Different cytokine patterns in patients coinfected with hepatitis C virus and Schistosoma mansoni

Schistosoma mansoni (S. mansoni) and hepatitis C virus (HCV) coinfection is common in Egypt and other developing countries. Patients coinfected with HCV and schistosomiasis exhibit a unique clinical, virological and histological pattern manifested by viral persistence with high HCV RNA titers as well as higher necroinflammatory and fibrosis scores in their liver biopsy samples. Dual infections of schistosomiasis and viral infections display significant influences on host immune reactions including cytokine shift pattern alteration, cytotoxic T lymphocyte response and other impaired immunologic functions with diminished capacity to clear the virus. We investigated the cytokine pattern against HCV and S. mansoni antigens in patients coinfected with HCV and S. mansoni and compared them with responses in patients infected with HCV or S. mansoni alone. This study included 4 groups; (Gr I) included 20 patients infected with chronic HCV, their sera were reactive for anti-HCV antibodies, samples were verified for RNA detection to identify those who have viremia. (Gr II) included 15 patients infected with schistosomiasis alone, they were subjected to detection of S. mansoni ova in stool, rectal snip or serological test. (Gr III) included 20 patients with chronic HCV and schistosomiasis coinfection, which were diagnosed by the above-mentioned criteria. (Gr IV) included 15 healthy individuals, who were matched for age and sex and have no evidence of liver diseases served as control subjects. The results showed that a highly significant increase in serum IFN-gamma and IL-18 levels in patients infected with HCV alone compared with the other patient groups and control. On the other hand, a highly significant increase was found in serum IL-4 and IL-10 levels in coinfected patients and patients with schistosomiasis alone compared with the control but a significant increase was found in the two groups compared with HCV patients. A significant increase in serum IL-4 and IL-10 were also found in HCV patients compared with the control. In conclusions, our data showed that coinfected patients have dominant Th2 cytokine profile induced by S. mansoni and this Th2 antagonized and down-regulated the antiviral activities of Th1 cytokine profile in HCV infection that probably acquired after S. mansoni infection resulting in failing to mount significant HCV specific Th1 response and thereby fail to clear the virus in coinfected, compared with patients infected with HCV or schistosomiasis alone.     

HIV-1 alters T helper cytokines, interleukin-12 and interleukin-18 responses to the protozoan parasite Leishmania donovani

OBJECTIVE: To investigate the in vitro and in vivo effect of HIV-1 on lymphoproliferative and T helper (Th) cytokine responses in leishmaniasis. METHODS: Th1 [interleukin (IL)-2 and interferon (IFN)-gamma] and Th2 (IL-4 and IL-10) as well as IFN-gamma-inducing cytokines (IL-12 and IL-18) were measured in antigen and mitogen-stimulated culture supernatants of peripheral blood mononuclear cells (PBMC) of healthy donors, HIV-infected and visceral leishmaniasis (VL) patients with or without HIV co-infection. RESULTS: Proliferative responses to phytohaemagglutinin (PHA) were significantly lower in PBMC from VL and asymptomatic HIV-infected persons compared with responses in healthy individuals. VL-HIV co-infected patients showed the lowest responses. Although there was no significant difference in the Leishmania-induced proliferative responses among the healthy group and those infected with HIV only, VL patients (with or without HIV) exhibited very low proliferation. When cultured with PHA or Leishmania, PBMC from healthy donors produced high levels of a Th1 cytokine (IFN-gamma) and low levels of Th2 cytokines (IL-4 and IL-10). In addition, co-culturing PBMC from healthy donors with a killed HIV preparation abrogated the production of IFN-gamma induced by Leishmania and augmented IL-4 and IL-10 production. Cells from HIV-infected patients produced low levels of IFN-gamma, but high levels of IL-10. The addition of anti-IL-10 did not increase Leishmania-induced proliferative responses or IFN-gamma production. Both IL-12 and/or IL-18 responses were lower in VL patients, HIV-infected, or VL-HIV co-infected patients as compared with those of healthy donors. CONCLUSION: The data suggest that the inhibitory effect of HIV and VL on proliferation and IFN-gamma production is not due to IL-10 alone, but that the defect induced by HIV and VL probably operates at the level of regulation of IFN-gamma-inducing factors, such as IL-12 and IL-18.     

Cytokine profile of peripheral blood mononuclear cells from patients with different outcomes of hepatitis C virus infection

SUMMARY: The relationship between the balance of helper T-cell type 1 (Th1) or type 2 (Th2) cytokines and the clinical course of hepatitis C virus (HCV) infection is unclear. We evaluated Th1 [interleukin (IL)-2, interferon-gamma (IFN-gamma)] and Th2 cytokine (IL-4, IL-10) and 2,5-oligoadenylate synthetase (OAS, an IFN-induced antiviral protein) production by peripheral blood mononuclear cells from 10 healthy anti-HCV-positive individuals (group A), 10 HCV-RNA-positive with persistently normal alanine aminotransferase (ALT) levels (group B), 10 HCV-RNA-positive with abnormal ALT (group C) and 10 uninfected healthy controls. IL-2 production was significantly increased in group B when compared with all the other groups. No difference was found for IFN-gamma. IL-4 was significantly higher in group C than in both group B (P = 0.0006) and controls (P = 0.004). Compared with controls, IL-10 was significantly decreased in group A (P = 0.013) and B (P = 0.004). The production of 2,5-OAS was significantly higher in group B than in A (P = 0.04) and in C (P = 0.004). Finally, in all HCV-RNA-positive patients, a significant correlation was found between ALT and both IL-2 (r = -0.78; P = 0.0008) and IL-4 (r = 0.75; P = 0.0008). In conclusion: (i) subjects who cleared HCV showed a cytokine profile similar to controls; (ii) a preferential shift towards a Th1 profile seems associated with a more favourable clinical outcome in chronic hepatitis C; and (iii) a prevalent Th2 profile seems implicated in HCV pathogenesis and severity of liver disease.     

Serum levels of interferon-gamma, interleukin-12, tumour necrosis factor-alpha, and interleukin-10, and bacterial clearance in patients with gastroenteric Salmonella infection

Cytokines as intercellular signal molecules are responsible to a great extent for the pathological processes in Salmonella infection, as well as for the development of protective mechanisms in the disease. The present study aimed to reveal the correlation between serum levels of IFN-gamma, IL-12, TNF-alpha and IL-10, measured by enzyme-immunoassay, and clearance of bacteria in stool of patients with gastroenteric Salmonella infection. The study included 36 patients with culture confirmed gastroenteric Salmonella infection. At discharge from hospital, 20 patients recovered with bacteriological negative stool culture for Salmonella and 16 were Salmonella excretors. Mean serum concentrations of IFN-gamma, IL-12, TNF-alpha and IL-10 in the acute stage were compared between the 2 groups of patients and with those of healthy controls. Serum levels of examined cytokines were increased (p<0.001) in the patients in comparison with the healthy controls. In patients with early bacterial clearance mean serum concentrations of IFN-gamma, IL-12 and TNF-alpha in the acute stage were significantly (p<0.05) higher than in the non-clearance group. IL-10 serum level showed an opposite correlation (p<0.01) and higher values in Salmonella excretors. The accumulated data imply that Th1 type cytokines probably participate in protective immunity and early bacterial clearance in patients with gastroenteric Salmonella infection.     

Increased frequency of interferon-gamma-producing peripheral blood CD4+ T cells in chronic hepatitis C virus infection

OBJECTIVES: To determine the profile of cytokine secretion by CD4+ T helper (Th) cells in chronic hepatitis C virus (HCV) infection, we used flow cytometry to determine the percentage of interferon (IFN)-gamma and interleukin (IL)-4 producing cells from CD4+ T lymphocytes in peripheral blood obtained from patients chronically infected with HCV. METHODS: Peripheral blood mononuclear cells isolated from 89 HCV infected subjects (22 asymptomatic carriers, 56 patients with chronic hepatitis, and 11 patients with liver cirrhosis) and 24 healthy controls were stained with surface CD4 and intracellular IFN-gamma and IL-4. Serum soluble IL-2 receptor (sIL-2R) levels were analyzed by ELISA. RESULTS: The frequency of IFN-gamma producing CD4+ cells in asymptomatic HCV carriers, patients with chronic hepatitis, and patients with liver cirrhosis were significantly higher than those of healthy controls (p<0.01, respectively). In contrast, the percentages of IL-4-producing CD4+ cells were very low, and there were no significant correlations with disease progression. A significant elevation in serum sIL-2R levels was found in chronic HCV infection compared to healthy controls, and serum sIL-2R levels significantly correlated with the frequency of IFN-gamma-producing cells. CONCLUSIONS: In HCV infected subjects, both serum sIL-2R and IFN-gamma are increased in chronic HCV infection no matter the stage of disease, meaning they are no different in asymptomatic carriers, patients with chronic hepatitis, and patients with liver cirrhosis, and that Th1 cytokine or Th1 cells may participate in the pathogenesis of liver damage in chronic HCV infection.     

Effects of oxymatrine on the serum levels of T helper cell 1 and 2 cytokines and the expression of the S gene in hepatitis B virus S gene transgenic mice: a study on the anti-hepatitis B virus mechanism of oxymatrine

BACKGROUND: Oxymatrine has been shown to have a remarkable inhibitory activity to hepatitis B virus (HBV) infection with a hepatitis B virus e antigen (HBeAg) serum conversion rate of approximately 45%. In order to explore the anti-HBV mechanism of oxymatrine, the effects of oxymatrine on serum levels of T helper (h)1 cytokines (interferon (IFN)-gamma and interleukin (IL)-2) and Th2 cytokines (IL-4 and IL-10), and the expression of S gene in HBV S gene transgenic mice were studied. METHODS: Each transgenic mouse was either injected with oxymatrine or saline intraperitoneally once a day for 30 days. Serum levels of IFN-gamma, IL-2, IL-4 and IL-10 were quantitated and compared to the data before the treatment. The expression of HBV S gene in transgenic mice was analyzed at the DNA, mRNA and protein levels. RESULTS: The serum levels of IFN-gamma in transgenic mice before or after oxymatrine treatment were 3.108 +/- 3.172 and 11.059 +/- 6.971 pg/mL, respectively. In contrast, serum levels before and after oxymatrine treatment for IL-4 were 29.045 +/- 13.235 and 13.024 +/- 9.002 pg/mL, respectively (P < 0.001). The serum levels of IL-2 in the control (saline injection) and oxymatrine-treated mice were 1.070 +/- 0.447 and 5.537 +/- 2.887 pg/mL, respectively (P < 0.0001); and that of IL-10 were 97.226 +/- 73.306 and 33.607 +/- 23.154 pg/mL, respectively (P < 0.01). No significant differences were observed in the expression of HBV S gene in the transgenic mice at the DNA, mRNA and protein levels before or after oxymatrine treatment. CONCLUSIONS: The fact that Th1 cytokines are increased while Th2 cytokines are decreased suggests that oxymatrine treatment triggers the change of immune response to hepatitis B infection in transgenic mice, which leads to improved HBV inhibitory activities. The study can help us better understand the mechanisms of the anti-HBV drug, oxymatrine, and how it has potential as an application in clinical chronic hepatitis B treatment.     

Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C virus-coinfected patients.

OBJECTIVE: Epidemiological data indicate that hepatitis C virus (HCV) infection runs a more rapid and severe course of disease in HIV-coinfected patients, probably because of an altered immune response. DESIGN: We investigated whether HCV-specific cytokine responses are affected by HIV coinfection. METHODS: Using triple colour flow cytometry on peripheral blood lymphocytes after stimulation with the four major immunodominant HCV core T cell epitopes, CT1-CT4, we determined intracytoplasmic production of IFN-gamma, IL-2, IL-4, IL-10 and CD30 expression, a putative surrogate marker of type 2 cells. Fifteen patients with asymptomatic HIV/HCV coinfection (group A), 15 patients with chronic HCV infection (group B) and 10 HIV-infected patients without hepatitis C (group C) were included in the study. RESULTS: In group A, HCV antigens induced significantly higher IL-2 and IFN-gamma production than groups B and C (P < 0.05). Groups A and B showed a similar induction of CD30, which was significantly higher than in group C (P < 0.001). Remarkably, in group A HCV antigens induced IL-4 production in addition to IL-10 and IFN-gamma in the CD30 subset, whereas in groups B and C no IL-4 induction was observed in this T cell subset (P < 0.002). CONCLUSION: Our data suggest that asymptomatic HIV coinfection importantly alters the HCV-specific cytokine response towards a greater production of proinflammatory type 1 cytokines. Moreover, the antiviral activity of type 1 cytokines may be modified by an increased production of type 2 cytokines in the CD30 subset. The altered cytokine pattern may contribute to the adverse natural course of hepatitis C in HIV coinfection.     

Intrahepatic and peripheral T-cell responses in genotype 1b hepatitis C virus-infected patients with persistently normal and elevated aminotransferase levels

AIM: To evaluate whether the cytokine responses in liver and serum differ in chronic hepatitis C patients with normal and high alanine aminotransferase (ALT) levels. METHODS: Thirty-three (16 with normal ALT level as group 1 and 17 with elevated ALT level as group 2) patients infected with genotype 1b hepatitis C virus (HCV) were examined. Liver infiltrating lymphomononuclear cells (LILMCs) were isolated from liver biopsy by collagenase type 1 and stimulated with phytohemagglutinin and interleukin 2 (IL-2). IL-10, IL-12, interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) were determined in serum and LILMCs by ELISA. RESULTS: Serum cytokine levels were similar in both groups (P>0.05). Stimulated IFN-γ and TNF-α levels in LILMCs were increased in both groups. IL-12 and IL-10 levels stimulated with IL-2 were higher in group 1 than in group 2 (P = 0.023). Histological activity index (HAI) and stage had a negative correlation with TNF-α and IFN-γ levels in group 2. CONCLUSION: Increased T-helper type 2 (Th2) cytokine response may regress inflammatory and biochemical activity. Progression of histological abnormalities in persons with elevated ALT probably depends on insufficient Th2 cytokine response, which does not balance Th1 cytokine response.     

Th1/Th2免疫应答系统在结核性胸膜炎患者中的表达

目的分析结核性胸膜炎患者辅助T细胞(Th)亚型Th1样细胞因子γ干扰素(IFN-γ)、白细胞介素(IL)-2和Th2样细胞因子IL-4、IL-10在血清与胸腔积液中的分布特点,探讨系统及局部的Th1/Th2免疫应答在人类结核性胸膜炎病理生理过程中的可能作用.方法应用夹心酶联免疫吸附测定(ELISA)法检测51例结核性胸膜炎患者(胸膜炎组)血清及胸液标本中IFN-γ、IL-2、IL-4、IL-10的浓度,并与肺结核患者(肺结核组,36例)和健康人(健康人组,24名)比较.结果(1)3组受试者血清IFN-γ、IL-2、IL-4、IL-10浓度中位数分别为胸膜炎组为118.60 ng/L、0.00 ng/L、1.49 ng/L、0.00 ng/L;肺结核组为265.75 ng/L、18.03 ng/L、16.00 ng/L、0.00 ng/L;健康人组为221.70 ng/L、18.52 ng/L、16.00 ng/L、0.00 ng/L.3组受试者血清IFN-γ、IL-2浓度差异无显著性(K-W检验χ2值分别是1.15、4.68,P> 0.05).肺结核组和健康人组受试者血清IL-4、IL-10浓度差异无显著性 (Mann-Whitney 检验Z值分别为-0.27、-1.93, P>0.05),结核性胸膜炎患者血清IL-4浓度明显低于肺结核组(Mann-Whitney检验Z值-2.84,P<0.01).(2)3组受试者血清IFN-γ与IL-4浓度之比依次为胸膜炎组27.93,肺结核组21.72,健康人组10.82,经检验差异无显著性(K-W检验χ2值为4.18,P>0.05).(3)结核性胸腔积液细胞因子浓度(中位数)IFN-γ为832.70 ng/L,IL-2为43.76 ng/L, IL-4为26.00 ng/L, IL-10为38.69 ng/L, 与血清浓度相比较差异有显著性(Wilcoxon Signed Rank检验,Z值分别为-4.34、-2.82、-3.29、-5.15,P<0.05 ).结论免疫功能健全的肺结核和结核性胸膜炎患者其系统的Th1应答相似;而结核性胸膜炎患者系统Th2应答降低,系统Th1/Th2平衡有所上调.结核性胸膜炎患者胸膜局部的Th1/Th2应答较系统明显增强,这可能是结核性胸膜炎病理生理的特征.Th1/Th2免疫应答在结核性胸膜炎病理生理过程中起重要作用,但这种作用的因果关系尚待进一步研究.     

Serum gamma-interferon-inducing factor (IL-18) and IL-10 levels in patients with acute hepatitis and fulminant hepatic failure

BACKGROUND AND AIMS: The aim was to determine the role of T-helper (Th)1/Th2 cytokine responses in the clinical outcome of patients with acute liver injury. METHODS: The serum levels of the cytokines, interleukin (IL)-18, gamma-interferon (IFN-gamma), IL-10 and IL-4 were measured in 20 fulminant hepatic failure (FHF), 18 acute hepatitis (AH), 30 chronic viral hepatitis and 20 liver cirrhosis (LC) patients. Thirteen cases were from the intensive care unit (ICU) and there were 21 healthy volunteers. Immunohistochemical staining of liver biopsies for IL-18 expression was also performed. RESULTS: Serum IL-18 levels in patients with FHF were significantly more elevated than in patients with other liver diseases, ICU cases and healthy volunteers. Furthermore, serum IFN-gamma levels in patients with FHF were also significantly higher than in patients with chronic viral hepatitis, LC and healthy volunteers. We found a positive correlation between the levels of IL-18 and IFN-gamma. However, no relationship was observed between these and clinical outcome. In immunohistochemical staining, CD68+ macrophage cells and IL-18-positive cells were observed in portal zones. Elevated serum IL-10 levels were restricted to patients presenting with FHF, and were significantly higher in surviving cases (P < 0.01). Furthermore, serum IL-10 levels, but not IL-4 levels, were inversely correlated with serum total bilirubin concentrations (P = 0.045) and the death rate (p) outlined in Japan (P = 0.030). CONCLUSION: These results suggest that IL-18 and IFN-gamma are involved in the pathogenesis of acute hepatic injury in humans, and that, in particular, elevated serum levels of IL-10 may be predictive of improved outcomes for these patients.     

Relationship between serum cytokine levels and histopathological changes of liver in patients with hepatitis B

AIM: To investigate whether there was a relationship between the liver functions and fibrosis scores of hepatitis B patients and their TNF-α, IFN-γ,IL-4, and TGF-β1 serum levels based on the studies of liver biopsies. METHODS: Thirty patients with chronic hepatitis B (CHB) receiving no treatment and 30 healthy individuals with negative hepatitis serology and normal values of liver biochemistry were studied. After serum samples of the patients were collected, liver needle biopsy was performed on each patient. Cytokine levels were studied by ELISA. The biopsy materials were scored based on Knodell's histological activity index. RESULTS: In comparison of cytokine levels between CHB patients and control group, TNF-α,IL-4, and TGPβ1 levels of the patients were higher in CHB patients than in the controls, while IFN-γ level was lower in the patients than in the controls. There were significant differences between the groups in TNF-α, IL-4, TGF-β1, and IFN-γ(P<0.005, 0.03, 0.002, 0.0001,respectively).There was a negative correlation between TGF-β1 and IL-4 and IFN-γ(P<0.05), TNF-α and the other cytokines and IFN-γ and IL-4 were not correlated (P>0.05). TGF-β1 was correlated with fibrosis (P<0.05).Liver necroinflammatory activity and fibrosis and TNF-α, IL-4, and IFN-γ were not correlated (P>0.05). CONCLUSION: In the course of HBV infection and its chronic progress, cytokines play an important role. IL-4 and IFN-γ are effective in the chronic progression, while TGF-β1 is effective in the development of fibrosis. Serum cytokine levels may be effective tools in the estimation of chronic progression and fibrosis development.     

白细胞介素7和15对肺结核患者Th1/Th2平衡的调节作用

目的探讨白细胞介素7(IL7)、IL15对肺结核病患者外周血单个核细胞(PBMC)分泌Th1型细胞因子γ干扰素(IFNγ)、肿瘤坏死因子α(TNFα)和Th2型细胞因子IL4、IL10的影响。方法选择2003年1至9月入院的60例肺结核患者和25名健康对照者,用葡聚糖泛影葡胺密度梯度离心法分离PBMC。按加入刺激物的不同,将每份标本分为6组:RPMI1640组、纯化蛋白衍生物(PPD组)、PPD+IL7组、PPD+IL7抗体组、PPD+IL15组、PPD+IL15抗体组。加入相应刺激物后培养72h,收集上清液,采用酶联免疫吸附法(ELISA)检测各组培养上清液中IFNγ、TNFα、IL4、IL10的水平。结果与PPD组相比,加入IL7的患者组PBMC分泌IFNγ和TNFα显著增高,分别为(107±42)～(157±74)ng/L、(460±128)～(887±242)ng/L;显著抑制IL4和IL10的合成,分别为(58±15)～(31±9)ng/L、(153±40)～(112±32)ng/L。健康对照组PBMC分泌IFNγ和TNFα显著增高,分别为(211±57)～(292±92)ng/L、(1203±390)～(1722±503)ng/L;显著抑制IL4和IL10的合成,分别为(43±13)～(36±11)ng/L、(135±37)～(96±36)ng/L。加入IL15患者组PBMC分泌IFNγ和TNFα显著增高,分别为(107±42)～(231±62)ng/L、(460±128)～(843±208)ng/L;显著抑制IL4和IL10的合成,分别为(58±15)～(37±9)ng/L、(153±40)～(116±41)ng/L。健康对照组PBMC分泌IFNγ和TNFα显著增高,分别为(211±57)～(343±108)ng/L、(1203±390)～(1468±235)ng/L;显著抑制IL4和IL10的合成,分别为(43±13)～(36±8)ng/L、(135±37)～(90±35)ng/L。加入IL7抗体或IL15抗体均可抑制IFNγ和TNFα的分泌,促进IL4和IL10的合成。肺结核患者各组IFNγ、TNFα水平均低于健康对照各组,而IL4、IL10水平比较差异无统计学意义。结论IL7和IL15可作为免疫调节剂,诱导IFNγ及TNFα分泌,抑制IL4及IL10合成,从而调节Th1/Th2平衡,发挥对结核分枝杆菌感染患者的免疫保护作用。     

Specific cellular immune response and cytokine patterns in patients coinfected with hepatitis C virus and Schistosoma mansoni

Patients coinfected with hepatitis C virus (HCV) and Schistosoma mansoni show high incidence of viral persistence and accelerated fibrosis. To determine whether immunological mechanisms are responsible for this alteration in the natural history of HCV, the HCV-specific peripheral CD4(+) T cell responses and cytokines were analyzed in patients with chronic hepatitis C monoinfection, S. mansoni monoinfection, or HCV and S. mansoni coinfection. An HCV-specific CD4(+) proliferative response to at least 1 HCV antigen was detected in 73.3% of patients infected with HCV, compared with 8.6% of patients coinfected with HCV and S. mansoni. Stimulation with HCV antigens produced a type 1 cytokine profile in patients infected with HCV alone, compared with a type 2 predominance in patients coinfected with HCV and S. mansoni. In contrast, there was no difference in response to schistosomal antigens in patients infected with S. mansoni alone, compared with those coinfected with HCV and S. mansoni. These findings suggest that the inability to generate an HCV-specific CD4(+)/Th1 T cell response plays a role in the persistence and severity of HCV infection in patients with S. mansoni coinfection.     

Decreased frequency of HCV core-specific peripheral blood mononuclear cells with type 1 cytokine secretion in chronic hepatitis C

BACKGROUND/AIM: Since the outcome of hepatitis C infection appears to be correlated with the immune response to the HCV core protein, the aim of this study was to investigate the T cell response to hepatitis C virus core and core-derived antigens. METHODS: As this response may be regulated importantly by differential secretion of cytokines, we determined the number of peripheral blood mononuclear cells (PBMC) that secreted IL-2, IL-4, IL-10, and IFN-gamma in response to a recombinant HCV core protein and a panel of 19 core-derived peptides, using the ELI-Spot-technique. Two groups of patients were studied: group A: 11 patients with previously self-limited HCV infection; group B: 12 patients with chronic hepatitis C. RESULTS: In group B significantly less IFN-gamma spot forming cells (SFC) could be detected, both after stimulation with the core protein (0.083+/-0.083 SFC vs. 1.3+/-0.4 SFC/10(5) PBMC; p = 0.005 and with the core-derived peptides (1.3+/-0.5 vs. 4.4+/-1.1 SFC SFC/10(5) PBMC; p = 0.007). By analyzing the cytokine response to each single peptide, we found IFN-gamma responses to peptides aa 39-63 and aa 148-172 in group A but not in group B (p<0.03). In group B also, fewer IL-2 secreting cells were found after peptide stimulation (p = 0.04). Whereas subjects of group B showed IL-10-specific responses to HCV peptides more frequently than patients with self-limiting hepatitis C (p = 0.03), the number of IL-4-producing cells was not different between the two groups. CONCLUSIONS: The data suggest that patients with persistent viremia and chronic liver disease (group B) have less PBMC showing type 1 cytokine (IL-2, IFN-gamma) responses to HCV core protein than patients with self-limited HCV infection (group A).     

哮喘患者外周血单个核细胞中Thh／Th2类细胞因子的偏移状？…

目的 观察支气管哮喘患者外周血单个核细胞（ＰＢＭＣ）中Ｔ输助淋巴细胞两个功能性亚群（Ｔｈ１／Ｔｈ２）的功能状态及红霉素对其的影响。方法 ２３例哮喘患者及正常对照组１０名,采用逆转录聚合酶链反应（ＲＴ－ＰＣＲ）技术,以白细胞介素２（ＩＬ－２）和干扰素γ（ＩＮＦ－γ）代表Ｔｈ１类细胞因子,ＩＬ－４、６、１０代表Ｔｈ２类细胞因子,分别检测了两组ＰＢＭＣ加红霉素体外培养前、后上述各种因子ｍＲＮＡ的表达。结     

乙型肝炎e抗原阳性慢性乙型肝炎患者在替比夫定治疗期间外周血Th1/Th2型细胞因子水平的动态变化情况

目的 探讨乙型肝炎e抗原(HBeAg)阳性的慢性乙型肝炎(CHB)患者在用替比夫定(LDT)治疗期间Th1/Th2型细胞因子水平的动态变化情况及其与治疗转归的关系.方法 收集接受LDT治疗的15例HBeAg阳性CHB患者在基线与治疗4、8、12、24、48周时的外周血,用流式细胞仪对其血清白细胞介素(IL)-2、-4、-6、-10,以及肿瘤坏死因子(TNF)α与干扰素(IFN)γ的表达水平进行动态检测;比较完全应答组,部分应答组、无应答组、病毒学突破组及各组在不同治疗时间点的Th1/Th2型细胞因子水平.对数据的统计学分析用重复测量设计方差分析与Spearman相关分析. 结果完全应答组的Th1型细胞因子水平高于部分应答组、无应答组及治疗中病毒学突破组;而Th2型细胞因子水平则低于其他各组,但各组之间的差异无统计学意义(P>0.05).在完全应答组内IL-2、TNF α及IFN γ水平自服用LDT 12周起及其后各时间点较基线时明显升高,差异具有统计学意义(P<0.05);部分应答组内从服药24周起IFN γ水平较基线时升高(P<0.05);无应答组在服药48周时IL-6及IL-10水平较基线时明显升高(P<0.05);在病毒学突破组自服药24周起的IL-4水平及服药12周起的IL-6水平与基线相比,逐渐升高,且差异具有统计学意义(P<0.05).结论 Th1/Th2型细胞因子的活性平衡与LDT治疗HBeAg阳性CHB患者的转归有一定相关性,这可能与LDT治疗对CHB患者的免疫应答有一定程度的恢复作用有关.     

Cytokine production in acute versus chronic human Schistosomiasis mansoni: the cross-regulatory role of interferon-gamma and interleukin-10 in the responses of peripheral blood mononuclear cells and splenocytes to parasite antigens

The contribution of interleukin (IL)-10 and interferon (IFN)-gamma to the regulation of type 1 and type 2 cytokine responses was investigated in Brazilians with different clinical forms of schistosomiasis mansoni. Cells from members of a family with acute intestinal schistosomiasis responded to schistosomal soluble egg antigen (SEA) or soluble adult worm antigen preparation (SWAP) with greater amounts of IFN-gamma than did cells from several patients with chronic intestinal schistosomiasis; IL-10 levels were similar. Neutralization of IL-10 had no effect on the SEA-specific IFN-gamma response in patients with acute infection, whereas SWAP-induced IFN-gamma was increased in both groups. Anti-IL-10 also up-regulated SEA-specific IFN-gamma protein and mRNA responses in most splenocyte cultures from hepatosplenic schistosomiasis patients but had no effect on antigen-specific IL-4 or IL-5 production. Neutralization of IFN-gamma resulted in a comparable increase in SWAP-specific IL-10 and IL-5, while IL-4 was not affected. These studies demonstrate that early disease in schistosomiasis is associated with a significant IFN-gamma response and that IL-10 contributes to the suppression of that response during both early and chronic infection.     

Study on the blood-borne virus co-infection and T lymphocyte subset among intravenous drug users

AIM: To investigate the features of various blood- borne virus infections and co-infection in intravenous drug users (IDUs), and to examine the correlation of T lymphocyte subsets with virus co-infection. METHODS: Four hundred and six IDUs without any clinical manifestation of hepatitis and 102 healthy persons were enrolled in this study. HBV-DNA and HCV-RNA were detected by fluorescence quantitative PCR. HBsAg, HBeAg, anti-HBc, anti-HCV, HDV-Ag, anti-HGV, anti-HIV, and HCMV-IgM were assayed by enzyme-linked immunosorbent assay (ELISA) and immunochromatographic tests. The levels of Th1 and Th2 cytokines were measured by ELISA and radioactive immune assay (RIA). The T lymphocyte subpopulation was detected by using fluorescence immunoassay. The similar indices taken from the healthy persons served as controls. RESULTS: The viral infection rate among IDUs was 36.45% for HBV, 69.7% for HCV, 47.3% for HIV, 2.22% for HDV, 1.97% for HGV, and 3.45% for HCMV. The co- infection rate of blood-borne virus was detected in 255 of 406 (62.81%) IDUs. More than 80% (161/192) of subjects infected with HIV were co-infected with the other viruses, such as HBV, HCV. In contrast, among the controls, the infection rate was 17.65% for HBV and 0% for the other viruses. Our investigation showed that there was a profound decrease in the proportion of CD4/CD8 and the percentage of CD3 and CD4, but not in the percentage of CD8. The levels of PHA-induced cytokines (IFN-γ and IL-4) and serum IL-2 were obviously decreased in IDUs. On the other hand, the level ofserum IL-4 was increased. The level of IFN-γ and the percentage of CD4 were continuously decreased when the IDUs were infected with HIV or HIV co-infection. IDUs with HIV and HBV co-infection was 15.1% (29/192). Of those 29 IDU with HIV and HBV co-infection, 51.72% (15/29) and 37.93% (11/29) were HBV-DNA-positive and HBeAg-positive, respectively. But, among IDUs without HIV infection, only 1.68% (2/119) of cases were HBV- DNA-positive. CONCLUSION: HCV, HBV and HIV infections are common in this population of IDU, leading to a high incidence of impaired Th1 cytokine levels and CD4 lymphocyte. IDUs with HIV and HBV/HCV co-infection have lower expression of Th1 cytokine with enhancement of the Th2 response. HIV may be causing HBV replication by decreasing Th1 function.     

Serum levels of interleukin-10, interleukin-12 and soluble interleukin-2 receptor in chronic liver disease type C

BACKGROUND/AIMS: It is still unclear whether and how Th1/Th2 type cytokines are involved in the progression of chronic liver disease type C. We therefore examined serum levels of IL-10, IL-12 and sIL-2R (soluble IL-2 receptor) in association with clinical parameters in chronic liver disease type C, whereas IL-12 and sIL-2R represent Th1 cytokine and IL-10 does Th2 cytokine, respectively. METHODOLOGY: Serum levels of IL-10, IL-12 and sIL-2R were measured in 110 patients, including 36 with chronic hepatitis, 24 with liver cirrhosis and 50 with hepatocellular carcinoma in comparison with 19 normal individuals, by an enzyme-linked immunosorbent assay. In 9 chronic hepatitis patients, serum levels of these cytokines were measured before and after interferon therapy. In 28 with hepatocellular carcinoma, they were also measured before and after transcatheter arterial embolization. RESULTS: Serum levels of IL-10 in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma were 3.9 +/- 1.8 pg/mL, 5.7 +/- 6.4 pg/mL and 5.6 +/- 8.9 pg/mL, respectively. IL-10 level was significantly correlated with level of y-globulin. Serum levels of IL-12 in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma were 347.4 +/- 150.3 pg/mL, 365.2 +/- 130.7 pg/mL and 399.4 +/- 258.2 pg/mL. sIL-2R levels in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma were 614.6 +/- 223.5 U/mL, 878.7 +/- 330.5 U/mL and 1037.9 +/- 412.0 U/mL. Serum levels of IL-12 and sIL-2R were significantly elevated on day 7 after interferon therapy compared to day 0 (p < 0.05 and p < 0.001, respectively), while no significant difference was seen in IL-10. Serum level of IL-10 was significantly elevated on day 3, and that of sIL-2R was elevated on day 3 and 7 after transcatheter arterial embolization, while that of IL-12 was decreased on day 3 and 7. CONCLUSIONS: The results of the present study suggest that Th1/Th2 type cytokines are changed in association with progression of chronic liver disease type C and in response to therapy.