Melatonin modulation of lymphocyte proliferation and Th1/Th2 cytokine expression.

Melatonin is hypothesized to play a role in neuroimmunomodulation. This study investigated the in vitro effects of melatonin (10(-12) - 10(-6) M) on human peripheral blood mononuclear cell (PBMC) proliferation and T helper type 1 and T helper type 2 (Th1/Th2) cytokine expression. In vitro doses of melatonin significantly increased PBMC proliferation (p<0.05) and decreased IL-10 production in culture supernatants (p<0.05). However, there was no effect of melatonin on the stimulated production of IFN-gamma or on the intracellular accumulation of the activation antigen CD69, IFN-gamma, or IL-10 as measured by flow cytometry. These data support the notion that physiologic doses of melatonin increase lymphocyte proliferation possibly due to decreases in production of the inhibitory cytokine IL-10.     

Cynical hostility and stimulated Th1 and Th2 cytokine production

Hostility has been associated with heightened proinflammatory activity. However, it is not known whether greater hostility contributes to greater inflammation by promoting higher Th1 activity, lower Th2 activity, or both. The present study examines the relation of hostility to mitogen-stimulated Th1 and Th2 cytokine production in vitro. Participants were 193 healthy men and women (mean age 37.3; 44% non-white). Hostility was assessed with a 20-item version of the Cook–Medley Hostility Scale (CMHS). PHA-stimulated interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were used to measure Th1 activity; PHA-stimulated IL-4, IL-5, and IL-10 were used to measure Th2 activity. Greater hostility was related to greater production of two of the three Th1 cytokines, TNF-α and IFN-γ. Hostility was not associated with any measure of Th2 cytokine production. Associations with Th1 cytokines were independent of age, sex, race, socioeconomic status, body mass index, depressive symptoms, and health-related behaviors, and were consistent across men and women. Associations were not explained by social network characteristics, social support, or personality traits closely associated with social behavior. Exploratory analyses substituting the CMHS cognitive, affective, and behavioral subscales for total hostility revealed that associations between hostility and Th1 cytokine production were primarily driven by the cognitive component of hostility (i.e., cynicism). Results suggest that a unique dimension of hostility, particularly the cynicism subcomponent, that is unrelated to social factors, may influence inflammation by promoting greater Th1 cytokine production. This effect on stimulated cytokine activity may have implications for a role of hostility in exacerbating immune-related disease.     

Epigenetic regulation of Th1 and Th2 cell development

All cells of the body, regardless of the tissue type, contain the same genetic material, but express this genetic material differently. Epigenetics is one process by which differential gene expression within a cell is regulated. Epigenetic mechanisms involve postsynthetic modifications to DNA and/or DNA-associated histones that do not change the DNA sequence itself, but which remodel chromatin, are passed along at each cell division, and occur during and after early development. The CD4⁺ T cell best represents a cell in which epigenetic mechanisms are used to affect mature cell physiology. As a naïve CD4⁺ T cell develops into either a Th1 or Th2 cell that secretes predominantly IFN-γ or IL-4, respectively, the expression of one cytokine gene and the permanent silencing of the other is orchestrated using epigenetic mechanisms. Because there appears to be an association between Th1/Th2 cell immunity, behavior, and/or disease, it is possible that an environmentally induced epigenetic change that occurs during Th1/Th2 cell development could explain how certain Th1/Th2-associated conditions develop. This article will review basic epigenetic mechanisms and what is known about how these mechanisms influence cytokine gene expression in a naïve CD4⁺ T cell as it develops into a Th1 or Th2 cell.     

Th1/Th2免疫应答系统在冠状动脉支架内再狭窄患者中的表达*☆

背景：支架再狭窄的机制尚未阐明,炎症失衡在多种疾病中起重要做用,可能与支架再狭窄有关。 目的：观察冠状动脉支架置入后支架内再狭窄患者辅助T细胞亚型Th1样细胞因子γ-干扰素、白细胞介素2和Th2样细胞因子白细胞介素4、白细胞介素10在血清中的分布特点。 方法：应用酶联免疫吸附法测定32例冠状动脉内支架置入后合并支架内再狭窄患者血清标本中γ-干扰素、白细胞介素2、白细胞介素4、白细胞介素10的浓度(实验2组),并与未行支架置入但排除冠心病患者30例(对照1组)、未行支架置入的冠心病患者30例(对照2组)及行支架置入但是无支架内狭窄患者30例(实验1组)进行比较。 结果与结论：对照2组血清中γ-干扰素、白细胞介素2、白细胞介素4、白细胞介素10的水平与对照1组相比,差异无显著性意义(P > 0.05);实验1组各指标与对照1组相比,差异亦无显著性意义(P > 0.05);实验2组患者血清中γ-干扰素、白细胞介素2水平高于其他3组(P < 0.01);白细胞介素4、白细胞介素10水平则低于对照1组和实验1组(P < 0.01)。结果表明支架内再狭窄患者存在Th1、Th2炎症水平的失衡,Th1型细胞因子上调,Th2型细胞因子下调,提示Th1/Th2失衡可能是冠状动脉支架内再狭窄的重要原因。 关键词：支架;冠心病;T淋巴细胞;辅助诱导;干扰素Ⅱ型;白细胞介素     

Th1 dominance in HAM/TSP and the optico-spinal form of multiple sclerosis versus Th2 dominance in mite antigen-specific IgE myelitis

To clarify the Th1/Th2 balance in spinal cord inflammation, we used ELISA to measure the total and allergen-specific IgE in 69 patients with clinically definite multiple sclerosis (MS), including 24 patients with the optico-spinal form of MS, 45 with HAM/TSP, 30 HTLV-I carriers without HAM/TSP, 40 patients with acute myelitis, 43 with neurodegenerative disorders, and 42 healthy subjects, and flow cytometry to study the intracellular IFNgamma-positive versus IL-4-positive cell ratio (intracellular IFNgamma/IL-4 ratio) in peripheral blood CD4(+) T cells in 40 patients with MS, including 17 patients with the optico-spinal form of MS, 23 with HAM/TSP, 22 with acute myelitis, 23 with neurodegenerative disorders, and 36 healthy subjects. Patients with HAM/TSP showed a significantly higher intracellular IFNgamma/IL-4 ratio, lower IL-4(+)/IFN-gamma(-) cell percentages, lower total IgE level, and lower frequency of cedar pollen-specific IgE than did the controls. The patients with optico-spinal MS showed a significantly higher intracellular IFNgamma/IL-4 ratio and higher IL-4(-)/IFN-gamma(+) cell percentages than the controls even at remission or in the convalescence phase. In contrast, in the patients with acute myelitis, the total serum IgE level and the frequency of mite antigen-specific IgE were significantly elevated in comparison to the controls, while those having mite antigen-specific IgE myelitis showed a significantly lower IFNgamma/IL-4 ratio in the CD4(+) T cells in comparison to the controls. These findings suggest that the Th1 cell response is predominant in HAM/TSP and optico-spinal MS, whereas the Th2 cell response is predominant in mite antigen-specific IgE myelitis.     

马索罗酚对实验性自身免疫性脑脊髓炎小鼠Th1/Th2细胞炎症因子平衡的影响

目的探讨马索罗酚对实验性自身免疫性脑脊髓炎(EAE)小鼠白细胞介素-4(IL-4)、IL-12、干扰素-γ(IFN-γ)表达的调节作用。方法将8~10周雌性C57BL/6小鼠54只随机分成对照组、模型组、治疗组。每组再随机均分为发病后10d及20d亚组,每亚组9只。采用皮下注射髓鞘少突胶质细胞糖蛋白35-55(MOG35-55)多肽0.1mL诱导EAE模型。自发病当天起,治疗组小鼠给予马索罗酚10mg/(kg·d)治疗,模型组及对照组给予等量5%二甲基亚砜(DMSO)10mL/(kg·d)处理。比较3组小鼠临床症状评分。应用实时定量PCR检测小鼠脊髓和脾组织中IL-4、IL-12、IFN-γmRNA表达水平。应用ELISA检测脑组织中IL-4、IL-12、IFN-γ蛋白表达水平。结果与模型组比较,治疗组小鼠临床症状较减轻(P0.05)。与模型组相比,治疗组小鼠10d时脊髓和脾组织IL-12、IFN-γmRNA表达水平降低(P0.05),IL-4mRNA水平增高(P0.05),脑组织IL-12、IFN-γ蛋白水平降低(P0.05),IL-4蛋白水平增高(P0.05);与模型组相比,治疗组20d时脊髓组织IL-12、IFN-γmRNA表达水平降低(P0.05),脑组织IFN-γ含量降低(P0.05)。结论马索罗酚可能通过降低脑、脊髓及脾组织中IL-12、IFN-γ表达,增加IL-4表达,调节Th1/Th2细胞炎症因子平衡,进而改善EAE小鼠疾病严重程度。     

重症肌无力患者血清Th1/Th2/Th17细胞因子的变化及意义

目的：分析重症肌无力（MG）患者血清CD4^＋ T细胞主要细胞因子的水平,探讨不同亚型CD4^＋ T细胞分泌的细胞因子在MG发病机制中的作用。方法：用ELISA测定93例MG患者和34名健康对照者血清中各项细胞因子（IL-2、IL-12、IFN-γ、TNF-α、IL-4、IL-10、IL-13和IL-17）的水平,分组行统计学分析。结果：与健康对照组相比,MG患者Th1细胞相关各细胞因子（IL-2、IL-12、IFN-γ及TNF-α）均明显升高,差异有统计学意义（P〈0.05）;Th2细胞相关的细胞因子IL-4、IL-10差异无统计学意义（P〉0.05）,仅IL-13水平升高;Th17细胞的细胞因子IL-17水平差异无统计学意义（P〉0.05）。MG眼肌型与全身型患者血清中各细胞因子水平的差异无统计学意义（P〉0.05）,在不同病程的MG患者中差异也无统计学意义（P〉0.05）。结论：Th1细胞因子在MG发病机制中发挥重要作用,而Th2细胞及其细胞因子在MG机制中的角色各异。     

Coemergence of insomnia and a shift in the Th1/Th2 balance toward Th2 dominance

OBJECTIVES: Insomnia is associated with physical and mental disorders. We examined the effect of insomnia on immune functions, focusing on the T helper 1 (Th1)/ T helper 2 (Th2) balance, by a cross-sectional design. METHODS: We provided a self-administered questionnaire to evaluate sleep habits, smoking and medical disorders to 578 men without any toxic exposure (20-64 years old), and measured natural killer (NK) cell activity in 324 men and production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) after stimulation with phytohemagglutinin in 254 men. According to the criteria of DSM-IV, in which insomnia is classified into primary and secondary insomnia, we assessed the effect of insomnia on immune functions, controlling for age and smoking in groups with and without medical disorders. RESULTS: The prevalence of insomnia in the present study was 9.2%. In the absence of medical disorders, insomniac men had a significantly lower IFN-gamma and ratio of IFN-gamma to IL-4 than noninsomniac men. Men with insufficient sleep or difficulty initiating sleep (DIS) had a significantly lower IFN-gamma to IL-4 ratio than those not suffering from insufficient sleep or DIS. In the presence of medical disorders, insomniac men had significantly higher IL-4 than noninsomniac men. Men with difficulty maintaining sleep (DMS) had a significantly lower IFN-gamma to IL-4 ratio than men without DMS. NK cell activity was independent of insomnia. CONCLUSIONS: The present results showed a link between insomnia unrelated to medical disorders and a shift in the Th1/Th2 balance toward Th2 dominance, indicating that the relationship between sleep quality and the etiology of immune-related diseases should be reconsidered.     

Semliki Forest virus infection is enhanced in Th1-prone SJL mice but not in Th2-prone BALB/c mice during Linomide-induced immunomodulation

We investigated the occurrence of T cells in the brain parenchyma of Alzheimer's disease (AD), non-AD degenerative dementias and controls by semi-quantitative analysis of immunohistochemically stained tissue sections. In all cases, we found at least some T cells. The number of T cells was increased in the majority of AD cases compared with other cases. The phenotype of T cells in the AD brain indicates that they are activated but are not fully differentiated. Antigen-triggered clonal expansion is not likely to take place. Local inflammatory conditions might cause accumulation and activation of T cells in the AD brain.     

Th1/Th2型细胞因子在实验性自身免疫性神经炎发病机制中的作用

目的 建立P2多肽诱导的实验性自身免疫性神经炎(EAN)大鼠模型,探讨Th1/Th2型细胞因子在EAN发病机制中的作用.方法 实验组用100 μg或200 μg P257-81多肽加完全弗氏佐剂(FCA)免疫Lewis大鼠,对照组单用FCA免疫,致敏后每日对大鼠进行临床评分,比较高峰期最高评分.致敏第14天测定淋巴结细胞培养液上清干扰素(IFN)-γ、IL-4及IL-10的含量,并进行坐骨神经病理学检查.结果 实验大鼠瘫痪高峰期最高评分P257-81 200 μg组(3.6±0.3)显著高于100 μg组(2.2±0.6,P＜0.01);P257-81 200 μg组大鼠病程显著长于100 μg组;IFN-γ含量,两组实验大鼠均显著高于对照组[分别为(530.6±91.7)、(806.3±132.4)和(35.0±5.9)pg/ml,均P＜0.01],而P257-81 200 μg组显著高于100 μg组(P＜0.01);IL-4和IL-10含量,P257-81 100 μg组均显著高于对照组(均P＜0.01),P257-81 200 μg组显著低于对照组(P＜0.05,P＜0.01);坐骨神经病理可见EAN急性期以炎性细胞浸润为主,P257-81 200 μg组慢性期无炎性细胞浸润,而表现为多发性局灶性脱髓鞘和神经纤维崩解未恢复.结论 EAN临床表现随致敏原P257-81多肽剂量增加而加重;在EAN急性期,IFN-γ水平与EAN临床表现大致平行;EAN疾病具有自限性可能与IL-4和IL-10水平增高有关,而疾病迁延可能与IL-4和IL-10水平降低有关.     

Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis

We investigated the immunoregulatory effects of ibudilast, a nonselective phosphodiesterase inhibitor, at a clinically applicable dose (60 mg/day p.o. for four weeks) in multiple sclerosis (MS) patients. Sensitive real-time PCR for quantifying cytokine mRNA in the blood CD4+ cells revealed that the ibudilast monotherapy significantly reduced tumour necrosis factor-alpha and interferon (IFN)-gamma mRNA and the IFN-gamma/interleukin-4 mRNA ratio, suggesting a shift in the cytokine profile from Th1 toward Th2 dominancy. In a flow cytometric analysis, natural killer T cells, which have been reported to relate to Th2 responses in MS and its animal model (experimental autoimmune encephalomyelitis), increased significantly after the therapy. None of the significant immunological changes were seen in healthy subjects or untreated MS patients. Ibudilast may be a promising therapy for MS and its clinical effects warrant further study.     

Immunization with a new DNA vaccine for Alzheimer's disease elicited Th2 immune response in BALB/c mice by in vivo electroporation

Immunization with synthetic amyloid β-protein (Aβ) peptide has resulted in preventing and clearing Aβ deposits as well as improving cognitive function in transgenic mouse models of Alzheimer's disease (AD). But similar immunization studies in humans were halted due to the risk of inducing T cell-mediated meningoencephalitis. A safe and effective vaccine for AD requires not only therapeutic levels of anti-Aβ antibodies but also the prevention of an adverse T cell-mediated, proinflammatory autoimmune response. In this study, we developed a DNA vaccine, p(Aβ(3-10))(10)-IL-4, encoding ten tandem repeats of Aβ(3-10) fused with mouse cytokine interleukin-4 (IL-4) as a molecular adjuvant. Wild-type mice were injected intramuscularly with p(Aβ(3-10))(10)-IL-4 followed by in vivo electroporation. The p(Aβ(3-10))(10)-IL-4 vaccine elicited high titer anti-Aβ antibodies which bound to Aβ plaque in brain tissue from a ten-month-old APP/PS1 transgenic mouse. The antibody isotype was mainly IgG(1) and the IgG(1)/IgG(2a) ratio in the p(Aβ(3-10))(10)-IL-4 group was approximately eight times greater than that of the Aβ(42) group. Ex vivo cultured splenocytes isolated from mice immunized with p(Aβ(3-10))(10)-IL-4 exhibited a low IFN-γ response and a high IL-4 response compared with the control group. These results indicate that immunization with the p(Aβ(3-10))(10)-IL-4 vaccine induced effective anti-Aβ antibodies and elicited a Th2-polarized immune response that had a lower potential to cause an inflammatory T cell response. Thus, the DNA vaccine, p(Aβ(3-10))(10)-IL-4, may be a safe and efficient vaccine for AD.     

Th1, Th2 and Th3 cytokine alteration in schizophrenia

BACKGROUND: Several studies have shown that there is an imbalance between T helper 1 (Th1) cytokines and T helper 2 (Th2) cytokines in patients with schizophrenia. The T helper 3 (Th3) cytokine, transforming growth factor beta-1 (TGF-beta1), has been shown to suppress the production of Th1 cytokines. Therefore it is hypothesized that it may play a role in schizophrenia by suppressing overactive Th1 system. METHODS: We recruited 88 schizophrenic patients and 88 matched controls. The basal plasma concentrations of IFN-gamma (Th1), IL-4 (Th2) and TGF-beta1 (Th3) were studied at the time the patients were admitted to the hospital and following 8 weeks of treatment with antipsychotics. RESULTS: The detection rate of plasma IFN-gamma and basal plasma TGF-beta1 level were significantly higher in schizophrenic patients than in controls whereas detection rate of plasma IL-4 was lower in patients. The ratio of Th1/Th2 cytokines (IFN-gamma/IL-4) was higher in schizophrenic patients. Following the neuroleptic treatment, the IFNgamma and TGF-beta1 levels returned to control values, and IL-4 concentration rose above the control value. CONCLUSION: Schizophrenic patients showed higher Th1/Th2 ratio which is attenuated by effective neuroleptic treatment. It is possible that TGF-beta1 plays a role in reducing the activity of Th1 cytokine.     

Nanoceria extend photoreceptor cell lifespan in tubby mice by modulation of apoptosis/survival signaling pathways

Cerium oxide nanoparticles, nanoceria, are inorganic antioxidants that have catalytic activities which mimic those of the neuroprotective enzymes superoxide dismutase and catalase. We have previously shown that nanoceria preserve retinal morphology and prevent loss of retinal function in a rat light damage model. In this study, the homozygous tubby mutant mouse, which exhibits inherited early progressive cochlear and retinal degeneration, was used as a model to test the ability of nanoceria to slow the progression of retinal degeneration. Tubby mice were injected systemically, intracardially, with 20 μl of 1mM nanoceria in saline, at postnatal day 10 and subsequently at P20 and P30 whereas saline injected and uninjected wild type (or heterozygous tubby) served as injected and uninjected controls, respectively. Assays for retinal function, morphology and signaling pathway gene expression were performed on P34 mice. Our data demonstrate that nanoceria protect the retina by decreasing Reactive Oxygen Species (ROS), up-regulating the expression of neuroprotection-associated genes; down-regulating apoptosis signaling pathways and/or up-regulating survival signaling pathways to slow photoreceptor degeneration. These data suggest that nanoceria have significant potential as global agents for therapeutic treatment of inherited retinal degeneration and most types of ocular diseases.     

Th1/Th2 balance and HTLV-I proviral load in HAM/TSP patients treated with interferon-alpha

We studied the immunological and virological effects of interferon-alpha (IFN-alpha) therapy in nine patients with HTLV-I-associated myelopathy (HAM/TSP). After therapy, the percentages of CCR5+ cells in CD4+ cells significantly decreased in the cerebrospinal fluid as well as blood. The therapy also significantly lowered the intracellular IFN-gamma+/interleukin-4+ T-cell ratio in blood. Those helper T-cell type 1 (Th1)-related responses tended to be higher and reduce more evidently following therapy in three patients who clinically improved. Also, all the three patients had one or more HTLV-I copies in five blood mononuclear cells. These results suggest that IFN-alpha suppresses Th1 responses in HAM/TSP and that the patients with higher Th1 immunity and proviral loads may be responders of the therapy. Larger-scale studies are needed to confirm the findings.     

Suppression of morphine withdrawal by electroacupuncture in rats: dynorphin and kappa-opioid receptor implicated

Our previous work has demonstrated that 100-Hz electroacupuncture (EA) or 100-Hz transcutaneous electrical nerve stimulation (TENS) was very effective in ameliorating the morphine withdrawal syndrome in rats and humans. The mechanism was obscure. (1) Rats were made dependent on morphine by repeated morphine injections (5-140 mg/kg, s.c., twice a day) for eight days. They were then given 100-Hz EA for 30 min 24 h after the last injection of morphine. A marked increase in tail flick latency (TFL) was observed. This effect of 100-Hz EA could be blocked by naloxone (NX) at 20 mg/kg, but not at 1 mg/kg, suggesting that 100-Hz EA-induced analgesia observed in morphine-dependent rats is mediated by kappa-opioid receptors. (2) A significant decrease of the concentration of dynorphin A (1-17) immunoreactivity (-ir) was observed in the spinal perfusate in morphine-dependent rats, that could be brought back to normal level by 100-Hz EA. (3) 100-Hz EA was very effective in suppressing NX-precipitated morphine withdrawal syndrome. This effect of EA could be prevented by intrathecal administration of nor-BNI (2.5 micrograms/20 microliters), a kappa-opioid receptor antagonist, or dynorphin A (1-13) antibodies (25 micrograms/20 microliters) administered 10 min prior to EA. In conclusion, while the steady-state spinal dynorphin release is low in morphine-dependent rats, it can be activated by 100-Hz EA stimulation, which may be responsible for eliciting an analgesic effect and ameliorating morphine withdrawal syndrome, most probably via interacting with kappa-opioid receptor at spinal level.     

Stress induced cognitive deficit is differentially modulated in BALB/c and C57Bl/6 mice: Correlation with Th1/Th2 balance after stress exposure

This work shows a comparative study on the effects of chronic mild stress upon learning and memory and immunity, in BALB/c and C57BL/6 mice. Stressed BALB/c, but not C57Bl/6 mice, showed a poor learning performance, morphological alterations in the hippocampus with an increase in oxidative stress. A correlation between poor memory performance and the increase of the Th2/Th1 balance was found. Our results suggest that vulnerability to cognitive deficit associated with stress exposition could be related to a differential regulation of Th1/Th2 cytokine balance, suggesting a better learning performance for individuals that produce Th1 type cytokine after stress exposition.