PCR. The results showed levels of dioxins and expression of Ahr, IL-1β, TNFα, and IL-6 were up-regulated while IL-22 expression was down-regulated in dioxin-exposed people. Various disease incidences in the study subjects was also examined. Interestingly, the incidence of rheumatoid arthritis (RA) in these individuals was increased compared to the estimated prevalence of this disease in the general Vietnamese population. Analyses also showed that expression levels of Ahr correlated to those of IL-6 and IL-22 in the dioxin-exposed people. Taken together, dioxins might be involved in an up-regulated expression of Ahr that might possibly relate to changes in level of inflammatory cytokines and, ultimately, in the incidence of select diseases in residents of Vietnam who had/continue to live near a dioxins-contaminated site.

越南战争期间,许多越南公民已经并将继续无意中接触到二恶英和类二恶英化合物。在动物模型中,二恶英可能通过影响芳烃受体(Ahr)和炎性细胞因子的表达而参与炎症性疾病的发生。由于Ahr在二恶英暴露人群中的作用尚未明确,因此进行了一项研究,以检查在越南二恶英严重污染地区附近居住的二恶英暴露公民中Ahr、炎症细胞因子的基因表达水平和疾病发病率。收集了岘港空军基地及其周围居民和居住在未喷洒地区的对照个体的全血。采用二恶英反应性化学激活荧光素酶基因表达生物测定法分析血清二恶英水平。采用实时荧光定量PCR检测全血Ahr、白细胞介素(IL)-1β、TNFα、IL-6、IL-22的基因表达。结果显示,二恶英暴露人群的二恶英水平及Ahr、IL-1β、TNFα和IL-6表达上调,IL-22表达下调。研究对象的各种疾病发病率也进行了检查。有趣的是,与越南一般人群中类风湿关节炎(RA)的估计患病率相比,这些个体的发病率有所增加。分析还表明,暴露于二恶英的人群中,Ahr的表达水平与IL-6和IL-22的表达水平相关。综上所述,二恶英可能参与了Ahr的上调表达,这可能与炎症细胞因子水平的变化有关,并最终与曾经或继续居住在二恶英污染地点附近的越南居民中某些疾病的发病率有关。
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引用次数: 8
Transferon™, a peptide mixture with immunomodulatory properties is not immunogenic when administered with various adjuvants. Transferon™是一种具有免疫调节特性的多肽混合物,当与各种佐剂一起使用时,不会产生免疫原性。
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2017-12-01 DOI: 10.1080/1547691X.2017.1346009
Sandra Avila, Leslie Muñoz-García, Said Vázquez-Leyva, Nohemí Salinas-Jazmín, Emilio Medina-Rivero, Lenin Pavón, Gabriela Mellado-Sánchez, Rommel Chacón-Salinas, Sergio Estrada-Parra, Luis Vallejo-Castillo, Sonia Mayra Pérez-Tapia

Transferon, a human dialyzable leukocyte extract (hDLE), is a biotherapeutic that comprises a complex mixture of low-molecular-weight peptides (< 10 kDa) and is used to treat diseases with an inflammatory component. Some biotherapeutics, including those composed of peptides, can induce anti-drug antibodies (ADA) that block or diminish their therapeutic effect. Nevertheless, few studies have evaluated peptide-derived drug immunogenicity. In this study, the immunogenicity of Transferon was examined in a murine model during an immunization scheme using the following adjuvants: Al(OH)3, incomplete Freund's adjuvant (IFA), or Titermax Gold. The inoculation scheme entailed three routes of administration (intraperitoneal, Day 1; subcutaneous, Day 7; and intramuscular, Day 14) using 200 μg Transferon/inoculation. Serum samples were collected on Day 21. Total IgG levels were quantitated by affinity chromatography, and specific antibodies against components of Transferon were analyzed by dot-blot and ELISA. Ovalbumin (OVA, 44 kDa) and peptides from hydrolyzed collagen (PFHC, < 17 kDa) were used as positive and negative controls, respectively, in the same inoculation scheme and analyses for Transferon. OVA, PFHC, and Transferon increased total IgG concentrations in mice. However, only IgG antibodies against OVA were detected. Based on the results, it is concluded that Transferon does not induce generation of specific antibodies against its components in this model, regardless of adjuvant and route of administration. These results support the safety of Transferon by confirming its inability to induce ADA in this animal model.

Transferon是一种人类可透析白细胞提取物(hDLE),是一种生物治疗药物,由低分子量肽(3)、不完全弗氏佐剂(IFA)或Titermax Gold的复杂混合物组成。接种方案包括三种给药途径(腹腔注射,第1天;皮下注射,第7天;肌注,第14天),200 μg Transferon/接种。第21天采集血清样本。亲和层析法测定总IgG水平,点印迹法和酶联免疫吸附法测定Transferon组分的特异性抗体。卵清蛋白(OVA, 44 kDa)和水解胶原蛋白肽(PFHC,
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引用次数: 3
Effect of nicotine on placental ischemia-induced complement activation and hypertension in the rat. 尼古丁对大鼠胎盘缺血补体活化及高血压的影响。
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2017-12-01 DOI: 10.1080/1547691X.2017.1394934
Connor F Laule, Cameron R Wing, Evan J Odean, Jacob A Wilcox, Jeffrey S Gilbert, Jean F Regal

Preeclampsia is a pregnancy-specific condition manifested by new-onset maternal hypertension with systemic inflammation, including increased innate immune system complement activation. While exact pathophysiology is unknown, evidence suggests that inadequate spiral artery invasion and resulting utero-placental insufficiency is the initiating event. Cigarette smoking during pregnancy decreases the risk of preeclampsia. Nicotine, a major component of cigarettes, stimulates the efferent cholinergic anti-inflammatory pathway through peripherally expressed nicotinic acetylcholine receptors (nAChR) and is known to attenuate ischemia-reperfusion injury in kidney and liver. Prior studies indicated that complement activation was critical for placental ischemia-induced hypertension in a rat model. Thus, it was hypothesized here that nicotine was responsible for the protective effect of cigarette smoking in preeclampsia and would attenuate placental ischemia-induced systemic complement activation and hypertension. The Reduced Utero-placental Perfusion Pressure (RUPP) model in the pregnant rat was employed to induce placental ischemia, resulting in complement activation, fetal resorptions, and hypertension. On gestation day (GD)14, nicotine (1 mg/kg) or saline was administered via subcutaneous injection prior to RUPP surgery and daily through GD18. On GD19, placental ischemia significantly increased mean arterial pressure (MAP) in saline injected animals. However, the placental ischemia-induced increase in blood pressure was not evident in nicotine-treated animals and nicotine treatment significantly increased MAP variability. Circulating C3a was measured as an indicator of complement activation and increased C3a in RUPP compared to Sham persisted with nicotine treatment, as did fetal resorptions. These data suggested to us that nicotine may contribute to the decreased risk of preeclampsia with cigarette smoking, but this protective effect was confounded by additional effects of nicotine on the cardiovascular system.

子痫前期是一种妊娠特异性疾病,表现为新发孕妇高血压伴全身性炎症,包括先天免疫系统补体激活增加。虽然确切的病理生理尚不清楚,但有证据表明,螺旋动脉侵袭不足和导致子宫胎盘功能不全是起始事件。怀孕期间吸烟可以降低先兆子痫的风险。尼古丁是香烟的主要成分,通过外周表达的尼古丁乙酰胆碱受体(nAChR)刺激输出胆碱能抗炎通路,已知可减轻肾和肝脏的缺血再灌注损伤。先前的研究表明,补体激活对大鼠胎盘缺血诱导的高血压模型至关重要。因此,我们假设尼古丁对吸烟对子痫前期的保护作用负责,并会减弱胎盘缺血引起的全身补体激活和高血压。采用妊娠大鼠子宫-胎盘灌注压降低(RUPP)模型诱导胎盘缺血,导致补体活化、胎儿再吸收和高血压。妊娠第14天(GD),在RUPP手术前皮下注射尼古丁(1 mg/kg)或生理盐水,直至妊娠第18天。在GD19时,胎盘缺血显著增加生理盐水注射动物的平均动脉压(MAP)。然而,在尼古丁治疗的动物中,胎盘缺血引起的血压升高并不明显,尼古丁治疗显著增加了MAP变异性。测量循环C3a作为补体激活的指标,与尼古丁治疗持续的Sham相比,RUPP中C3a的增加,胎儿吸收也是如此。这些数据向我们表明,尼古丁可能有助于降低吸烟的子痫前期风险,但这种保护作用与尼古丁对心血管系统的额外影响相混淆。
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引用次数: 12
Effects of immunization and checkpoint inhibition on amodiaquine-induced liver injury. 免疫和检查点抑制对阿莫地喹所致肝损伤的影响。
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2017-12-01 DOI: 10.1080/1547691X.2017.1290716
Alastair Mak, Alexander Johnston, Jack Uetrecht

If idiosyncratic drug-induced liver injury (IDILI) is immune-mediated, it is possible that an individual's prior exposure to antigens may affect their susceptibility to IDILI. An individual's repertoire of memory immune cells is shaped by every past exposure to antigens. Subsequent drug-induced adverse drug reactions may therefore involve an immune cell's cross reactivity between a prior antigen and resulting drug-modified proteins. Therefore in this experiment, mice were immunized with amodiaquine (AQ)-modified hepatic proteins to mimic a previous exposure; treated with a RIBI adjuvant and anti-CD40 antibodies to stimulate an immune response; and, treated with anti-PD1 and anti-CTLA-4 antibodies prior to AQ treatment in order to overcome immune tolerance. This treatment led to greater liver injury than treatment with AQ alone. However, the mice did not develop serious liver injury. PD1-/- mice were then immunized and treated with AQ and anti-CTLA-4 antibodies so that immune tolerance would be impaired, both during immunization and also during AQ treatment. However, even this did not result in liver failure, and the liver injury was not significantly increased relative to un-immunized PD1-/- mice treated with anti-CTLA-4 and AQ. From these results we conclude that, although previous antigen exposure may affect the risk of IDILI, it appears that a very strong stimulus is required, and impairing immune tolerance remains the most effective method for producing an animal model of IDILI.

如果特异性药物性肝损伤(IDILI)是免疫介导的,则个体先前暴露于抗原可能会影响其对IDILI的易感性。一个人的记忆免疫细胞库是由过去每次接触抗原形成的。因此,随后的药物引起的药物不良反应可能涉及免疫细胞在先前抗原和由此产生的药物修饰蛋白之间的交叉反应。因此,在本实验中,小鼠用阿莫地喹(AQ)修饰的肝脏蛋白免疫,以模拟先前的暴露;用RIBI佐剂和抗cd40抗体治疗以刺激免疫反应;在AQ治疗前用抗pd1和抗ctla -4抗体治疗,以克服免疫耐受。这种治疗比单独使用AQ治疗导致更大的肝损伤。然而,小鼠没有发生严重的肝损伤。然后用AQ和抗ctla -4抗体对PD1-/-小鼠进行免疫和处理,使免疫和AQ处理期间的免疫耐受均受到损害。然而,即使这样也没有导致肝功能衰竭,肝损伤也没有明显增加,相对于未免疫的PD1-/-小鼠,用抗ctla -4和AQ处理。从这些结果我们得出结论,尽管先前的抗原暴露可能会影响IDILI的风险,但似乎需要非常强的刺激,损害免疫耐受仍然是产生IDILI动物模型的最有效方法。
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引用次数: 4
Genetics and immunodysfunction underlying Behçet's disease and immunomodulant treatment approaches. behaperet病的遗传和免疫功能障碍及免疫调节治疗方法。
IF 3.3 4区 医学 Q3 TOXICOLOGY Pub Date : 2017-12-01 DOI: 10.1080/1547691X.2017.1346008
Arash Salmaninejad, Arezoo Gowhari, Seyedmojtaba Hosseini, Saeed Aslani, Meysam Yousefi, Tayyeb Bahrami, Masoume Ebrahimi, Abolfazl Nesaei, Masoud Zal

Behçet's disease (BD) is a chronic autoimmune condition primarily prevalent in populations along the Mediterranean Sea. The exact etiology of BD has not been fully explained yet, but the disease occurrence is associated with a genetic factor, human leukocyte antigen (HLA)-B51 antigen. Among the various immunodysfunctions that are found in BD, patients are increased neutrophil motility and superoxide production, as well as elevated production of tumor necrosis factor (TNF)-α and decreased production of interleukin (IL)-10. Elevated levels of inflammatory cytokines like IL-1 and IL-17 in BD have been found associated with aberrant expression of microRNA. Gene polymorphisms in BD patients have been observed in molecules involved in responses to pathogens that can ultimately modulate the host antimicrobial response. Moreover, several single nucleotide polymorphisms (SNPs) have been reported in genes encoding chemokines and adhesion molecules; many of these changes manifest as increases in vascular inflammation and vascular damage. Lastly, genetic and epigenetic changes have been suggested as involved in the pathogenesis of BD. Modifications in DNA methylation have been found in BD patient monocytes and lymphocytes, leading to adverse function of these cells. This review presents a comprehensive compilation of the literature with regard to the immunodysfunction underlying BD, as well as of the genetics, newly described clinical specifications and novel treatment strategies using immunomodulants based on the current understanding of BD.

behet病(BD)是一种慢性自身免疫性疾病,主要流行于地中海沿岸人群。BD的确切病因尚未完全解释,但疾病的发生与遗传因素人类白细胞抗原(HLA)-B51抗原有关。在BD患者中发现的各种免疫功能障碍中,中性粒细胞运动性和超氧化物的产生增加,肿瘤坏死因子(TNF)-α的产生升高,白细胞介素(IL)-10的产生减少。炎性细胞因子如IL-1和IL-17在BD中的升高与microRNA的异常表达有关。在BD患者中已经观察到参与病原体反应的分子中的基因多态性,这些分子最终可以调节宿主的抗菌反应。此外,在编码趋化因子和粘附分子的基因中已经报道了几个单核苷酸多态性(snp);许多这些变化表现为血管炎症和血管损伤的增加。最后,遗传和表观遗传改变被认为参与了双相障碍的发病机制。在双相障碍患者的单核细胞和淋巴细胞中发现DNA甲基化的改变,导致这些细胞的不良功能。本文综述了有关双相障碍的免疫功能障碍、遗传学、新描述的临床特征和基于当前对双相障碍的理解使用免疫调节剂的新治疗策略的文献。
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引用次数: 27
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Journal of Immunotoxicology
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