非小细胞肺癌不同胸腔积液严重程度及预后患者lncRNA MEG3表达及其与Th17/CD4^(+)T细胞的关系

目的:研究非小细胞肺癌(NSCLC)不同胸腔积液严重程度及预后患者lncRNA MEG3表达及其与Th17/CD4^(+)T细胞的关系。方法:选取2020年1月至2022年12月福建医科大学附属泉州第一医院收治的104例NSCLC恶性胸腔积液患者作为研究对象,根据胸腔积液量分为3组:少量胸腔积液组(35例)、中量胸腔积液组(42例)、大量胸腔积液组(27例)。根据患者疾病实际发展转归分为预后良好组(29例未出现复发和转移)和预后不良组(75例出现复发和转移)。另选取同期于福建医科大学附属泉州第一医院治疗的60例肺炎良性胸腔积液患者作为对照组。实时荧光定量PCR检测两组胸腔积液中MEG3表达。收集受试者外周静脉血,流式细胞术检测外周血Th17细胞、CD4^(+)T细胞比例,并计算Th17/CD4^(+)T。对比各组患者lncRNA MEG3及外周血Th17、CD4^(+)T细胞水平。Logistic回归分析NSCLC胸腔积液及预后的影响因素。结果:NSCLC组胸腔积液lncRNA MEG3表达及CD4^(+)T细胞百分比低于对照组,Th17细胞百分比、Th17/CD4^(+)T高于对照组(P<0.05)。大量胸腔积液组lncRNA MEG3表达及CD4^(+)T细胞百分比低于少量胸腔积液组、中量胸腔积液组,中量胸腔积液组lncRNA MEG3表达及CD4^(+)T细胞百分比低于少量胸腔积液组,大量胸腔积液组Th17细胞百分比、Th17/CD4^(+)T高于少量胸腔积液组、中量胸腔积液组,中量胸腔积液组Th17细胞百分比、Th17/CD4^(+)T高于少量胸腔积液组(P<0.05)。预后不良组lncRNA MEG3表达及CD4^(+)T百分比低于预后良好组,而Th17细胞百分比、Th17/CD4^(+)T高于预后良好组(P<0.05)。Logistic回归分析结果显示,lncRNA MEG3为NSCLC胸腔积液的保护因素,Th17/CD4^(+)T为危险因素(P<0.05);lncRNA MEG3为NSCLC预后的保护因素,Th17/CD4^(+)T为危险因素(P<0.05)。结论:NSCLC不同胸腔积液严重程度及预后患者lncRNA MEG3表达及Th17/CD4^(+)T不同,且lncRNA MEG3为NSCLC胸腔积液及预后的保护因素,Th17/CD4^(+)T为危险因素,可作为胸腔积液严重程度及预后诊断的有效生物标志物。

Correlation between Abdominal Ultrasonographic Findings and CD4 Cell Count in Adult Patients with HIV/AIDS in Jos, Nigeria

Acquired Immunodeficiency Syndrome (AIDS) is caused by Human Immunodeficiency Viruses (HIV) resulting in progressive destruction of cell mediated immunity. The abdominal manifestations of AIDS are related to the level of CD+4 cells count as well as viral load. Abdominal ultrasound examination is easy to perform, non-invasive, inexpensive, readily available and reproducible investigation which provides valuable information about abdominal findings in AIDS. The objective of the study was to evaluate abdominal ultrasound findings in adult HIV/AIDS patients in Jos, Plateau State, Nigeria and correlate these findings with the patients’ CD+4 counts. A cross-sectional study of abdominal ultrasound findings of adult patients with HIV/AIDS was conducted over a period of six months. The abdominal ultrasound findings and CD+4 counts were studied. Two hundred (40%) of the patients had normal abdominal ultrasound, while 60% (300) had various abnormalities. The common abnormalities included increased liver parenchymal echogenicity in 25.0%, hepatomegaly in 23.4%, splenomegaly in 6.6%, increased splenic echogenicity in 6.2% and thickened gallbladder wall in 12.6%, elevated renal parenchymal echogenicity in 6.4%, enlarged kidneys in 2.6%, lymphadenopathy in 6.0%, and ascites in 2.4%. Pelvic abscess was the least pathology in 0.2%. Most of the findings did not correlate with the patients’ CD+4?count except for lymphadenopathy and ascites. Although abdominal ultrasound examination is invaluable in the management of these patients, however, it has not shown to be useful in predicting the patients’ immune status.

Bayesian Joint Modelling of Survival Time and Longitudinal CD4 Cell Counts Using Accelerated Failure Time and Generalized Error Distributions

Survival of HIV/AIDS patients is crucially dependent on comprehensive and targeted medical interventions such as supply of antiretroviral therapy and monitoring disease progression with CD4 T-cell counts. Statistical modelling approaches are helpful towards this goal. This study aims at developing Bayesian joint models with assumed generalized error distribution (GED) for the longitudinal CD4 data and two accelerated failure time distributions, Lognormal and loglogistic, for the survival time of HIV/AIDS patients. Data are obtained from patients under antiretroviral therapy follow-up at Shashemene referral hospital during January 2006-January 2012 and at Bale Robe general hospital during January 2008-March 2015. The Bayesian joint models are defined through latent variables and association parameters and with specified non-informative prior distributions for the model parameters. Simulations are conducted using Gibbs sampler algorithm implemented in the WinBUGS software. The results of the analyses of the two different data sets show that distributions of measurement errors of the longitudinal CD4 variable follow the generalized error distribution with fatter tails than the normal distribution. The Bayesian joint GED loglogistic models fit better to the data sets compared to the lognormal cases. Findings reveal that patients’ health can be improved over time. Compared to the males, female patients gain more CD4 counts. Survival time of a patient is negatively affected by TB infection. Moreover, increase in number of opportunistic infection implies decline of CD4 counts. Patients’ age negatively affects the disease marker with no effects on survival time. Improving weight may improve survival time of patients. Bayesian joint models with GED and AFT distributions are found to be useful in modelling the longitudinal and survival processes. Thus we recommend the generalized error distributions for measurement errors of the longitudinal data under the Bayesian joint modelling. Further studies may investigate the models with various types of shared random effects and more covariates with predictions.

Sustained heavy ethanol drinking affects CD4⁺cell counts in HIV-infected patients on stavudine (d4T), lamivudine (3TC) and nevirapine (NVP) treatment regimen during 9 months follow-up period

Sustained heavy ethanol drinking is a common problem globally and ethanol is one of the most abused drugs among individuals of different socio-economic status including the HIV-infected patients on antiretroviral drugs. Ethanol is reward drug and a CNS depressant especially at high doses. The study determined the effect of sustained heavy ethanol drinking by HIV-infected patients on d4T/3TC/NVP regimen on CD4+ cell counts in Uganda using WHO AUDIT tool and chronic alcohol-use biomarkers. A case control study using repeated measures design with serial measurements model was used. The patients on stavudine (d4T) 30 mg, lamivudine (3TC) 150 mg and nevirapine (NVP) 200 mg and chronic alcohol use were recruited. A total of 41 patients (20 in alcohol group and 21 in control group) were screened for chronic alcohol use by WHO AUDIT tool and chronic alcohol use biomarkers. They were followed up for 9 months with blood sampling done at 3 months intervals. CD4+ cell count was determined using Facscalibur Flow Cytometer system. Results were then sorted by alcohol-use biomarkers (GGT, MCV and AST/ ALT ratio). Data were analysed using SAS 2003 version 9.1 statistical package with repeated measures fixed model and the means were compared using student t-test. The mean CD4+ cell counts in all the groups were lower than the reference ranges at baseline and gradually increased at 3, 6 and 9 months of follow-up. The mean CD4+ cell counts were higher in the control group as compared to the chronic alcohol use group in both WHO AUDIT tool group and chronic alcohol-use biomarkers group though there was no significant difference (p > 0.05). Chronic alcohol use slightly lowers CD4+ cell count in HIV-infected patients on d4T/3TC/NVP treatment regimen.

Factors Associated with Sample Rejection for CD4+/CD8+ T Cell Count Analyses at the Kenyatta National Hospital Comprehensive Care Center Laboratory, Kenya

Background: The appropriate time to initiate antiretroviral therapy (ART) in HIV/AIDS patients is determined by measurement of CD4+/CD8+ T cell count. The CD4/CD8+ T cell count is also useful, together with viral load, in monitoring disease progression and effectiveness treatment regimens. Several factors may contribute to sample rejection during the CD4+/CD8+ T cells count, resulting in negative effects on patient management. Objective: Evaluate the causes for CD4+CD8+ T cell count sample rejection at the Kenyatta National Hospital Comprehensive Care Center Laboratory. Method: A retrospective cross-sectional study was conducted between 2018 and 2020. Data was obtained from the “rejected samples” for PartecR FlowCyp flow cytometry file. Designed data collection sheet was used for data capture. A total of 3972 samples were submitted for CD4+/CD8+ T cell count during the study period. Causes for sample rejection were numbered 1 to 12, each representing a reason for sample rejection. Number 1 was sub-categorized into clotted, hemolyzed, short-draw and lipemic. Data was analyzed using excel, and presented using tables, graphs and pie charts. Approval to conduct the study was obtained from KNH/UoN ERC. Results: In the study period, 81/3972 (2.0%) samples were rejected. Samples submitted more than 48 hours after collection were mostly rejected. Other factors included improper collection technique, delayed testing, patient identification error and incorrect use of vacutainer. A combination of clotted samples, specimen submission more than 48 hours caused the most frequent sample rejection, followed with combination of specimen submission more than 48 hours, delayed testing and delayed specimen processing. Together, clotted samples, incorrect vacutainer and poor specimen label caused the least sample rejection. Conclusion: Sample rejection rate for CD4/CD8+ T cell count was relatively low, and multiple factors contributed to rejection. However, improved quality assurance will enable more benefit to patients who seek this test in the laboratory.

Greater Expansion of IFN-<i>γ</i>^﹣CD4⁺NKT Cells in HIV-1 Compared with HIV-2-Infected Subjects with Preserved CD4⁺T Cell Counts

Context: Human Natural Killer T cells are T lymphocytes that express an invariant αβ T cells receptors and NK cells receptors. They regulate innate and adaptive immune response but are susceptible to HIV-1 infection. Objective: We compare the frequency and the activity of NKT cells in HIV-1 and HIV-2 infected individuals with CD4+ counts greater than 500/mm3 using flow cytometry after overnight stimulation with phytohemagglutinin (PHA). Results: The frequency of NKT cells was similar between both groups and also to sero-negative control subjects. There were also no significant differences in the proportions of total NKT cells and the CD4+ NKT subset that secreted interferon gamma (IFN-γ) after polyclonal stimulation. However, there was a significantly higher frequency of IFN-γ﹣ CD4+ NKT cells in HIV-1-infected compared with HIV-2 infected subjects (p = 0.043). Conclusion: These data suggest there is no relationship between the functional activity of NKT cell subsets and the total NKT cell population in HIV infection. The expansion of IFN-γ﹣ CD4+ NKT cells in HIV-1 infection may serve as target for viral infection and may eventually result in their depletion during chronic infection.

新发HIV/AIDS患者抑郁心理干预效果及其与CD_(4)^(+)T细胞计数的关系研究

背景HIV/AIDS与抑郁症相关,抑郁症加大HIV相关认知紊乱(HAND)风险,并降低患者抗逆转录病毒治疗(ART)依从性,加剧HIV传播风险。国内研究较少报道新发HIV/AIDS患者(PLWHA)抑郁心理干预效果及与CD_(4)^(+)T细胞计数相关性。目的探究新发PLWHA抑郁心理干预效果及与CD_(4)^(+)T细胞计数相关性,为AIDS临床诊疗提供参考。方法2020年4月—2022年6月采用方便取样方法在江西省ART定点医院抽取新发PLWHA抑郁患者,患者确诊后立即启动ART及心理干预,干预总周期为12周。在干预前后采用汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)进行评估,并检测CD_(4)^(+)T细胞计数进行分析。结果共纳入新发PLWHA抑郁患者200例,有效随访178例,有效率为89.0%。178例PLWHA抑郁患者轻中度88例(49.4%)、重度90例(50.6%),伴焦虑者173例(97.2%)。患者CD_(4)^(+)T细胞计数均值在干预前为(346.39±156.87)个/μL,干预后为(421.93±149.61)个/μL。干预后,新发PLWHA抑郁患者CD_(4)^(+)T细胞计数高于干预前(t_(配对)=10.971,P<0.05),HAMD、HAMA总分及各因子评分均低于干预前(P<0.05)。干预前,HAMD总分与CD_(4)^(+)T细胞计数分级(以500个/μL为分界值)呈负相关(r_(s)=-0.157,P=0.036)、与HAMA总分呈正相关(r_(s)=0.764,P<0.001)。干预后,HAMD总分与干预后CD_(4)^(+)T细胞计数呈负相关(r_(s)=-0.150,P=0.046)、与HAMA总分呈强正相关(r_(s)=0.939,P<0.001)。干预前,新发PLWHA抑郁患者CD_(4)^(+)T细胞计数<500个/μL者HAMD、HAMA总分高于CD_(4)^(+)T细胞计数≥500个/μL者(P<0.05)。结论新发PLWHA抑郁严重程度与CD_(4)^(+)T细胞计数相关,经专业心理干预能显著改善。

外周血CD4^(+)PD-1^(+)Tcells及CD4^(+)T淋巴细胞ATP含量与复发性卵巢癌疗效的相关性分析

目的 探讨外周血CD4^(+)程序性细胞死亡受体-1(PD-1)^(+)T cells及CD4^(+)T淋巴细胞三磷酸腺苷(ATP)含量与复发性卵巢癌疗效的相关性。方法 选取30例复发性卵巢癌患者为复发组,30例未复发卵巢癌患者为非复发组;另选取30名同期体检健康者作为对照组。评估外周血CD4^(+)PD-1^(+)T cells及CD4^(+)T淋巴细胞ATP含量与复发性卵巢癌疗效的相关性。结果 复发组和非复发组的CD4^(+)PD-1^(+)T cells较对照组明显升高(P<0.05)。复发组和非复发组的CD4^(+)T淋巴细胞ATP含量较对照组明显降低(P<0.05)。复发组治疗后CD4^(+)PD-1^(+)Tcells显著低于治疗前(P<0.05),治疗后CD4^(+)T淋巴细胞ATP含量显著高于治疗前(P<0.05)。CD4^(+)PD-1^(+)T cells与复发性卵巢癌疗效成负相关(r=-0.393,P=0.039),CD4^(+)T淋巴细胞ATP含量与复发性卵巢癌疗效成正相关(r=0.449,P=0.031)。结论 复发性卵巢癌患者外周血CD4^(+)PD-1^(+)T cells及CD4^(+)T淋巴细胞ATP含量与疗效密切相关。

Effects of estrogen on CD4^+ CD25^+ regulatory T cell in peripheral blood during pregnancy

Objective To investigate the effects of estrogen(E_2)level on regulatory T cells(Treg)in peripheral blood during pregnancy.Methods:A total of 30 healthy non-pregnant women were selected as control group,90 pregnant women of early,middle and late pregnancy and 30 postpartum women at 1 month after parturition were selected as experimental groups including early pregnancy group,middle pregnancy group and late pregnancy group;the proportions of CD4^+CD25^+Treg and CD4^+CD25^+CD127^-Treg among CD4 T cells were detected by flow cytometry;the serum estrogen content in peripheral blood was detected by electrochemical immune luminescence method.Results:E_2 level was coincident with the change of Tregs number during pregnancy.The estrogen content in peripheral blood increased gradually from early pregnancy to late pregnancy,then decreased significantly after parturition,and the level at 1 month after parturition down to the level in non-pregnancy group(P>0.05);the level of E_2 in pregnancy groups were significantly higher than those in non-pregnancy group(P<0.01);and there were significant differences among early pregnancy group,middle pregnancy group and late pregnancy group(P<0.05).The proportions of CD4^+CD25^+Treg and CD4^+CD25^+CD127^-Treg in pregnancy groups were significantly higher than those in non-pregnancy group(P<0.05),but decreased significantly after parturition,and there was no significant difference between non-pregnancy group and postpartum women group(P>0.05):the proportions in middle and late pregnancy groups were significantly higher than those in early pregnancy group(P<0.05).but decreased slightly in late pregnancy group,there was no significant difference between late pregnancy group and middle pregnancy group(P>0.05).There was correlation between Tregs number with estrogen level during pregnancy.The proportion of CD4^+CD25^+Treg and CD4^+CD25^+CD 127^-Treg were positively correlated with estrogen level.Conclusions:High proportion of CD4^+CD25^+Trcg and CD4^+CD25^+CD127^-Treg is closely related to the high level of E,during pregnancy.It suggested that high level of estrogen may induce an increase of CD4^+CD25^+Treg in peripheral blood.and then influence the immune function of pregnant women.The results of this experiment might play an important role of estrogen in immune-modulation during pregnancy.

Study on the effect and mechanism of the dysfunction of CD4^+ T cells in the disease process of chronic cardiac failure

Objective: To study the effect and mechanism of the dysfunction of CD4+ T cells in the disease process of chronic cardiac failure (CHF).Methods:According to different group technologies, 100 CHF patients were divided into the following groups: ischemia group and non-ischemia group, heart function Ⅰ-Ⅱ group and heart function Ⅲ-Ⅳ group, event group and non-event group, and 50 healthy volunteers were included in the control group. Realtime PCR was used to detect transcription factors T-bet and GATA-3 of Th1 and Th2; flow cytometry was applied to determine the ratio of Th17 and Treg cells; ELISA was employed to test cytokines IFN-γ, IL-4, IL-17 and IL-10 of peripheral blood Th1, Th2, Th17 and Treg cells, respectively; ultrasonic cardiogram was used to exploit to LVEF and LVEDd; and electrochemilu minescene immunoassay was used to examine plasma BNP. The differences of all indexes of all groups were analyzed and the correlation between CD4 T cells and clinical indexes was analyzed by Pearson correlation analysis. Results: As compared to the control group, the transcription factors T-bet and GATA-3 of Th1 and Th2, the ratio of cytokines Th17 and IFN-γ, cytokines IL-17, T-bet/GATA-3, IFN-γ/IL-4, Th17 cells/Treg cells, IL-17/IL-10 of the ischemia group and non-ischemia group, heart functionⅠ-Ⅱgroup and heart function Ⅲ-Ⅳ group, event group and non-event group were all increased significantly, while their transcription factor GATA-3 of Th2, cytokines IL4, Treg cells ratio, cytokines IL10 were decreased obviously. The differences showed statistical significance (P < 0.05). The increase or decrease of the partial CD4+ T cells of the ischemia group, heart function Ⅲ-Ⅳ group and event group was more distinctly. The results of Pearson correlation analysis showed that IFN-γ and IL-17 were significantly positively correlated with LVEDd and BNP, IL-4 and IL-10 were also significantly positively correlated with LVEF, but correlated negatively with BNP, and IL-17 was negatively correlative with LVEF. Conclusions: There was a correlation between CHF and the dysfunction of CD4+ T cells showing immune activation phenomenons of deviations from the Th1/Th2 balance towards Th1 and from the Th17/Treg balance towards Th17, which was also related to the types, severity and prognosis of the disease.

An Association between Immunosenescence and CD4^+CD25^+ Regulatory T Cells: A Systematic Review

Objective Age-related increment of the prevalence of CD4^＋CD25^＋ regulatory T （Treg） cells were described controversially, and whether such changes explain immune dysfunction in the elderly is still unclear. The aim of this systematic review is to evaluate the role of the Tregs in immunosenescence. Methods Medline and manual searches were performed to identify all published epidemiological and animal studies investigating the efficacy of the association between immunosenescence and Treg cells. Results It was founded that the frequency, phenotypic characteristics, and number/function of Tregs were altered significantly with aging. Medical conditions in individuals with advanced ageas well as apoptosis intensity of Treg cells had an impact on the accumulation of Tregs which in turn could deteriorate cytotoxic activity of CD8＋ T and NK cells and production of IL-2. The range of immune cells that could be suppressed by Treg cells was quite wide and covered CD4^＋CD25^＋ T cells, NK cells, dendritic cells and even monocytes. These changes were observed both in humans and experimental animals. Besides, it was believed that frequency of Tregs increased with age and was accompanied by intensified suppressive activity for Tregs in patients, for example, with Alzheimer disease （AD） and Parkinson disease （PD）. The impaired condition of CD4＋ T cells, so-called immunosenescence, rendered transplant recipients less responsive to an allogeneic kidney graft, an effect that was limited to transplant recipients who were aged over 60 years. Conclusions Treg cells are associated with immunosenescence. All these changes contribute to the aging-related decline of immune responses and lead to the higher risk of immune-mediated diseases, cancer or infections in aged individuals.

Analysis of CD4^+CD25^+ Regulatory T Cells and Foxp3 mRNA in the Peripheral Blood of Patients with Asthma

The changes of CD4^＋CD25^＋ regulatory T cells （CD4^＋CD25^＋ Treg） and Foxp3 mRNA in peripheral blood mononuclear cells （PBMCs） from patients with asthma were investigated in order to elucidate the possible roles of CD4^＋CD25^＋ Treg in the development of asthma. The peripheral blood samples were collected from 29 healthy controls （normal control group） and 78 patients with asthma which included 30 patients in exacerbation group, 25 patients in persistent group, and 23 patients in remission group. By using flow cytometry and RT-PCR, the CD4^＋CD25^＋ Treg ratio and Foxp3 mRNA in PBMCs were detected. The CD4^＋CD25^＋ Treg ratio and Foxp3 mRNA in PBMCs of exacerbation and persistent groups were lower than that of remission and normal control groups （P〈0.05）. Although the CD4^＋CD25^＋ Treg ratio and Foxp3 mRNA of remission group were also lower than that of normal control group, there was no significant difference between them （P〉0.05）. As compared with persistent group, exacerbation group had lower CD4^＋CD25^＋ Treg ratio and Foxp3 mRNA （P〈0.05）. It was indicated that the decrease of CD4^＋CD25^＋ Treg ratio and its function in PBMCs may be responsible for pathogenesis of asthma.

Depletion of CD4^+CD25^+ regulatory T cells can promote local immunity to suppress tumor growth in benzo[a]pyrene-induced forestomach carcinoma

AIM： To elucidate the distribution of CD4^＋CD25^＋ regulatory T cells （Tregs） in different lymphoid tissues and its local enhancement on tumor growth before and after depletion of CD4^＋CD25^＋ Tregs. METHODS： Female ICR mice were garaged with benzo[a]pyrene （BaP） to induce forestomach carcinoma. CD4^＋CD25^＋ Tregs were intraperitoneally depleted with monoclonal antibody PC61. These mice were divided into BaP-only, BaP ＋ IgG, BaP ＋ PC61, and control groups. The forestomach of mice was dissected for histological analysis, and tunnel test was performed for apoptosis of tumor cells. CD4^＋CD25^＋ Tregs were sorted from different lymphoid tissues and expression of Foxp3, IL-10, and chemokine receptors was analyzed by flow cytometry, semi-quantitative and veal-time polymerase chain reaction. RESULTS： The mice gavaged with only BaP showed increased forestomach papilloma and carcinoma at wk 16 and 32. The proportion of CD4^＋CD25^＋ Tregs was significantly higher in peri-stomach regional lymph nodes than in other lymphoid tissues. These CD4^＋CD25^＋ Tregs in regional lymph nodes expressed higher levels of Foxp3 and IL-10, enriched in the CD62L-subset, and CCR1 and CCR5 chemokine receptors. In mice gavaged with BaP ＋ PC61, the number of tumor nodules and tumor volume decreased significantly with massive infiltrating cells and apoptosis of tumor cells. In the draining regional lymph nodes, the number of CD4^＋CD25^＋ Tregs also decreased significantly. CONCLUSION： Inducible and activated CD4^＋CD25^＋ Tregs in the draining regional lymph nodes suppress host local immunity during tumor growth. Depletion of CD4^＋CD25^＋ Tregs can promote host local immunity to suppress tumor growth.

All-transRetinoic Acid Regulates Th1/Th2 Balance in CD4+T cells When GATA-3 is Deficient

The essential effect of vitamin A on immune function occurs through various mechanisms including direct effect on ThloTh2 balance modulation. However, it is unclear whether or not vitamin A can regulate Thl-Th2 balance under a strong Thl-polarizing condition. Therefore, the purpose of our study was to examine the effect of vitamin A metabolite allotrans retinoic acid （ATRA） on ThloTh2 differentiation in CD4~ T cells under GATA-3 deficiency, which can induce Thl-polarizing condition. In the present study, GATA-3 deficiency T cells were induced by siRNA and checked by real-time quantitative PCR and western blot. GATA-3 deficiency CD4＋ T cells and normal CD4＋ T were treated for 48 h with or without ATRA.

CD4+ T cell responses in hepatitis C virus infection

Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. Evidence that CD4+ T cell responses to HCV play an important role in the outcome of acute infection has been shown in several studies. However, the mechanisms behind viral persistence and the failure of CD4+ T cell responses to contain virus are poorly understood. During chronic HCV infection, HCV-specific CD4+ T cell responses are rela- tively weak or absent whereas in resolved infection these responses are vigorous and multispecific. Persons with a T-helper type I profile, which promotes cellular effec- tor mechanisms are thought to be more likely to experi- ence viral clearance, but the overall role of these cells in the immunopathogenesis of chronic liver disease is not known. To define this, much more data is required on the function and specificity of virus-specific CD4+ T cells, especially in the early phases of acute disease and in the liver during chronic infection. The role and possible mechanisms of action of CD4+ T cell responses in deter- mining the outcome of acute and chronic HCV infection will be discussed in this review.

Ribavirin and IFN-α combination therapy induces CD4+ T-cell proliferation and Th1 cytokine secretion in patients with chronic hepatitis B

AIM: To investigate the anti-viral mechanism of combination therapy of interferon (IFN)-α and ribavirin in patients with chronic hepatitis B. METHODS: Twenty patients were assigned to receive either IFN-α plus ribavirin (group A,n = 14) or no treatment as a control (group B,n = 6). Patients were analyzed for T-cell proliferative responses specific for hepatitis B virus (HBV)-antigen and cytokine production by peripheral blood mononuclear cells (PBMCs). RESULTS: Combination therapy induced HBV-antigen specific CD4+ T-cell proliferative responses in four patients (28.6%). Production of high levels of HBV-specific IFN-γ,tumor necrosis factor (TNF)-α,interleukin (IL)-12 by PBMCs was found in five patients (35.7%),who showed significantly lower HBV DNA levels in serum at 12 mo after treatment ended (P = 0.038) and at 24 mo of follow-up (P = 0.004) than those without high levels of cytokine production. CONCLUSION: HBV-antigen specific CD4+ T cells may directly control HBV replication and secretion of anti-viral T helper 1 (Th1) cytokines by PBMCs during combination therapy of chronic hepatitis B with ribavirin and IFN-α.

Super-resolution immunohistochemistry study on CD4 and CD8 cells and the relation to macrophages in human cochlea

Recently, the human cochlea has been shown to contain numerous resident macrophages under steady-state. The macrophages accumulate in the stria vascularis, among the auditory nerves, and are also spotted in the human organ of Corti. These macrophages may process antigens reaching the cochlea by invasion of pathogens and insertion of CI electrode. Thus, macrophages execute an innate, and possibly an adaptive immunity. Here, we describe the molecular markers CD4 and CD8 of T cells, macrophage markers MHCⅡ and CD11b, as well as the microglial markers TEME119 and P2Y12, in the human cochlea. Immunohistochemistry and the advantageous super-resolution structured illumination microscopy(SR-SIM) were used in the study. CD4^+ and CD8^+ cells were found in the human cochleae. They were seen in the modiolus in a substantial number adjacent to the vessels, in the peripheral region of the Rosenthal's canal, and occasionally in the spiral ligament. While there are a surprisingly large number of macrophages in the stria vascularis as well as between the auditory neurons,CD4^+ and CD8^+ cells are hardly seen in these areas, and neither are seen in the organ of Corti. In the modiolus,macrophages, CD4^+ and CD8^+ cells appeared often in clusters. Interaction between these different cells was easily observed with SR-SIM, showing closely placed cell bodies, and the processes from macrophages reaching out and touching the lymphocytes. Otherwise the CD4^+ and CD8^+ cells in human cochlear tissue are discretely scattered. The possible roles of these immune cells are speculated.

Advanced Glycation End Products Promote Differentiation of CD4^+ T Helper Cells toward Pro-inflammatory Response

This study investigated the effect of advanced glycation end products（AGEs） on differentiation of na ve CD4＋T cells and the role of the receptor of AGEs（RAGE） and peroxisome proliferator-activated receptors（PPARs） activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin（BSA） with glucose. Human na ve CD4＋T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin（sh） RNA knock-down experiment, na ve CD4＋T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-XTM293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4＋T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T（Treg） cells was determined by a [3H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from na ve CD4＋T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in na ve CD4＋T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4＋T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα; PPARγ agonist, PGJ2, inhibited the effect of AGEs on na ve CD4＋T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It was concluded that AGEs may promote CD4＋T cells development toward pro-inflammatory state, which is associated with increased RAGE mRNA expression and reduced PPARγ activity. ＋

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

Regulatory T cells （Treg） play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Thl responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4＋CD25＋ T cells from the immunized mice. Moreover, CD4＋CD25＋Foxp3＋ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naive mice. Further analysis showed that the serum of immunized mice contains a high level ofanti-CD25 antibody （about 30 ng/ml, p〈0.01 vs controls）. Consistent with a role ofanti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naive mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4＋CD25＋Foxp3＋ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Thl response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.

Proliferation and Apoptosis of Bone Marrow CD4^+ T Cells in Patients with Aplastic Anemia and Impacts of the Secreted Cytokines on Hematopoietic Stem Cells from Umbilical Cord Blood

Recent studies indicate that immune-associated aplastic anemia(AA)resembles such autoimmune diseases as insulin-dependent diabetes and chronic autoimmune thyroiditis that belong to organ-specific autoimmune diseases.Many independent investigation groups have successfully isolated the pathopoiesis-associated T cell clone causing hematopoiesis failure with a CD4 phenotype from peripheral blood and bone marrow(BM)in AA patients.In the current study,BM CD4+ T cells were isolated from AA patients and healthy con...