Pregnancy-specific glycoprotein 1a activates dendritic cells to provide signals for Th17-, Th2-, and Treg-cell polarization

Because of their plasticity and central role in orchestrating immunity and tolerance, DCs can respond to pregnancy-specific signals, thus promoting the appropriate immune response in order to support pregnancy. Here, we show that pregnancy-specific glycoprotein (PSG1a), the major variant of PSG released into the circulation during pregnancy, targets DCs to differentiate into a subset with a unique phenotype and function. This semi-mature phenotype is able to secrete IL-6 and TGF-β. PSG1a also affected the maturation of DCs, preventing the up-regulation of some costimulatory molecules, and inducing the secretion of TGF-β or IL-10 and the expression of programmed death ligand 1 (PD-L1) in response to TLR-9 or CD40 ligation. In addition, PSG1a-treated DCs promoted the enrichment of Th2-type cytokines, IL-17-producing cells, and Treg cells from CD4(+) T cells from DO11.10 Tg mice. Moreover, in vivo expression of PSG1a promoted the expansion of Ag-specific CD4(+) CD25(+) Foxp3(+) Treg cells and IL-17-, IL-4-, IL-5-, and IL-10-secreting cells able to protect against Listeria monocytogenes infection. Taken together, our data indicate that DCs can be targeted by PSG1a to generate the signals necessary to mount an appropriate, well-balanced, and effective immune response able to protect against invading pathogens while at the same time being compatible with a successful pregnancy.     

喘可治注射液对人外周血单个核细胞Th1/Th2细胞因子谱的影响

目的：通过研究喘可治注射液对人外周血单个核细胞（PBMCs）Th1／Th2细胞因子谱的影响，探讨喘可治注射液的免疫调节作用机制。方法：以流式微球分析（CBA）法检测不同处理情况下，人外周血单个核细胞分泌Th1（IFN-γTNF-α、IL-2）和Th2（IL4、IL-6、IL-10）细胞因子水平。结果：健康人PBMCs体外培养12小时后，上清中细胞因子主要为TNF-α和IL-6，喘可治使Th1和Th2细胞因子全面升高；喘可治对PDB加离子霉素诱导的PBMCs分泌Th1和Th2细胞因子具有抑制作用，并能抑制流感病人异常升高的INF-γ、TNF-α、IL-6和IL-10分泌。结论：喘可治注射液上调健康人PBMCs分泌TH1和Th2细胞因子，对异常活化的PBMCs分泌的Th1和Th2细胞因子则具有下调作用。     

慢性乙肝患者树突状细胞对Th1/Th2分化的影响

探讨慢性乙肝患者树突状细胞(dendritic cells,DC)对CD4+Th细胞亚群分化的影响。分离慢性乙肝患者外周血单个核细胞(PBMC),以rhIL-4(50 ng/ml)、rhGM-CSF(10 ng/ml)和rhTNF-α(100 u/ml)诱导培养DC。以流式细胞仪检测DC表面CD1a、CD83、CD80、CD86、HLA-DR分子表达情况。MTT法检测DC刺激同种异体淋巴细胞增殖能力。免疫磁珠分离外周血CD4+T细胞亚群,PMA+Ionomycin刺激后胞内荧光染色,流式细胞仪检测辅助性T细胞(helper T cell,Th)内特征性细胞因子IFN-γ/IL-4以判断Th1/Th2分化。ELISA法检测DC或Th细胞培养上清中IL-6、IL-12、IFN-γ和IL-4的含量。结果:慢性乙肝患者的DC表达CD1a、CD83、CD80、CD86、HLA-DR分子水平明显低于正常人(P<0.01);培养至第7天,慢性乙肝患者DC分泌的IL-12水平低于正常人(P<0.01),而分泌的IL-6水平增高(P<0.05)。与正常人相比,慢性乙肝患者外周血中Th1细胞占CD4+T细胞的百分比较低(P<0.01),其Th细胞培养上清中IFN-γ的量也较低(P<0.01)。患者DC与同种异体的健康人Th细胞共培养,刺激Th1型细胞因子IFN-γ产生的能力低于正常人(P<0.01)。慢性乙肝患者体内DC功能的异常可能导致了外周血Th1细胞分化不足。     

Selective down-regulation of Th2 immune responses following treatment with antigen-coupled splenocytes

Intravenous injection of antigen-coupled splenocytes has been widely used to induce specific tolerance to a variety of antigens. In this study, we investigated the effects of such a treatment on Th1 and Th2 antigen-specific immune responses. Using both well-characterized model antigens and crude homogenates from Leishmania major promastigotes, we found that intravenous injection of antigen-coupled splenocytes strongly down-regulated antigen-specific Th2 responses but had no or only moderate effects on Th1 responses. Because the susceptibility of inbred strains of mice to murine leishmaniasis has been found to be correlated with a strong Th2 response against parasite antigens, we investigated whether administration of splenocytes chemically coupled to parasite antigens could protect susceptible mice from murine leishmaniasis. We found that this was indeed the case and further demonstrated that protection was associated with a strong decrease in the number of parasite-specific Th2-like cells. Because administration of antigen-coupled splenocytes is believed to induce ligation of the T cell receptor complex without inducing a co-stimulatory signal, our results further suggest that priming of Th1 cells is less dependent on co-stimulatory signals than the priming of Th2 cells.     

TLSFJM对Th1/Th2样细胞亚群比率的影响

目的 :探讨TLSFJM 对同种异体抗原活化的Th1/Th2样细胞亚群变化的影响。方法 :在混合淋巴细胞反应 (MLR)体系中加入TLSFJM 或IL 4 ,用细胞内免疫荧光染色结合流式细胞术分析TLSFJM 对Th1/Th2样细胞亚群比率的影响。结果 :在TLSFJM实验组中 ,活化淋巴母细胞分化为IFN γ 细胞的比率略有降低 (49.8%→ 4 3.1% ) ,IL 4 、IL 6 细胞的比率有明显降低 ,IL 4 细胞的比率由 75 .4 %降至 4 3.7% ,IL 6 细胞的比率由6 7.8%降至 5 2 .6 %。在未活化小淋巴细胞中 ,也观察到同样的趋势。结论 :TLSFJM 对Th1、Th2样细胞亚群都有抑制 ,但似乎主要作用于Th2样细胞亚群 ,从而使其在Th1/Th2样细胞的比例降低     

CCK-8对KLH免疫小鼠脾细胞Th1/Th2平衡的影响

目的： 探讨八肽胆囊收缩素（CCK-8）对Th1/Th2平衡的调节作用。方法: 给予BALB/c小鼠钥孔戚血蓝蛋白（KLH）免疫同时体内给予不同剂量的CCK-8,酶联免疫吸附试验(ELISA)检测其脾细胞培养上清中Th1型细胞因子γ-干扰素(IFN-γ)、白细胞介素-2（IL-2）和Th2型细胞因子白细胞介素-4（IL-4）、白细胞介素-5（IL-5）水平,逆转录聚合酶链式反应(RT-PCR)法检测脾细胞中IFN-γ、IL-2、IL-4、IL-5 mRNA表达;ELISA法检测血清中Th1型抗KLH抗体IgG2a和Th2型抗KLH抗体IgG1水平。结果: ①KLH免疫使小鼠脾细胞分泌Th1/Th2型细胞因子水平明显增高,mRNA表达增高,KLH免疫同时给予CCK-8可使脾细胞培养上清中IFN-γ、IL-2含量进一步增加和IFN-γ、IL-2mRNA表达增高,而使IL-4、IL-5含量降低,IL-4、IL-5 mRNA表达减低和降低IL-4/IFN-γ比值。②KLH免疫小鼠血清中IgG2a、IgG1发生不同程度增高,CCK-8可使其血清中IgG1水平减低而使IgG2a水平增高。结论: CCK-8可促进KLH免疫小鼠体内Th1反应,使Th2优势反应向Th1方向转变。     

树突细胞与哮喘Th1/Th2失衡

特应性哮喘患者以Th2免疫反应为主,导致气道炎症,Th1／Th2失衡是特庆性哮喘重要的免疫病理机制,树突细胞（DCs）中肺部主要抗原递呈细胞,不但可以介志对吸入抗原初始的免疫反应,活化辅助性T细胞,而且在可以决定T细胞的分化方向,维持哮喘Th2免疫反应和Th1／Th2失衡机制中发挥重要作用而日益受到重视。本文就近年来对特应性哮喘免疫病理机制中DCs对Th1／Th2失衡影响认识作一综述。     

Th1/Th2漂移与HCV感染慢性化

Thl和Th2细胞分别介导机体的细胞免疫和体液免疫,它们来自一个共同的前体细胞Th0,在不同的细胞因子、抗原等因素的影响下,可发生Thl与Th2的转换。HCV感染时,Th1应答与丙型肝炎的好转有关,Th2应答与丙型肝炎慢性化有关。因此,Thl与Th2之间的漂移对HCV感染的转归有重要影响,是HCV感染慢性化的重要机制。     

外周血Th1/Th2细胞在大鼠肝移植早期的变化

目的观察外周血Th1/Th2细胞在大鼠肝移植早期不同免疫状态下的变化趋势是否和免疫状态有关。方法大鼠分3组：A组：同基因移植组（BN→BN）;B组：异基因移植（Lewis→BN）＋环孢素A（CsA）组;C组：异基因移植组。均36只,另外各设观察组观察生存期。于移植后1、3、5、7和14d应用流式细胞分析外周血CD4^＋CD45RC^&#177;的百分数,观察移植肝排斥反应病理分级及受体存活时间。结果（1）A组和B组的生存期平均大于100d,明显长于C组（34.3&#177;3.6）d。（2）除第1天外,C组和B组各时间段的排斥分级明显高于A组（P〈0.05或〈0.01）;C组亦明显高于B组（P〈0.05或〈0.01）。（3）移植后3d起CD4^＋CD45RC^＋%/CD4^＋CD45RC^-%在C组明显高于A组和B组（P〈0.05或〈0.01）。（4）CD4^＋CD45RC^＋%/CD4^＋CD45RC^-%在B组和排斥分级存在负相关（r=-0.565,P〈0.01）,而在C组CD4^＋CD45RC^＋%/CD4^＋CD45RC^-%和排斥分级存在正相关（r=0.745,P〈0.01）。结论外周血Th1/Th2细胞的变化趋势和大鼠肝移植早期不同免疫状态有关。     

The role of IL-12 in the maintenance of an established Th1 immune response in experimental leishmaniasis

IL-12 initiates the development of cell-mediated immunity by promoting the differentiation of naive T cells into the Th1 phenotype, and is essential in the development of a Th1 immune response to the intracellular protozoan parasite, Leishmania major. The present study investigated whether IL-12 is also required for the maintenance and effector function of an established Th1 immune response in L. major -infected mice. While neutralization of IL-12 com promised the ability of a leishmanial antigen-reactive Th1 cell clone to produce IFN-γ in vitro, lymphnode cells taken from 2-week L. major -infected mice were able to secrete IFN-γ in an IL-12-independent manner. However, when a short-term T cell line was established in vitro from lymph node cells, the production of IFN-γ again became IL-12 dependent. These results suggest that other factors may compensate for IL-12 in vivo in promoting IFN-γ production during L. major infection. To directly assess if IL-12 was required in vivo for resistance to L. major, we studied the effect of IL-12 neutralization on both a primary and secondary L. major infection in C3H mice. L. major infection in C3H mice is characterized by the development of a small lesion that heals by 8 weeks, and these animals are resistant to reinfection. As previously reported, administration of anti-IL-12 monoclonal antibody (mAb) during a primary infection led to severe disease. However, mice that had healed from a primary infection with L. major and were treated with anti-IL-12 mAb were as resistant as control animals. These findings suggest that once Th1 cells have developed, their effector function in vivo is independent of IL-12, and that this independence is not due to an intrinsic property of the T cell, but to the microenvironment created by the infection.     

Effects of adjuvants on the immune response to allergens in a murine model of allergen inhalation: cholera toxin induces a Th1-like response to Bet v 1, the major birch pollen allergen

Based on the fact that type I allergies are frequently elicited by inhalant allergens, we have established a model of aerosol inhalation leading to allergic sensitization in BALB/c mice. Using this model we studied the effects of aluminium hydroxide (Al(OH)₃), known to enhance IgE antibody responses, compared with cholera toxin (CT), a potent mucosal adjuvant, on the immune response to birch pollen (BP) and its major allergen Bet v 1. Two groups of BALB/c mice were either systemically immunized with recombinant Bet v 1 in Al(OH)₃ and subsequently aerosol exposed to BP allergen, or aerosolized with BP and CT. IgE-mediated skin reactions were only elicited in the mice which had received Bet v1/Al(OH)₃. Allergen-specific serum IgE and IgG1 antibodies dominated in the Al(OH)₃ group, IgG2a antibody levels to BP and rBet v 1 were markedly higher in the sera of mice exposed to CT with the allergen. IgA antibodies were only detected in the bronchial lavage of the CT-treated group. Moreover, the latter group displayed consistently higher T cell proliferative responses to BP and interferon-gamma production in vitro. Thus, the systemic immunization with rBet v 1 in Al(OH)₃ before inhalation of the BP extract promoted a Th2-like immune response, while CT mixed with the aerosolized BP extract rather induced a Th1-like immune response. In an attempt to reverse these ongoing immune responses we could achieve a shift towards a Th0 response. Immunization with BP extract without adjuvant treatment led to undetectable antibody or cellular immune responses. We conclude from the present study that the induction of an immune response to BP allergen after aerosol inhalation can be directed towards a Th1- or a Th2-like response. Once established, the immune response can be modulated.     

Analysis of apoptosis and a Th1/Th2 phenotype in HIV-infected patients

Lymphocytes from HIV patients, unlike those from normal HIV-negative subjects, underwent apoptosis upon in vitro culture. We found that the percentage of lymphocytes undergoing apoptosis was significantly higher (P = 0.005) in patients with low CD4 cell counts (< 200 CD4 cells/μl) (60%) than in patients at earlier stage (> 500 CD4 cells/μl) (35%). Serum IgE levels increased in two of six patients at last stage and in two of five patients at earlier stage. Spontaneous production of both IL-2 and IL-10, by peripheral blood mononuclear cells (PBMC) after 48 h in culture, was greater in HIV-infected subjects and increased with disease progression. IFN-γ production was greater in HIV-infected subjects but there was no evident change with disease progression. IL-4 production was barely detectable or not detected in both HIV-infected and HIV-negative individuals. These results indicate that spontaneous apoptosis is associated with advanced disease. However, there was no evidence of in vivo switch from the Th1 to Th2 phenotype in HIV-infected patients.     

Development of Neonatal Th1/Th2 Function

Newborn animals generally mount poor T cell-mediated immune responses in vivo. As a result, neonates fall prey to infectious agents and diseases which have little impact on immunocompetent adult animals. For some time, it was believed that this phenomenon was due to an intrinsic inability of newborns to mount developmentally mature Th1 responses. Recent studies in mice have challenged that view; under certain conditions, adult-level Th1 function has been achieved in newborns. More often, however, neonates develop Th2-dominant responses. A major challenge in the field of developmental immunology is to understand why the ‘default’ response for neonates is Th2 function. Cell intrinsic as well as environmental influences may contribute to Th2 skewing in neonates.     

特应性皮炎患者外周血细胞亚群DC1/DC2、Th1/Th2检测的临床意义

为探讨特应性皮炎（AD）患者外周血细胞亚群DC（DC1/DC2）与细胞亚群Th（Th1/Th2）分化状态及其临床意义,采用免疫荧光三标记流式细胞术检测35例特应性皮炎患者外周血DC1/DC2亚群（DC1/CD11 c＋和DC2/CD123＋）、Th1/Th2亚群（CD3＋CD4＋CD30-/CD3＋CD4＋CD30＋）,并以35名正常人作为对照组。结果表明,特应性皮炎患者DC CD123＋百分率比对照组明显增高（P＆lt;0.05）,而CD11 c＋DC百分率与对照组相比,无统计学意义（P＆gt;0.05）;Th2（CD3＋CD4＋CD30＋）显著增高（P＆lt;0.05）,Th1亚型（CD3＋CD4＋CD30-）与对照组比较,差异无统计学意义（P＆gt;0.05）。特应性皮炎患者外周血细胞亚群DC2呈优势,导致向细胞亚群Th2的免疫反应偏移,这可能与特应性皮炎的发病有关。     

腹腔镜子宫肌瘤剔除术对Th1/Th2细胞平衡的影响

目的:为了探讨腹腔镜子宫肌瘤剔除术对Th1/Th2细胞平衡的影响。方法:择期子宫肌瘤患者4 0例,分别采用腹腔镜手术和常规开腹手术,测定术前、术后2、2 4、4 8小时Th1、Th2细胞数量及血清IL 18、IL 10水平。结果:两组术后2小时均出现Th1/Th2细胞平衡向Th2反应转换,Th1细胞、Th1/Th2比值、IL 18下降(腹腔镜组:P <0 0 5 ,P <0 0 1,P <0 0 5 ;开腹组:P <0 0 1,P <0 0 1,P <0 0 1) ,而Th2细胞、抗炎因子IL 10上升(腹腔镜组:P <0 0 1,P <0 0 1;开腹组:P <0 0 1,P <0 0 1)。但腹腔镜组术后2 4小时各项指标即恢复,而开腹组各项指标的变化与术后2小时类似,并持续至术后4 8小时。结论:腹腔镜子宫肌瘤剔除术对Th1/Th2细胞平衡影响小,恢复快,优于开腹手术。     

Th1/Th2、Tc1/Tc2亚群在乙肝肝硬化患者中的作用

目的 :探讨乙肝肝硬化患者外周血 (PBMC)中CD4 和CD8 T细胞内Th1和Th2类细胞的平衡状态 ,探明Th1、Th2类细胞在乙肝肝硬化中的作用。方法 :乙肝肝硬化患者CD4 T细胞和CD8 T细胞中IFN γ 和IL 4 细胞的百分率 ,观察乙肝肝硬化患者Th1 Th2、Tc1 Tc2比例的变化。结果 :乙肝肝硬化患者PBMC中CD4 ,CD8细胞 ,CD4 CD8比值与健康对照者相比无统计学差异 (P >0 0 5 ) ,Th1细胞及Tc1细胞百分率为 8 8% ,9 0 % ,较健康对照者 7 5 % ,7 7%升高 (P <0 0 5 )。结论 :乙肝肝硬化患者外周血T细胞亚群发生Th1类偏移 ,在乙肝肝硬化的发生和发展中可能起重要作用     

Th1/Th2 cytokine responses following HIV-1 immunization in seronegative volunteers

The Th1/Th2 profile that follows human vaccination may profoundly influence the subsequent course of disease after infection. However, the ability to detect IL-4 has been limited outside trials of live vaccination. By using methods in which memory effector cells are allowed to antigenically expand by short term culture, followed by low-dose mitogenic stimulation, we have been able to follow the Th1/Th2 profile in HIV-1^?volunteers enrolled in two phase I studies of HIV immunogens (a recombinant gp120 and a multivalent, octomeric V3 loop peptide). Antigen-specific interferon-gamma (IFN-γ) could be detected in primary stimulation, but IL-4 was observed only after antigenic expansion and restimulation. In both of these studies the responses after initial immunizations were dominated by IFN-γ, with IL-4 appearing only after multiple rounds of immunization, and IL-4 was temporally related to antibody production. Concomitant with the IL-4 production, the amount of supernatant IFN-γ declined. Antigen-specific IL-10 was not detected in either study. Such techniques, which have been shown to correlate with outcomes in immunotherapy, may prove useful as future surrogates of human vaccine response.     

Live varicella vaccine polarizes the mucosal adjuvant action of cholera toxin or its B subunit on specific Th1-type helper T cells with a single nasal coadministration in mice

This study was undertaken to determine whether the specific Th1- or Th2-cell response to varicella-zoster virus was induced predominantly by a mucosal adjuvant, cholera toxin, in mice. A commercially available live varicella vaccine (Oka strain) and cholera toxin or its B subunit were administered simultaneously via the nasal route. Delayed-type hypersensitivity to the Oka vaccine was induced, but the systemic neutralizing antibody response was low. The delayed-type hypersensitivity evoked after a single administration was relatively higher than that on administration three times. When spleen cells from mice immunized once with the vaccine and cholera toxin or its B subunit were restimulated with the live vaccine in vitro, there was greater thymidine uptake and production of interleukin- 2 (IL-2) than controls, but only a low level of IL-4 production. The production of IL-2 induced by the B subunit of cholera toxin was less than that by cholera toxin and a mutant of Escherichia coli enterotoxin on co-immunization with the vaccine in mice. Cholera toxin and its B subunit have been reported to induce predominantly a specific Th2-type T-cell response to various antigens. However, the Oka vaccine is an antigen that polarizes the activation of specific Th1/Th2-type T cells by cholera toxin or its B subunit to the Th1-type side. Cholera toxin and its B subunit are thus useful mucosal adjuvants for inducing cellular immunity to the Oka vaccine similar to Escherichia coli enterotoxin.