Cimetidine augments Th1/Th2 dual polarized immune responses to recombinant HBV antigens

Zhang, Wenjuan; Wang, Junpeng; Su, Baowei; Li, Ruiguo; Zheng, Dong; Kang, Youmin; Wang, Bin

doi:10.1016/j.vaccine.2011.03.091

Cited by 20 publications

(24 citation statements)

References 14 publications

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“…The progressive increase in level of pAkt up to 12 h reciprocally reflected the decreasing level of Foxp3 protein. This result was consistent with our previous observation, 17 suggesting that the pAkt activation may affect the Foxp3 protein.…”

Section: Cimetidine Reduces Foxp3 By Modulating the Pi3k-akt Pathwaysupporting

confidence: 94%

“…17 In this study, we showed that the PI3K inhibitor LY294002 could block the effect of CIM on Foxp3 degradation. This suggested that CIM-induced Foxp3 destabilization likely was due to the activation of PI3K-Akt-mTOR pathway which in turn activated Stub1-induced ubiquitination and degradation.…”

Section: Discussionmentioning

confidence: 70%

“…Sauer S. et al had demonstrated that constitutive PI3K-AktmTOR activity antagonized Foxp3 induction 28 and our previous study revealed that CIM could activate PI3K-Akt-mTOR pathway, 17 therefore we reasoned that CIM might enhance Stub1 activity to destabilize the Foxp3 protein via the same pathway. To assess the relationship of the CIM-induced Foxp3 reduction to Stub1 and PI3K-Akt-mTOR changes, we performed an immunoblotting analysis of the cell lysates of HAFoxp3 Jurkat T cells after stimulation with CIM.…”

Section: Cimetidine Reduces Foxp3 By Modulating the Pi3k-akt Pathwaymentioning

confidence: 89%

“…The immune adjuvant effects of CIM have been confirmed by several other groups. 1,[15][16][17][18] Furthermore, the adjuvant effects were found to be mediated not only by facilitation of inflammation-related immune activation, but also by impairment of CD4 C…”

Section: Introductionmentioning

confidence: 99%

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Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

Zhang

Chen

Luo

et al. 2016

Human Vaccines & Immunotherapeutics

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Foxp3-expressing Treg cells have been well documented to provide immune regulation by promoting immune tolerance and suppressing immune over-reaction. Cimetidine (CIM), used to inhibit stomach acid secretion, has been reported to promote immune responses and suppress Treg cell function in several studies. However, the underlying mechanism is unknown. To investigate CIM effects on the suppressive function of Treg and Foxp3, here we used CIM to stimulate human CD4 C CD25 C Treg cells and Jurkat T cells and evaluated changes of Foxp3 expression and stability. Our data showed that CIM leads to a reduction of Foxp3 via E3 ligase Stub1-mediated proteosomal degradation, which is dependent on an activated PI3K-AKTmTOR pathway. Thus, CIM affects the suppressive function of Treg cells by destabilizing their Foxp3 expression.

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Section: Cimetidine Reduces Foxp3 By Modulating the Pi3k-akt Pathwaysupporting

confidence: 94%

Section: Discussionmentioning

confidence: 70%

Section: Cimetidine Reduces Foxp3 By Modulating the Pi3k-akt Pathwaymentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

Zhang

Chen

Luo

et al. 2016

Human Vaccines & Immunotherapeutics

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“…Several potential adjuvants have been examined in various systems, and the results have been reviewed. [11][12][13] Granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine produced by macrophages, T cells, NK cells, endothelial cells, and fibroblasts, has been used clinically as a hematopoietic growth factor for more than 20 years. 14 It can increase neutrophil counts and induce the differentiation and maturation of myeloid dendritic cells (DCs) to improve the functions of antigen-presenting cells (APCs), as well as promote the development and perpetuation of Th1 responses.…”

Section: Chronic Hepatitis B Virus (Hbv) Infection Is a Global Healthmentioning

confidence: 99%

Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice

Wang

Dong²,

Xiao

et al. 2015

Cell Mol Immunol

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses and regimens of GM-CSF that were used, given that either mature or immature dendritic cells (DCs) could be induced under different conditions. To test the hypothesis that GM-CSF can be used as a novel adjuvant for a hepatitis B virus (HBV) therapeutic vaccine, we administered GM-CSF once per day for three days prior to vaccination with recombinant HBV vaccine (rHBVvac) in mice. We observed greater DC maturation in these pre-treated animals at day 3 as compared to day 1 or day 2 of daily GM-CSF administration. This strategy was further investigated for its ability to break the immune tolerance established in hepatitis B surface antigen-transgenic (HBsAg-Tg) animals. We found that the levels of induced anti-HBsAg antibodies were significantly higher in animals following three days of GM-CSF pre-treatment before rHBV vaccination after the third immunization. In addition to the increase in anti-HBsAg antibody levels, cell-mediated anti-HBsAg responses, including delayed-type hypersensitivity, T-cell proliferation, interferon-c production, and cytotoxic T lymphocytes, were dramatically enhanced in the three-day GM-CSF pre-treated group. After adoptive transfers of CD8 1 T cells from immunized animals, antigen-specific CD8 1 T cells were observed in the livers of recipient HBsAg-Tg animals. Moreover, the three-day pre-treatments with GM-CSF prior to rHBVvac vaccination could significantly eliminate HBsAg-positive hepatocytes, suggesting beneficial therapeutic effects. Therefore, this protocol utilizing GM-CSF as an adjuvant in combination with the rHBVvac vaccine has the potential to become a novel immunotherapy for chronic hepatitis B patients. Cellular & Molecular Immunology

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