Th1/Th2/Th17/Treg cytokines in Guillain–Barré syndrome and experimental autoimmune neuritis

Guillain–Barré syndrome (GBS) is an immune-mediated acute inflammatory disorder in the peripheral nervous system (PNS) of humans characterized by inflammatory infiltration and damage to myelin and axon. Experimental autoimmune neuritis (EAN) is a useful animal model for GBS. Although GBS and EAN have been widely studied, the pathophysiological basis of GBS/EAN remains largely unknown. Immunocompetent cells together with cytokines produced by various cells contribute to the inflammatory process of EAN by acting as mediators or effectors. Both GBS and EAN have hitherto been attributed to T helper (Th)1 cells-mediated disorders, however, some changes in GBS and EAN could not be explained by the pathogenic role of Th1 cells and a disturbance of the Th1/Th2 balance, which has previously been considered to be important for the homeostatic maintenance of the immune responses and to explain the adaptive immunity and autoimmune diseases. The Th1/Th2 paradigm in autoimmune diseases has been greatly challenged in recent years, with the identification of a particular T cell subset Th17 cells. Studies on the associations between Th17 cells/cytokines and GBS/EAN are reviewed. But some of them occasionally yield conflicting results, indicating an intricate network of cytokines in immune response.     

Short-term therapy with celecoxib and lansoprazole modulates Th1/ Th2 immune response in human gastric mucosa

Background: Selective cyclooxygenase‐2 (COX‐2) inhibitors and proton pump inhibitors may exert immune‐mediated effects in human gastric mucosa. T‐cell immune response plays a role in Helicobacter pylori‐induced pathogenesis. This study evaluated effects of celecoxib and lansoprazole on T‐helper (Th) 1 and Th2 immune response in human gastric mucosa. Methods: Dyspeptic patients with or without osteoarticular pain were given one of the following 4‐week therapies: celecoxib 200 mg, celecoxib 200 mg plus lansoprazole 30 mg, and lansoprazole 30 mg daily. Expression of COX‐2, T‐bet, and pSTAT6 and production of prostaglandin E₂ (PGE₂), interferon (IFN)‐γ, and interleukin (IL)‐4 were determined in gastric biopsies before and after therapy. Histology was evaluated. Results: Cyclooxygenase‐2 expression and PGE₂ production was higher, and Th1 signaling pathway was predominant in H. pylori‐infected vs. uninfected patients. T‐bet expression and IFN‐γ production increased, while STAT6 activation and IL‐4 production decreased following therapy with celecoxib and celecoxib plus lansoprazole, respectively. Th1 and Th2 signaling pathways down‐regulated after therapy with lansoprazole, and this was associated with an improvement of gastritis. Effect of therapy was not affected by H. pylori status. Conclusion: Celecoxib and lansoprazole modulate Th1/Th2 immune response in human gastric mucosa. The use of these drugs may interfere with long‐term course of gastritis.     

Multimarker scores of Th1 and Th2 immune cellular profiles in peripheral blood predict response and immune related toxicity with CTLA4 blockade and IFNα in melanoma

Neoadjuvant therapy with ipilimumab in combination with high dose IFNα was evaluated in patients with locally/regionally advanced melanoma in a previously reported clinical trial [NCT01608594]. In this study, peripheral immune cell profiling was performed in order to investigate the underlying mechanisms of tumor immune susceptibility and resistance. Peripheral blood mononuclear cells (PBMCs) from treated patients (N = 28) were collected at baseline and then at 6-weeks, 3-months and 12-months. High complexity (14-color) flow cytometry, designed to detect key immunological biomarkers was used to evaluate the frequencies of immune cell subsets. Statistical significance was determined using R-package employing Kruskal's test. We found that higher levels of Th1 cells at baseline (defined as CD45RA- CCR6- CXCR3+ CCR4-) correlated with the preoperative radiological response (p = 0.007) while higher Th2 cells (defined as CD45RA- CCR6- CXCR3- CCR4+) were associated with progressive disease (p = 0.009). A multimarker score consisting of higher levels of Th1 cells and CD8+ central memory T-cells was associated with pathologic complete response (pCR) (p = 0.041) at surgical resection. On the other hand, high TIM3 expression on T-cells correlated with gross viable tumor (p = 0.047). With regard to immune related toxicity, higher levels of phenotypically naive (defined as CCR7+CD45RA+) and effector memory (defined as CCR7-CD45RO+) CD8+ T-cells (p = 0.014) or lower levels of Th2 cells were associated with lower toxicity (p = 0.024). Furthermore, a multimarker score consisting of higher CD19+ and CD8+ cells was associated with lower toxicity (p = 0.0014). In conclusion, our study yielded mechanistic insights related to the immune impact of CTLA4 blockade and IFNα and potential biomarkers of immune response and toxicity.     

A High Frequency of Circulating Th22 and Th17 Cells in Patients with New Onset Graves’ Disease

T-helper (Th) 22 and Th17 cells are involved in the pathogenesis of autoimmune diseases. However, their roles in the pathogenesis of Graves’disease (GD) are unclear. This study is aimed at examining the frequency of peripheral blood Th22, Th17, and Th1 cells and the levels of plasma IL-22, IL-17, and IFN-γ in patients with GD. A total of 27 patients with new onset GD and 27 gender- and age-matched healthy controls (HC) were examined for the frequency of peripheral blood Th22, Th17, and IFN-γ cells by flow cytometry. The concentrations of plasma IL-22, IL-17, and IFN-γ were examined by enzyme-linked immunosorbent assay. The levels of serum TSHR antibodies (A-TSHR), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) were examined by radioimmunoassay and chemiluminescent assay, respectively. The levels of serum TSAb were examined by enzyme-linked immunosorbent assay. In comparison with those in the HC, significantly elevated percentages of Th22 and Th17 cells, but not Th1 cells, and increased levels of plasma IL-22 and IL-17, but not IFN-γ, were detected in GD patients (P<0.0001, for both). The percentages of both Th22 and Th17 cells and the levels of plasma IL-22 and IL-17 were correlated positively with the levels of serum TSAb in GD patients (r = 0.7944, P<0.0001; r = 0.8110, P<0.0001; r = 0.7101, p<0.0001; r = 0.7407, p<0.0001, respectively). Th22 and Th17 cells may contribute to the pathogenesis of GD.     

Th1 and Th2 cytokines are elevated in HCV-infected SVR(−) patients treated with interferon-α

Interferon-α-based treatment is a standard therapy to cure hepatitis C virus-infected patients. However, the reasons for the failure of interferon-α treatment in some patients have not been fully elucidated. We evaluated the differences in the expression levels of various cytokines among patients with and without sustained viral response (SVR). We found that the chemokines (MIG and IP-10) and inflammation-related cytokines (IL-6) were transiently elevated in patients with SVR(+) before interferon-α treatment and in the early phase of treatment (week 2), indicating that these cytokines may be related to viral clearance. Furthermore, higher serum levels of Th1 and Th2 cytokines (IL-2, IL-4, IL-5, IL-10, tumor necrosis factor, and IFN-γ) were observed in SVR(−) than in SVR(+) patients, indicating that they may be associated with ineffective anti-HCV immune response. Our data revealed that the patterns of cytokines varied greatly between SVR(+) and SVR(−) patients before and after IFN-α treatment.     

Estrogen receptor α signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis

Estrogen treatment exerts a protective effect on experimental autoimmune encephalomyelitis (EAE) and is under clinical trial for multiple sclerosis therapy. Estrogens have been suspected to protect from CNS autoimmunity through their capacity to exert anti-inflammatory as well as neuroprotective effects. Despite the obvious impacts of estrogens on the pathophysiology of multiple sclerosis and EAE, the dominant cellular target that orchestrates the anti-inflammatory effect of 17β-estradiol (E2) in EAE is still ill defined. Using conditional estrogen receptor (ER) α-deficient mice and bone marrow chimera experiments, we show that expression of ERα is critical in hematopoietic cells but not in endothelial ones to mediate the E2 inhibitory effect on Th1 and Th17 cell priming, resulting in EAE protection. Furthermore, using newly created cell type-specific ERα-deficient mice, we demonstrate that ERα is required in T lymphocytes, but neither in macrophages nor dendritic cells, for E2-mediated inhibition of Th1/Th17 cell differentiation and protection from EAE. Lastly, in absence of ERα in host nonhematopoietic tissues, we further show that ERα signaling in T cells is necessary and sufficient to mediate the inhibitory effect of E2 on EAE development. These data uncover T lymphocytes as a major and nonredundant cellular target responsible for the anti-inflammatory effects of E2 in Th17 cell-driven CNS autoimmunity.     

Cutting edge: loss of α4 integrin expression differentially affects the homing of Th1 and Th17 cells

The neutralization of α4 integrin is currently used as treatment in several autoimmune diseases and is thought to prevent the entry of most immune cells in target tissues. In this study, we showed that selective deletion of α4 integrin in T cells did not prevent but delayed the development of experimental autoimmune encephalomyelitis. Whereas both Th1 and Th17 cells infiltrate the CNS of wild-type mice, T cells present in the CNS of mice lacking α4 integrin were mainly enriched in Th17 cells, suggesting that this T cell subset uses other integrins to access the CNS. In contrast, α4 integrin expression is important for Th1 cells to enter the CNS and for the stability of their Th1-associated genetic program. Therefore, our data suggest that anti-α4 integrin Ab treatment may be more efficient in the treatment of Th1- rather than Th17-mediated disease.     

Vaccination with CD133+ melanoma induces specific Th17 and Th1 cell�Cmediated antitumor reactivity against parental tumor

Accumulating evidence suggests that cancer cells possess a small subpopulation that survives during potentially lethal stresses, including chemotherapy, radiation treatment, and molecular-targeting therapy. CD133 is a putative marker that distinguishes a minor subpopulation from normal differentiated tumor cells in many cancers. Although it is necessary to eradicate all cancer cells to obtain a cure, effective treatment to eliminate the CD133(+) treatment-tolerant cells has not been elucidated. In this study, we demonstrated that a CD133(+) subpopulation in murine melanoma is immunogenic and that effector T cells specific for the CD133(+) melanoma cells mediated potent antitumor reactivity, curing the mice of the parental melanoma. CD133(+) melanoma antigens preferentially induced type 17 T helper (Th17) cells and Th1 cells but not Th2 cells. CD133(+) melanoma cell-specific CD4(+) T-cell treatment eradicated not only CD133(+) tumor cells but also CD133(-) tumor cells while inducing long-lasting accumulation of lymphocytes and dendritic cells with upregulated MHC class II in tumor tissues. Further, the treatment prevented regulatory T-cell induction. These results indicate that T-cell immunotherapy is a promising treatment option to eradicate CD133(+) drug-tolerant cells to obtain a cure for cancer.     

Isolation and Th17 Differentiation of Na?ve CD4 T Lymphocytes

Th17 cells are a distinct subset of T cells that have been found to produce interleukin 17 (IL-17), and differ in function from the other T cell subsets including Th1, Th2, and regulatory T cells. Th17 cells have emerged as a central culprit in overzealous inflammatory immune responses associated with many autoimmune disorders. In this method we purify T lymphocytes from the spleen and lymph nodes of C57BL/6 mice, and stimulate purified CD4+ T cells under control and Th17-inducing environments. The Th17-inducing environment includes stimulation in the presence of anti-CD3 and anti-CD28 antibodies, IL-6, and TGF-β. After incubation for at least 72 hours and for up to five days at 37 °C, cells are subsequently analyzed for the capability to produce IL-17 through flow cytometry, qPCR, and ELISAs. Th17 differentiated CD4+CD25- T cells can be utilized to further elucidate the role that Th17 cells play in the onset and progression of autoimmunity and host defense. Moreover, Th17 differentiation of CD4+CD25- lymphocytes from distinct murine knockout/disease models can contribute to our understanding of cell fate plasticity.     

Th1／Th2迁移与支气管哮喘研究进展

支气管哮喘是由多种炎症细胞和细胞组分参与的气道慢性炎症疾病。发病机制尚未明了,但作为一种免疫调节异常性疾病已取得大多学者的共识。支气管哮喘是一种Th1／Th2细胞数量及其功能失衡,主要表现为Th2数量及其功能优势的疾病。     

Th1/Th2细胞分化的分子机制

Th1/Th2细胞亚群的分化是不同的细胞因子、抗原及环境等综合因素作用的结果。在细胞因子参与的Th细胞分化中,JAK/STAT信号途径是细胞因子受体转导细胞内信号的一种主要机制。本文主要就Th1/Th2细胞的功能、分化的分子机制及其影响因素作一综述。     

Th1/Th2细胞在心肌梗死中的作用

Th1/Th2细胞因子平衡对于维持机体的正常免疫状态是重要因素,其平衡的紊乱与很多疾病密切相关,如感染性疾病、自身免疫性疾病、肿瘤、心血管疾病等.在心肌梗死的发生发展过程中存在炎症反应,病变的心肌细胞及其他炎症细胞均可产生大量炎症细胞因子和炎症介质,有研究证实这些细胞因子影响心肌重构.近年来关于Th1/Th2细胞因子的平衡与心血管疾病的关系已成为研究的重点.急性心肌梗死的发作与免疫应答的关系越来越引起人们的关注.本文就Th1/rh2细胞在心肌梗死中的作用做一简要综述.     

乙型肝炎与Th1—Th2细胞失衡的研究进展

根据分泌细胞因子的不同将Ｔｈ细胞分为Ｔｈ０、Ｔｈ１、和Ｔｈ２细胞。Ｔｈ０细胞是Ｔｈ前体细胞,Ｔｈ１细胞促进细胞免疫应答,Ｔｈ２细胞参与体液免疫应答,在感染性疾病中,Ｔｈ１细胞应答抗御感染,Ｔｈ２细胞应答则导致易感。慢性持续性乙型肝炎与Ｔｈ２细胞亚群偏离有关。转基因鼠的研究表明：ＨＢｅＡｇ可选择性诱导Ｔｈ１细胞无反应性,Ｔｈ１－Ｔｈ２细胞亚群失衡受ＴＣＲ－肽－ＭＨＣ复合体及细胞因了环境等多种因素影响     

正确认识Th1—Th2细胞在传染病中的作用

本文对Ｔｈ１及Ｔｈ２细胞在传染病中的作用提出了置疑，认为Ｔｈ１应符保护细胞内寄生病原，Ｔｈ２应答保护细胞外寄生病原体的说法是教条，严重地影响研究的进展。作者认为不应把复杂的免疫学现象简单化。     

Th2 cytokines and asthma — Interleukin-9 as a therapeutic target for asthma

Asthma is a complex heritable inflammatory disorder of the airways in which the development of clinical disease depends on environmental exposure. It has been well established that T helper type 2 (T_H2) lymphocytes and their cytokines have an important role in allergic asthma. Interleukin (IL)-9, a member of the T_H2 cytokine family, has recently been implicated as an essential factor in determining mucosal immunity and susceptibility to atopic asthma. In this review we examine the critical experiments and observations that support this hypothesis. We also discuss these results in comparison with the experiments supporting the involvement of other T_H2 cytokines such as IL-4, IL-5 and IL-13.