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Viktor Schneidt, Marta Ilecka, Peter Dreger, Dwain G van Zyl, Susanne Fink, Josef Mautner, Henri-Jacques Delecluse
Chronic lymphocytic leukemia (CLL) is the most frequent B cell malignancy in Caucasian adults. The therapeutic armamentarium against this incurable disease has recently seen a tremendous expansion with the introduction of specific pathway inhibitors and innovative immunotherapy. However, none of these approaches is curative and devoid of side effects. We have used B-cell-specific antibodies conjugated with antigens (AgAbs) of the Epstein-Barr virus (EBV) to efficiently expand memory CD4+ cytotoxic T lymphocytes (CTLs) that recognized viral epitopes in 12 treatment-naive patients with CLL...
June 20, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Taizo Wada
CD5 is a cell surface molecule that is expressed on most circulating T cells and a small population of B cells and is involved in modulation of antigen-specific receptor-mediated activation. Down-regulation of CD5 on CD8+ T cells is a poorly understood but increasingly recognized phenomenon that may be associated with dysregulated T-cell activation. An increased subpopulation of activated CD8+ T cells with down-regulation of CD5 has recently been described in patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (HLH) and familial HLH caused by perforin deficiency and Munc 13-4 deficiency...
June 19, 2018: Pediatrics International: Official Journal of the Japan Pediatric Society
Qing Ming Wang, Patrick Ming-Kuen Tang, Guang-Yu Lian, Chunjie Li, Jinghong Li, Xiao-Ru Huang, Ka-Fai To, Hui-Yao Lan
Natural killer (NK) cells, early effectors in anti-cancer immunity, are paralyzed by TGF-β1, an immunosuppressive cytokine produced by cancer cells. Development and activity of NK cells are largely inhibited in the Smad3-dependent tumor microenvironment. Here, we used genetic engineering to generate a stable SMAD3-silencing human NK cell line NK-92-S3KD, whose cancer-killing activity and cytokine production were significantly enhanced under TGF-β1-rich condition compared to the parental cell line. Interestingly, we identified that IFNG gene is a direct E4BP4 target gene...
June 18, 2018: Cancer Immunology Research
Annette Fox, Kim L Harland, Katherine Kedzierska, Anne Kelso
Effector CD8+ T cells generally produce type-1 cytokines and mediators of the perforin/granzyme cytolytic pathway, yet type-2-polarized CD8+ cells (Tc2) are detected in type-2 (T2) cytokine-driven diseases such as asthma. It is unclear whether T2 cytokine exposure during activation is sufficient to polarize human CD8+ T cells. To address this question, a protocol was developed for high-efficiency activation of human CD8+ T cells in which purified single cells or populations were stimulated with plate-bound anti-CD3 and anti-CD11a mAb for up to 8 days in T2 polarizing or neutral conditions, before functional analysis...
2018: Frontiers in Immunology
Qing Li
It is well known that natural killer (NK) cells are involved in defense against viruses and some tumors. NK cells kill target cells by the directed release of cytolytic granules that contain perforin, granzymes, and granulysin. It is increasingly important to evaluate NK cell function in immunotoxicity testing. NK cell function can be evaluated by determining cytolytic activity against target tumor cells by the 51 Cr-release assay and also by determining the number of NK cells in peripheral blood in humans and in the spleen in animals using flow cytometry...
2018: Methods in Molecular Biology
Paul A Moore, Kalpana Shah, Yinhua Yang, Ralph Alderson, Penny Roberts, Vatana Long, Daorong Liu, Jonathan C Li, Steve Burke, Valentina Ciccarone, Hua Li, Claudia B Fieger, Jeff Hooley, Ann Easton, Monica Licea, Sergey Gorlatov, Kathleen L King, Peter Young, Arash Adami, Deryk Loo, Gurunadh R Chichili, Liqin Liu, Douglas H Smith, Jennifer G Brown, Francine Z Chen, Scott Koenig, Jennie Mather, Ezio Bonvini, Syd Johnson
We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART® protein designed to redirect T-cells to target gpA33 expressing colon cancer. The gpA33 target was selected based on an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic CRC specimens, including putative cancer stem cell populations. MGD007 displays the anticipated bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T-cells...
June 4, 2018: Molecular Cancer Therapeutics
Tian Zhang, Chunyan Liu, Hui Liu, Lijuan Li, Ting Wang, Rong Fu
Severe aplastic anemia (SAA) is characterized by pancytopenia and failure of hematopoietic function and is caused by excessive functioning of cytotoxic T lymphocytes (CTLs). EBNA-1, a nucleoprotein of the Epstein Barr virus (EBV), can influence the proliferation and function of lymphocytes. We therefore tested the number of EBV copies in the CD8+ T cells of 27 patients with SAA and 10 healthy control subjects and observed the influences of EBNA-1 upon the CD8+ T cells of patients with SAA. The results showed that more EBV copies were found in the CD8+ T cells of patients with untreated SAA than in patients with SAA in remission or in the healthy control subjects...
2018: BioMed Research International
Mohanraj Manangeeswaran, Jennifer L Kielczewski, H Nida Sen, Biying C Xu, Derek D C Ireland, Ian L McWilliams, Chi-Chao Chan, Rachel R Caspi, Daniela Verthelyi
Zika-infected patients can have eye involvement ranging from mild conjunctivitis to severe chorioretinal lesions, however the possible long-term sequelae of infection and timeline to recovery remain unknown. Here we describe the partial recovery of chorioretinal lesions in an immunocompetent patient diagnosed with bilateral posterior uveitis associated with Zika infection and show that some lesions resolved with focal atrophy evident as pigmentary changes on funduscopy. To better understand the progression of the lesions and correlate the changes in fundus imaging with local viral load, immune responses, and retinal damage, we developed a symptomatic mouse model of ocular Zika virus infection...
May 25, 2018: Emerging Microbes & Infections
Matthew D Taylor, Thomas N Burn, E John Wherry, Edward M Behrens
Familial hemophagocytic lymphohistiocytosis 2 (FHL2) is a cytokine storm syndrome characterized by immune hyperactivation with viral infection due to a CD8 T cell cytotoxic killing defect secondary to a perforin deficiency. As most studies of FHL2 mice have used pathogen naïve animals, the effects of immune memory on FHL2 are understudied. We utilized an immunization model of the perforin-deficient mouse to study the effects of immune memory on FHL2. Prior CD8 T cell specific antigen exposure leads to enhanced HLH disease with increased morbidity and decreased time to mortality...
February 2018: ImmunoHorizons
G Joelsons, T Domenico, L F Gonçalves, R C Manfro
The aim of the present study was to evaluate messenger RNA expression in kidney allograft recipients. Forty-four kidney transplant recipients were evaluated up to three months after grafting. After transplantation, peripheral blood samples were drawn sequentially for real-time polymerase chain reaction analyses of perforin and TIM-3 genes. Biopsies were obtained to evaluate acute graft dysfunction and interpreted according to the Banff classification. Eight patients presented episodes of acute rejection. Recipients with rejection had significantly higher levels of TIM-3 mRNA transcripts compared to those without rejection (median gene expression 191...
2018: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Huanling Zhang, Yanyan Li, Xiaoping Liu, Zhaoduan Liang, Mengyong Yan, Qiang Liu, Anan Chen, Yifeng Bao, Chengzhi Zhou, Shiyue Li, Cassian Yee, Yi Li
Recently, bi-functional molecules that can redirect immune effectors to tumor cells have emerged as potentially robust mediators of tumor regression in clinical trials. Two modalities, in particular, bi-specific antibodies for T cell redirection and activation (BiTe) and immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC) are being evaluated in efficacy studies as 'off-the-shelf' reagents. Optimal therapy will require an understanding and means to address regulatory mechanisms of limiting efficacy...
May 23, 2018: Immunology
Conor J Kearney, Stephin J Vervoort, Simon J Hogg, Kelly M Ramsbottom, Andrew J Freeman, Najoua Lalaoui, Lizzy Pijpers, Jessica Michie, Kristin K Brown, Deborah A Knight, Vivien Sutton, Paul A Beavis, Ilia Voskoboinik, Phil K Darcy, John Silke, Joseph A Trapani, Ricky W Johnstone, Jane Oliaro
Immunotherapy has revolutionized outcomes for cancer patients, but the mechanisms of resistance remain poorly defined. We used a series of whole-genome clustered regularly interspaced short palindromic repeat (CRISPR)-based screens performed in vitro and in vivo to identify mechanisms of tumor immune evasion from cytotoxic lymphocytes [CD8+ T cells and natural killer (NK) cells]. Deletion of key genes within the tumor necrosis factor (TNF) signaling, interferon-γ (IFN-γ) signaling, and antigen presentation pathways provided protection of tumor cells from CD8+ T cell-mediated killing and blunted antitumor immune responses in vivo...
May 18, 2018: Science Immunology
Sumana Narayanan, Tsutomu Kawaguchi, Li Yan, Xuan Peng, Qianya Qi, Kazuaki Takabe
BACKGROUND: Elevated tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T cells release cytolytic proteins such as perforin (PRF1) and pro-apoptotic granzymes (GZMA) to attack cancer cells, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity. METHODS: Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA)...
May 16, 2018: Annals of Surgical Oncology
Catherine S Forconi, Cormac P Cosgrove, Pryia Saikumar-Lakshmi, Christina E Nixon, Joslyn Foley, John Michael Ong'echa, Juliana A Otieno, Galit Alter, Christian Münz, Ann M Moormann
Natural killer (NK) cells are critical for restricting viral infections and mediating tumor immunosurveillance. Epstein-Barr virus (EBV) and Plasmodium falciparum malaria are known risk factors for endemic Burkitt lymphoma (eBL), the most common childhood cancer in equatorial Africa. To date, the composition and function of NK cells have not been evaluated in eBL etiology or pathogenesis. Therefore, using multiparameter flow cytometry and in vitro killing assays, we compared NK cells from healthy children and children diagnosed with eBL in Kenya...
May 22, 2018: Blood Advances
Alix Besançon, Zeynep Demir, Tania Goncalves, Fabrice Valette, Emilie Panafieu, Lucienne Chatenoud, Sylvaine You
BACKGROUND: T-cell-mediated graft rejection is mostly correlated with potent Th1 responses. However, since IFNγ mice reject their graft as efficiently as wild-type (WT) mice, the exact contribution of IFNγ and its transcription factor T-bet remains a matter of debate. Here, we address this question in the context of pancreatic islet allograft to better inform the molecular pathways that hampers islet survival in vivo. METHODS: Pancreatic islets from BALB/c mice were transplanted in WT, IFNγ or T-bet C57BL/6 mice...
May 2, 2018: Transplantation
Marco Tucci, Francesco Mannavola, Anna Passarelli, Luigia Stefania Stucci, Mauro Cives, Franco Silvestris
Exosomes (Exo) are small vesicles produced by melanoma cells and the accessory cells of the tumor microenvironment. They emerge via both classical and direct pathways and actively participate in tumor colonisation of distant tissues. The proteins, nucleic acids, cytokines and growth factors engulfed by Exo are transferred to recipient cells, where they drive numerous functions required for the tumor escape from immune system control and tumor progression. By positively or negatively modulating immune cell properties, Exo provoke immune suppression and, in turn, defective dendritic cell (DC) functions...
April 17, 2018: Oncotarget
Tao Ni, Sophie I Williams, Saša Rezelj, Gregor Anderluh, Karl Harlos, Phillip J Stansfeld, Robert J C Gilbert
Toxoplasma and Plasmodium are the parasitic agents of toxoplasmosis and malaria, respectively, and use perforin-like proteins (PLPs) to invade host organisms and complete their life cycles. The Toxoplasma gondii PLP1 ( Tg PLP1) is required for efficient exit from parasitophorous vacuoles in which proliferation occurs. We report structures of the membrane attack complex/perforin (MACPF) and Apicomplexan PLP C-terminal β-pleated sheet (APCβ) domains of Tg PLP1. The MACPF domain forms hexameric assemblies, with ring and helix geometries, and the APCβ domain has a novel β-prism fold joined to the MACPF domain by a short linker...
March 2018: Science Advances
Björn Bulitta, Werner Zuschratter, Isabel Bernal, Dunja Bruder, Frank Klawonn, Martin von Bergen, Henrikus Stephanus Paulus Garritsen, Lothar Jänsch
Mucosal-associated invariant T cells (MAIT) constitute the most abundant anti-bacterial CD8+ T cell population in humans. MR1/TCR-activated MAIT cells were reported to organize cytotoxic and innate-like responses but knowledge about their molecular effector phenotype is still fragmentary. Here, we have examined the functional inventory of human MAIT cells (CD3+Vα7.2+CD161+) in comparison with those from conventional non-MAIT CD8+ T cells (cCD8+ ) and NK cells. Quantitative mass spectrometry characterized 5500 proteins of primary MAIT cells and identified 160 and 135 proteins that discriminate them from cCD8+ T cells and NK cells donor-independently...
May 11, 2018: European Journal of Immunology
Janko Kos, Milica Perišić Nanut, Mateja Prunk, Jerica Sabotič, Esmeralda Dautović, Anahid Jewett
Cysteine cathepsins are lysosomal peptidases involved in the regulation of innate and adaptive immune responses. Among the diverse processes, regulation of granule-dependent cytotoxicity of cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cells during cancer progression has recently gained significant attention. The function of cysteine cathepsins is regulated by endogenous cysteine protease inhibitors-cystatins. Whereas other cystatins are generally cytosolic or extracellular proteins, cystatin F is present in endosomes and lysosomes and is thus able to regulate the activity of its target directly...
May 10, 2018: Cancer Immunology, Immunotherapy: CII
Wen Jiang, Cai Zhang, Zhigang Tian, Jian Zhang
PURPOSE: Natural killer (NK) cells can kill transformed cells and represent anti-tumor activities for improving the immunotherapy of cancer. In previous works, we established human interleukin-15 (hIL-15) gene-modified NKL cells (NKL-IL15) and demonstrated their efficiency against human hepatocarcinoma cells (HCCs) in vitro and in vivo. To further assess the applicability of NKL-IL15 cells in adoptive cellular immunotherapy for human leukemia, here we report their natural cytotoxicity against leukemia in vitro and in vivo...
May 8, 2018: Journal of Cancer Research and Clinical Oncology
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