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Felix S Lichtenegger, Maurine Rothe, Frauke M Schnorfeil, Katrin Deiser, Christina Krupka, Christian Augsberger, Miriam Schlüter, Julia Neitz, Marion Subklewe
Immune checkpoint inhibition has been shown to successfully reactivate endogenous T cell responses directed against tumor-associated antigens, resulting in significantly prolonged overall survival in patients with various tumor entities. For malignancies with low endogenous immune responses, this approach has not shown a clear clinical benefit so far. Therapeutic vaccination, particularly dendritic cell (DC) vaccination, is a strategy to induce T cell responses. Interaction of DCs and T cells is dependent on receptor-ligand interactions of various immune checkpoints...
2018: Frontiers in Immunology
Silvia Gregori, Maria Grazia Roncarolo
T regulatory cells, a specialized subset of T cells, are key players in modulating antigen (Ag)-specific immune responses in vivo . Inducible T regulatory type 1 (Tr1) cells are characterized by the co-expression of CD49b and lymphocyte-activation gene 3 (LAG-3) and the ability to secrete IL-10, TGF-β, and granzyme (Gz) B, in the absence of IL-4 and IL-17. The chief mechanisms by which Tr1 cells control immune responses are secretion of IL-10 and TGF-β and killing of myeloid cells via GzB. Tr1 cells, first described in peripheral blood of patients who developed tolerance after HLA-mismatched fetal liver hematopoietic stem cell transplantation, have been proven to modulate inflammatory and effector T cell responses in several immune-mediated diseases...
2018: Frontiers in Immunology
Sawsan Sudqi Said, Guliz Tuba Barut, Nesteren Mansur, Asli Korkmaz, Ayca Sayi-Yazgan
Regulatory B cells (Bregs) play a crucial role in immunological tolerance primarily through the production of IL-10 in many diseases including autoimmune disorders, allergy, infectious diseases, and cancer. To date, various Breg subsets with overlapping phenotypes have been identified. However, the roles of Bregs in Helicobacter infection are largely unknown. In the present study, we investigate the phenotype and function of Helicobacter -stimulated B cells. Our results demonstrate that Helicobacter felis -stimulated IL-10- producing B cells (Hfstim - IL-10+ B) are composed of B10 and Transitional 2 Marginal Zone Precursor (T2-MZP) cells with expression of CD9, Tim-1, and programmed death 1 (PD-1)...
February 26, 2018: Molecular Immunology
Pavlína Ptáčková, Jan Musil, Martin Štach, Petr Lesný, Šárka Němečková, Vlastimil Král, Milan Fábry, Pavel Otáhal
BACKGROUND AIMS: Clinical-grade chimeric antigenic receptor (CAR)19 T cells are routinely manufactured by lentiviral/retroviral (LV/RV) transduction of an anti-CD3/CD28 activated T cells, which are then propagated in a culture medium supplemented with interleukin (IL)-2. The use of LV/RVs for T-cell modification represents a manufacturing challenge due to the complexity of the transduction approach and the necessity of thorough quality control. METHODS: We present here a significantly improved protocol for CAR19 T-cell manufacture that is based on the electroporation of peripheral blood mononuclear cells with plasmid DNA encoding the piggyBac transposon/transposase vectors and their cultivation in the presence of cytokines IL-4, IL-7 and IL-21...
February 20, 2018: Cytotherapy
Glenn J Hanna, Patrick Lizotte, Megan Cavanaugh, Frank C Kuo, Priyanka Shivdasani, Alexander Frieden, Nicole G Chau, Jonathan D Schoenfeld, Jochen H Lorch, Ravindra Uppaluri, Laura E MacConaill, Robert I Haddad
Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling...
February 22, 2018: JCI Insight
Lukasz Bialkowski, Kevin Van der Jeught, Sanne Bevers, Patrick Tjok Joe, Dries Renmans, Carlo Heirman, Joeri L Aerts, Kris Thielemans
Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include, but are not limited to (1) adaptive expression of inhibitory checkpoint molecules in response to the pro-inflammatory environment and (2) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission...
February 21, 2018: International Journal of Cancer. Journal International du Cancer
Deepak Tripathi, Satyanarayana S Cheekatla, Padmaja Paidipally, Rajesh Kumar Radhakrishnan, Elwyn Welch, Ramya Sivangala Thandi, Amy R Tvinnereim, Ramakrishna Vankayalapati
CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here, we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in c-Jun N-terminal kinase 1 (JNK1) signaling prolongs islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM). Adoptively transferred JNK1-/- but not wild-type (WT) Tregs survive longer in the liver parenchyma of CDM. JNK1-/- Tregs are resistant to apoptosis and express anti-apoptotic molecules...
February 19, 2018: Scientific Reports
Michelle L McCully, Kristin Ladell, Robert Andrews, Rhiannon E Jones, Kelly L Miners, Laureline Roger, Duncan M Baird, Mark J Cameron, Zita M Jessop, Iain S Whitaker, Eleri L Davies, David A Price, Bernhard Moser
Human skin harbors two major T cell compartments of equal size that are distinguished by expression of the chemokine receptor CCR8. In vitro studies have demonstrated that CCR8 expression is regulated by TCR engagement and the skin tissue microenvironment. To extend these observations, we examined the relationship between CCR8+ and CCR8- skin T cells in vivo. Phenotypic, functional, and transcriptomic analyses revealed that CCR8+ skin T cells bear all the hallmarks of resident memory T cells, including homeostatic proliferation in response to IL-7 and IL-15, surface expression of tissue localization (CD103) and retention (CD69) markers, low levels of inhibitory receptors (programmed cell death protein 1, Tim-3, LAG-3), and a lack of senescence markers (CD57, killer cell lectin-like receptor subfamily G member 1)...
March 1, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Claudia Maletzki, Yvonne Saara Gladbach, Mohamed Hamed, Georg Fuellen, Marie-Luise Semmler, Jan Stenzel, Michael Linnebacher
Mismatch-repair deficiency (MMR-D) is closely linked to hypermutation and accordingly, high immunogenicity. MMR-D-related tumors thus constitute ideal vaccination targets for both therapeutic and prophylactic approaches. Herein, the prophylactic and therapeutic impact of a cellular vaccine on tumor growth and tumor-immune microenvironment was studied in a murine MLH1-/- knockout mouse model. Prophylactic application of the lysate (+/- CpG ODN 1826) delayed tumor development, accompanied by increased levels of circulating T cell numbers...
2018: Oncoimmunology
Sigurd M Hald, Mehrdad Rakaee, Inigo Martinez, Elin Richardsen, Samer Al-Saad, Erna-Elise Paulsen, Egil Støre Blix, Thomas Kilvaer, Sigve Andersen, Lill-Tove Busund, Roy M Bremnes, Tom Donnem
BACKGROUND: Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor and a putative therapeutic target in non-small-cell lung cancer (NSCLC). We explored the prognostic effect of LAG-3+ tumor-infiltrating lymphocytes (TILs) in primary tumors and metastatic lymph nodes in NSCLC and its potential for inclusion in an immunoscore, supplementing the TNM classification. MATERIALS AND METHODS: Primary tumor tissue from 553 stage I-IIIB NSCLC patients and 143 corresponding metastatic lymph nodes were collected...
December 11, 2017: Clinical Lung Cancer
Ziwei Liao, Xuewen Lv, Sichu Liu, Zifan He, Shaohua Chen, Liang Wang, Wenyu Li, Yangqiu Li
AIM: To better understand the T-cell immunodeficiency status in patients with peripheral T-cell lymphomas (PTCLs) and NK/T-cell lymphomas (NK/T-CLs), the T-cell inhibitory receptors expression pattern was investigated. METHODS: The expression levels of programmed death 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), B/T lymphocyte attenuator (BTLA), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT) genes were detected in peripheral blood mononuclear cells (PBMCs) from patients and healthy volunteers by quantitative real-time-PCR, the correlation between different gene expression levels was analyzed...
January 25, 2018: Asia-Pacific Journal of Clinical Oncology
Varun Sasidharan Nair, Eyad Elkord
Regulatory T cells (Tregs) play essential roles in immune homeostasis; however, their role in tumor microenvironment (TME) is not completely evident. Several studies reported that infiltration of Tregs into various tumor tissues promotes tumor progression by limiting antitumor immunity and supporting tumor immune evasion. Furthermore, in TME, Tregs include heterogeneous subsets of cells expressing different immunosuppressive molecules favoring tumor progression. For an effective cancer therapy, it is critical to understand the Treg heterogeneity and biology in the TME...
January 2018: Immunology and Cell Biology
Lina Quan, Xiuwen Lan, Yuanyuan Meng, Xiuchen Guo, Yiwei Guo, Lina Zhao, Xue Chen, Aichun Liu
Immunotherapy has shown encouraging results in lymphoma. Pre-clinical and clinical trials have proven checkpoint blockade, such as PD-1 antibody, as an effective treatment for lymphoma, including diffuse large B-cell lymphoma (DLBCL). Combination of checkpoint blockades has emerged as a new way to treat lymphoma, however, the status of checkpoints expression and their function in DLBCL has not been fully elucidated yet. In this study, we examined the expression of BTLA, PD-1, TIM-3, LIGHT and LAG-3 in tumor micro-environmental T cells of DLBCL using flow cytometry, and compared the cytotoxicity and differentiation status of BTLA+ and BTLA- T-cells...
January 15, 2018: Experimental Hematology
Michelle Fleury, Anna C Belkina, Elizabeth A Proctor, Christopher Zammitti, Robert W Simms, Douglas A Lauffenburger, Jennifer E Snyder-Cappione, Robert Lafyatis, Hans Dooms
OBJECTIVE: Immune dysfunction is an important component of the disease process underlying Systemic Sclerosis (SSc), but the mechanisms contributing to altered immune cell function in SSc remain poorly defined. Here, we measured the expression and function of the co-inhibitory receptors (co-IRs) PD-1, TIGIT, TIM-3, and LAG-3 in lymphocyte subsets from the peripheral blood of SSc patients. METHODS: Co-IR expression levels on immune cell subsets were analyzed using a 16-color flow cytometry panel...
December 15, 2017: Arthritis & Rheumatology
Huiling Zhang, Qingan Wang, Yajuan Zhang, Yi Yang, Yi Zhao, Jianren Sang, Yulong Zhang, Yine Zhang, Fan Xie, Shanshan Li, Yuhong Zhang, Yuming Guo
No evidence is available on whether cardiovascular mortality is affected by the ambient temperatures in Yinchuan, which is located in the northwestern region of China, with a typical continental semi-humid semi-arid climate. Daily data on cardiovascular mortality and meteorological factors was collected from Yinchuan city for the period of 2010-2015. A distributed lag non-linear model with quasi-Poisson link was used to assess the association between daily temperatures and cardiovascular deaths, after controlling for seasonality, day of the week, atmospheric pressure, humidity, sunshine duration, and wind speed...
December 14, 2017: Environmental Science and Pollution Research International
Kimberly M Ramonell, Wenxiao Zhang, Annette Hadley, Ching-Wen Chen, Katherine T Fay, John D Lyons, Nathan J Klingensmith, Kevin W McConnell, Craig M Coopersmith, Mandy L Ford
Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis...
2017: PloS One
Isobel Okoye, Afshin Namdar, Lai Xu, Nicole Crux, Shokrollah Elahi
Regulation of T cell function in the steady state is mediated by co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3 and LAG-3. Persistent antigen stimulation, during chronic viral infections and cancer, results in sustained expression of multiple co-inhibitory receptors and subsequently poor effector T cell function. Immune checkpoint blockade using monoclonal antibodies against PD-1, PDL-1 and CTLA-4 has been implemented as an immunotherapy strategy- resulting in restoration of T cell function and reduction of viral load or tumour growth...
November 17, 2017: Oncotarget
Jianlin Qiao, Qi Luo, Na Liu, Guangyu Wei, Xiaoqing Wu, Jun Lu, Kai Tang, Yulu Wu, Jie Zi, Xiaoqian Li, Yun Liu, Wen Ju, Kunming Qi, Zhiling Yan, Zhenyu Li, Lingyu Zeng, Kailin Xu
Immune thrombocytopenia (ITP) is an autoimmune disease, which is characterized by abnormal of T immunity. A disintegrin and metalloproteinase (ADAM) 10, a member of proteinase family, has been demonstrated to regulate T cell proliferation and effector function. Considering the closely association of dysregulation of T cell function with ITP, whether ADAM10 involves in the pathogenesis of ITP remains unclear. In this study, 54 active ITP patients, 18 ITP in remission and 24 age and gender matched healthy control were enrolled...
February 2018: International Immunopharmacology
Anna Leonte, Lorenza S Colzato, Laura Steenbergen, Bernhard Hommel, Elkan G Akyürek
In a randomized, double-blind, and placebo-controlled experiment, the acute effects of gamma-aminobutyric acid (GABA) supplementation on temporal and spatial attention in young healthy adults were investigated. A hybrid two-target rapid serial visual presentation task was used to measure temporal attention and integration. Additionally, a visual search task was used to measure the speed and accuracy of spatial attention. While temporal attention depends primarily on the distribution of limited attentional resources across time, spatial attention represents the engagement and disengagement by relevant and irrelevant stimuli across the visual field...
February 2018: Brain and Cognition
Hui Jiang, Yunfan Ti, Yicun Wang, Jun Wang, Menghan Chang, Jianning Zhao, Guojing Sun
Bone fracture healing is a multistage regenerative process that requires the collaboration of various cell types, with approximately 5%-10% of fractures not healing properly. Accumulating evidence suggests that dysregulations in the immune system are associated with defective healing. In a cohort of 30 bone fracture patients between 50 and 62 years of age, 8 patients displayed delayed healing. Compared to the 22 normal healing patients, these 8 delayed healing patients presented significantly lower frequencies of CD4+ CD25hi Foxp3+ canonical regulatory T cells immediately following bone fracture and early on during the healing process...
December 7, 2017: Clinical and Experimental Pharmacology & Physiology
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