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Xiaowen Wang, Qingyang Dong, Qian Li, Yuanyuan Li, Dianyuan Zhao, Jinjie Sun, Junliang Fu, Fanping Meng, Hu Lin, Junjie Luan, Biao Liu, Min Wang, Fusheng Wang, Fuchu He, Li Tang
BACKGROUND & AIMS: Production of neutralizing antibodies against hepatitis B surface antigen (HBsAg) is dysregulated in patients with persistent hepatitis V virus (HBV) infection. We investigated mechanisms by which this immune response to the virus is disrupted and whether it can be restored to promote clearance of HBV. METHODS: Immune-competent C57BL/6N and C57BL/6J, as well as mice deficient in follicular helper T cells (Tfh cell-deficient), B cells, or Foxp3+ T-regulatory cells (Treg cell-deficient), were given hydrodynamic injections of pAAV/HBV1...
March 12, 2018: Gastroenterology
Marius Jacob, Kim Ohl, Tannaz Goodarzi, Sigrid Harendza, Thomas Eggermann, Christina Fitzner, Ralf-Dieter Hilgers, Anna Bolte, Jürgen Floege, Thomas Rauen, Klaus Tenbrock
BACKGROUND/AIMS: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and still constitutes one of the most important causes of end-stage renal disease. Abnormal T cell responses may play a role in IgAN pathogenesis. Co-stimulatory molecules such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are important for naive T cells to initiate and terminate immune responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 gene locus are associated with several autoimmune diseases...
March 8, 2018: Kidney & Blood Pressure Research
Nehad A Fouad, Aml M Saeed, Ahmed W Mahedy
Graves' disease (GD) is an organ specific autoimmune disease of thyroid gland with genetic and environmental causes. One of genetic factors that have been implicated in the development of this disease is CTLA-4 gene polymorphism. This study aimed to investigate the association of CTLA-4 polymorphisms at position +49A/G, and CT60 with susceptibility to Graves' disease in Saudi patients. 40 adult Saudi patients with GD and 30 healthy controls were genotyped for the +49 A/G and CT60 of the CTLA4 gene using restriction fragment length polymorphism analysis (RFLP)...
June 2017: Egyptian Journal of Immunology
Vida Sheikh, Pinar Kasapoglu, Alireza Zamani, Zahra Basiri, Ahmad Tahamoli-Roudsari, Mahdi Alahgholi-Hajibehzad
1 α, 25-dihydroxyvitamin D3 (VitD3) has been suggested to have strong modulatory properties in the immune system. Researchers in the present study primarily aimed to understand the effect of VitD3 on human CD4+ T cell proliferation in antigen presenting cells (APCs) free condition in vitro. The effect of VitD3 on intracellular cytokine responses trend to Th1, Th2, Th17 and Th22 was evaluated using the flow cytometry. Moreover the effect of VitD3 on the expression of inhibitory markers such as PD1, PD-L1, and CTLA4 which are induced upon polyclonal T cell receptor (TCR) activation on CD4+ T cells, was assessed...
March 6, 2018: Human Immunology
Soo Jung Lee, Sun-Young Jun, In Hee Lee, Byung Woog Kang, Su Yeon Park, Hye Jin Kim, Jun Seok Park, Gyu-Seog Choi, Ghilsuk Yoon, Jong Gwang Kim
PURPOSE: This study attempted to reveal the prognostic impact of microsatellite instability-high (MSI-H) colon cancer with tumor-infiltrating immune cells (TIICs) and immune checkpoint protein expression, which are good candidates for immunotherapy. MATERIALS AND METHODS: The study included 89 patients with MSI-H colon cancer who underwent curative surgery at Kyungpook National University Chilgok Hospital. The expression status of specific inhibitory receptors, such as CD274 (programmed death-ligand 1, PD-L1), PDCD1 (programmed cell death 1, PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and indolamine 2'3'-dioxygenase 1 (IDO1), was retrospectively analyzed using immunohistochemistry (IHC)...
March 8, 2018: Journal of Cancer Research and Clinical Oncology
Mohamed B Ezzelarab, Lien Lu, William F Shufesky, Adrian E Morelli, Angus W Thomson
Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg)...
2018: Frontiers in Immunology
Grace Thompson, Andrew Mclean-Tooke, Jeremy Wrobel, Melanie Lavender, Michaela Lucas
Interstitial lung disease (ILD) is a significant complication of Sjögren syndrome (SS) associated with increased morbidity and mortality. The mainstay of treatment remains corticosteroid administration, with or without additional immunosuppressive therapies. Preliminary studies in SS have shown benefit in glandular and serologic parameters following treatment with the CTLA4 immunoglobulin fusion protein abatacept. Topical tacrolimus has been effective for ocular symptoms in SS, but systemic therapy has not been reported...
March 2018: Chest
Katjana S Schwab, Glenn Kristiansen, Hans H Schild, Stefanie E A Held, Annkristin Heine, Peter Brossart
Treatment options for patients with platinum-refractory, recurrent, metastatic head and neck squamous cell carcinoma (HNSCC) are limited, and prognosis is poor. Nivolumab (Opdivo) has been approved by the US Food and Drug Administration (FDA) for the treatment of patients with recurrent or metastatic HNSCC who have disease progression on or after platinum-based therapy. Recently, in patients with metastatic malignant melanoma a significant improvement of outcome and response was achieved with the combination of ipilimumab (CTLA4 antibody) and the programmed death (PD)-1 inhibitor nivolumab compared with monotherapy...
January 2018: Case Reports in Oncology
Maria Rita Gaiser, Nikolas von Bubnoff, Christoffer Gebhardt, Jochen Sven Utikal
During the last six years, several innovative, systemic therapies for the treatment of metastatic malignant melanoma (MM) have emerged. Conventional chemotherapy has been superseded by novel first-line therapies, including systemic immunotherapies (anti-CTLA4 and anti-PD1; authorization of anti-PDL1 is anticipated) and therapies targeting specific mutations (BRAF, NRAS, and c-KIT). Thus, treating physicians are confronted with new challenges, such as stratifying patients for appropriate treatments and monitoring long-term responders for progression...
March 7, 2018: Journal der Deutschen Dermatologischen Gesellschaft, Journal of the German Society of Dermatology: JDDG
Matthew Wiest, Katherine Upchurch, Wenjie Yin, Jerome Ellis, Yaming Xue, Bobby Lanier, Mark Millard, HyeMee Joo, SangKon Oh
Background: T cells play a central role in chronic inflammation in asthma. However, the roles of individual subsets of T cells in the pathology of asthma in patients remain to be better understood. Methods: We investigated the potential signatures of T cell subset phenotypes in asthma using fresh whole blood from adult atopic asthma patients (n = 43) and non-asthmatic control subjects (n = 22). We further assessed their potential clinical implications by correlating asthma severity...
2018: Allergy, Asthma, and Clinical Immunology
Aileen Weiwei Li, Miguel C Sobral, Soumya Badrinath, Youngjin Choi, Amanda Graveline, Alexander G Stafford, James C Weaver, Maxence O Dellacherie, Ting-Yu Shih, Omar A Ali, Jaeyun Kim, Kai W Wucherpfennig, David J Mooney
Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations...
March 5, 2018: Nature Materials
Qin'e Fan, Juanjuan Zhang, Yu Cui, Chaoyun Wang, Yongjun Xie, Qiurong Wang, Libing Wu
The current study was aimed to investigate the association of CLTA-4/Foxp3 polymorphisms and chromosomal abnormalities with recurrent spontaneous abortion (RSA) risk in a Chinese Han population. Altogether, 1284 RSA women and 1046 women with normal pregnancy were incorporated in this study. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was implemented to genotype the single-nucleotide polymorphisms (SNPs) located within CTLA4 and Foxp3. Moreover, the cytogenetic diagnosis was performed in line with the standards of G banding karyotype...
February 23, 2018: Journal of Human Genetics
Arnaud Jannin, Emilie Merlen, Christine Do Cao, Nicolas Penel
Recently developed immunotherapeutic agents, like anti-cytotoxic T lymphocyte antigen 4 antibody (CTLA4), anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1), have demonstrated substantial potential for the treatment of a variety of malignancies. Autoimmune side effects from these agents are diverse and can include multiple endocrinopathies like immunotherapy induced hypophysitis (IH). These toxicities appear to be more frequent in patients receiving anti-CTLA4 antibody compared to PD1/PDL1 agents...
February 20, 2018: Bulletin du Cancer
Xuexiang Du, Fei Tang, Mingyue Liu, Juanjuan Su, Yan Zhang, Wei Wu, Martin Devenport, Christopher A Lazarski, Peng Zhang, Xu Wang, Peiying Ye, Changyu Wang, Eugene Hwang, Tinghui Zhu, Ting Xu, Pan Zheng, Yang Liu
It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4h/h ) or human CD34+ stem cell-reconstituted NSG™ mice...
February 22, 2018: Cell Research
Alanna M Dubrovsky, Mie Jin Lim, Nancy E Lane
Osteoporosis in rheumatic diseases is a very well-known complication. Systemic inflammation results in both generalized and localized bone loss and erosions. Recently, increased knowledge of inflammatory process in rheumatic diseases has resulted in the development of potent inhibitors of the cytokines, the biologic DMARDs. These treatments reduce systemic inflammation and have some effect on the generalized and localized bone loss. Progression of bone erosion was slowed by TNF, IL-6 and IL-1 inhibitors, a JAK inhibitor, a CTLA4 agonist, and rituximab...
February 22, 2018: Calcified Tissue International
Christel Rothe Brinkmann, Jesper Falkesgaard Højen, Thomas Aagaard Rasmussen, Anne Sofie Kjær, Rikke Olesen, Paul W Denton, Lars Østergaard, Zhengyu Ouyang, Mathias Lichterfeld, Xu Yu, Ole Schmeltz Søgaard, Charles Dinarello, Martin Tolstrup
Histone deacetylase inhibitors (HDACi) modulate the transcriptional activity of all cells, including innate and adaptive immune cells. Therefore, we aimed to evaluate immunological effects of treatment with the HDACi panobinostat in HIV-infected patients during a clinical phase IIa latency reversal trial. Using flow cytometry, we investigated changes in T cell activation (CD69, CD38, HLA-DR) and the expression of CD39 and CTLA4 on regulatory T cells (Tregs). Whole-blood stimulations were performed and cytokine responses measured using Luminex...
January 2018: MSphere
Rajani Ravi, Kimberly A Noonan, Vui Pham, Rishi Bedi, Alex Zhavoronkov, Ivan V Ozerov, Eugene Makarev, Artem V Artemov, Piotr T Wysocki, Ranee Mehra, Sridhar Nimmagadda, Luigi Marchionni, David Sidransky, Ivan M Borrello, Evgeny Izumchenko, Atul Bedi
A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH 1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd)...
February 21, 2018: Nature Communications
Xuexiang Du, Mingyue Liu, Juanjuan Su, Peng Zhang, Fei Tang, Peiying Ye, Martin Devenport, Xu Wang, Yan Zhang, Yang Liu, Pan Zheng
Anti-CTLA-4 monoclonal antibodies (mAbs) confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAE). Targeting CTLA-4 has shown remarkable long-term benefit and thus remains a valuable tool for cancer immunotherapy if the irAE can be brought under control. An animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. Here, we report such a model using mice harboring the humanized Ctla4 gene. In this model, the clinically used drug, Ipilimumab, induced severe irAE especially when combined with an anti-PD-1 antibody; whereas another mAb, L3D10, induced comparable CITE with very mild irAE under the same conditions...
February 20, 2018: Cell Research
Shiraj Sen, Kenneth Hess, David S Hong, Aung Naing, Sarina Piha-Paul, Filip Janku, Siqing Fu, Ishwaria M Subbiah, Holly Liu, Rahil Khanji, Le Huang, Shhyam Moorthy, Daniel D Karp, Apostolia Tsimberidou, Funda Meric-Bernstam, Vivek Subbiah
BACKGROUND: We sought to develop a prognostic scoring system to aid in patient selection for immune checkpoint inhibitor (ICI) phase 1 clinical trials. METHODS: Clinical data from patients treated in phase 1 ICI clinical trials at MD Anderson (MDA) Center were analysed. Seventeen clinical factors were studied. Recursive partitioning analysis, a tree-based model, was used to develop a regression tree and identify optimal cut-points based on differences in survival for each clinical factor...
February 20, 2018: British Journal of Cancer
Cuili Huang, Lidan Zhang, Fang Ling, Sijian Wen, Yanyan Luo, Hui Liu, Jingping Liu, Wenjun Zheng, Ming Liang, Jian Sun, You-Kun Lin
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease in which tissue damage is caused by autoantibodies. The induction of specific immune tolerance, including the utilization of immune regulatory cells, may enhance the therapeutic effects of organ transplantation in patients with SLE. Furthermore, inhibiting immune responses has been reported to be an effective treatment for SLE. However, few studies have explored the association between an increased immune tolerance and a decreased immune response in SLE treatment...
March 2018: Experimental and Therapeutic Medicine
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