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Junichiro Kawamura, Fumiaki Sugiura, Yasushi Sukegawa, Yasumasa Yoshioka, Jin-Ichi Hida, Shoichi Hazama, Kiyotaka Okuno
The safety and immunological responsiveness of a peptide vaccine of ring finger protein 43 and 34-kDa translocase of the outer mitochondrial membrane combined with uracil-tegafur/leucovorin (UFT/LV) was previously demonstrated in metastatic colorectal cancer (CRC) in a phase I clinical trial. To clarify the survival benefit of a peptide vaccine combined with UFT/LV as adjuvant treatment, a phase II clinical trial was conducted involving patients with stage III CRC. All enrolled patients, whose human leukocyte antigen (HLA)-A status was double-blinded, were administered the same regime of a peptide vaccine and UFT/LV chemotherapy...
April 2018: Oncology Letters
Liam V Brown, Eamonn A Gaffney, Jonathan Wagg, Mark C Coles
Tumour immunotherapy is dependent upon activation and expansion of tumour-targetting immune cells, known as cytotoxic T-lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterized. To elucidate these mechanisms, we developed a human-parametrized, in silico , agent-based model of vaccination-driven CTL activation within a clinical short-peptide vaccination context. The simulations predict a sharp transition in the probability of CTL activation, which occurs with variation in the separation rate (or off-rate) of tumour-specific immune response-inducing peptides (cognate antigen) from the major histocompatibility class I (MHC-I) receptors of dendritic cells (DCs) originally at the vaccination site...
March 2018: Journal of the Royal Society, Interface
Li Liu, Xuyan Zhang, Sizhou Feng
Epstein-Barr virus related post-transplant lymphoproliferative disorders (EBV-PTLDs) are rare but potentially fatal complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT), characterized by uncontrolled proliferation of EBV-infected lymphocytes. The most frequent risk factors include T cell depletion of graft, HLA mismatch, severe graft versus host disease (GVHD), EBV sero-mismatch (recipient-/donor+) and so on. EBV-PTLDs commonly manifest as fever and lymphadenopathy and may rapidly progress to multi-organ failure and even death...
March 9, 2018: Biology of Blood and Marrow Transplantation
Masahiko Mori, Nuanjun Wichukchinda, Reiko Miyahara, Archawin Rojanawiwat, Panita Pathipvanich, Toshiyuki Miura, Michio Yasunami, Koya Ariyoshi, Pathom Sawanpanyalert
BACKGROUND: Class I HLA molecules contribute to HIV control through antigen presentation to both cytotoxic T lymphocytes (CTLs) and NK cells. Contribution of CTLs to HIV clinical outcome by HLA alleles has been well studied. However, reports about the role of NK cells in HIV clinical outcome, particularly, about the effect of HLA-KIR pairs, remain incomplete. METHODS: The effects of HLA allele-KIR pairs on HIV clinical outcome were statistically analyzed in a Thai cohort of treatment-naïve chronically infected (n=209)...
March 8, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Tsukasa Seya, Yohei Takeda, Ken Takashima, Sumito Yoshida, Masahiro Azuma, Misako Matsumoto
The immune system eliminates advanced cancer when treated with programmed cell death protein-1 (PD-1) or its ligand (PD-L1) blockade, but PD-1 therapy is effective in only ∼20% of patients with solid cancer. The PD-1 antibody mainly acts on the effector phase of cytotoxic T lymphocytes (CTLs) in tumors but induces no activation of the priming phase of antigen-presenting dendritic cells (DCs). It is reasonable that both DC-priming and PD-1/L1 blocking are mandatory for efficient CTL-mediated tumor cytolysis...
2018: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
Xiaoling Xie, Weijun Zhou, Yuxing Hu, Yiran Chen, Honghao Zhang, Yuhua Li
The identification and characterization of tumor-associated antigens (TAAs) that generate specific cytotoxic T lymphocytes (CTLs) are vital to the development of cancer immunotherapy. The epidermal growth factor receptor (EGFR) pathway substrate 8 gene (Eps8) is involved in regulating cancer progression and might be an ideal antigen. In this study, we searched for novel human leukocyte antigen (HLA)-A*2402-restricted epitopes derived from the Eps8 protein via the HLA-binding prediction algorithm. Among four candidates, peptides 327 (EFLDCFQKF), 534 (KYAKSKYDF) and 755 (LFSLNKDEL) induced peptide-specific CTLs to secrete higher levels of interferon-gamma (IFN-γ) and showed enhanced cytotoxic activity against malignant cancer cells...
March 7, 2018: Cell Death & Disease
John Wonderlich, Gene Shearer, Alexandra Livingstone, Andrew Brooks, Mark J Soloski, Matthew M Presby
Cytotoxic T cells (CTLs) are important immune effector cells in the adaptive immune response. It has been well documented that CTLs are important in host immune responses to viral and bacterial intracellular pathogens, tumors, and transplanted tissues. The properties of CTLs have been studied extensively in murine models, and their roles validated in the human setting. Frequently, the presence of these cells correlates well with protective immunity, so the ability to readily measure the activity of these cells is an important immunological measurement...
February 21, 2018: Current Protocols in Immunology
Alexei F Kirkin, Karine N Dzhandzhugazyan, Per Guldberg, Johnny Jon Fang, Rikke S Andersen, Christina Dahl, Jann Mortensen, Tim Lundby, Aase Wagner, Ian Law, Helle Broholm, Line Madsen, Christer Lundell-Ek, Morten F Gjerstorff, Henrik J Ditzel, Martin R Jensen, Walter Fischer
In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens...
March 6, 2018: Nature Communications
Ida Hafstrand, Elien M Doorduijn, Renhua Sun, Anna Talyzina, Marjolein Sluijter, Sara Pellegrino, Tatyana Sandalova, Adil Doganay Duru, Thorbald van Hall, Adnane Achour
Human cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell-based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)-based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP...
March 5, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Emanuel Della-Torre, Emanuele Bozzalla-Cassione, Clara Sciorati, Eliana Ruggiero, Marco Lanzillotta, Silvia Bonfiglio, Hamid Mattoo, Cory A Perugino, Enrica Bozzolo, Lucrezia Rovati, Paolo Giorgio Arcidiacono, Gianpaolo Balzano, Dejan Lazarevic, Chiara Bonini, Massimo Falconi, John H Stone, Lorenzo Dagna, Shiv Pillai, Angelo A Manfredi
OBJECTIVE: An unconventional population of CD4+ SLAMF7+ cytotoxic TEM cells (CD4+ CTLs) has been linked causally to IgG4-related disease (IgG4-RD). Glucocorticoids represent the first line therapeutic approach in patients with IgG4-RD but their mechanism of action in this specific condition remains unknown. Here we describe the impact of glucocorticoids on CD4+ CTLs in IgG4-RD. METHODS: CD8α, granzyme A, perforin, and SLAMF7 expression within the effector/memory compartment of CD45RO (TEM ) and CD45RA (TEMRA ) CD4+ T cells was quantified by flow cytometry in 18 active IgG4-RD patients at baseline and after 6 months of glucocorticoid treatment...
March 2, 2018: Arthritis & Rheumatology
Andrew P Trembath, Neekun Sharma, Saravanan Raju, Bojan Polić, Mary A Markiewicz
The NK group 2 member D (NKG2D) immune receptor is implicated in both human and mouse autoimmune diabetes. However, the significance of NKG2D in diabetes pathogenesis has been unclear due to conflicting reports as to the importance of this receptor in the NOD mouse model. In this study we demonstrate that NKG2D expression affects NOD diabetes development by at least two previously undescribed, and opposing, mechanisms. First, we demonstrate that the NKG2D ligand H60a is induced on activated NOD T cells, and that NKG2D-H60a interaction during CD8+ T cell differentiation into CTLs generally decreases the subsequent CTL effector cytokine response...
November 1, 2017: ImmunoHorizons
Angela R Elia, Matteo Grioni, Veronica Basso, Flavio Curnis, Massimo Freschi, Angelo Corti, Anna Mondino, Matteo Bellone
PURPOSE: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTLs). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intra-tumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors...
February 28, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kenta Shimizu, Kumiko Yoshimatsu, Midori Taruishi, Yoshimi Tsuda, Jiro Arikawa
Hemorrhagic fever with renal syndrome (HFRS) is caused by hantavirus infection. Although host immunity is thought to be involved in the pathogenesis of HFRS, the mechanism remains to be elucidated. A mouse model of HFRS, which showed renal hemorrhage similar to that seen in patients, has been developed previously. In this study, we aimed to clarify whether CD4+ and CD8+ T cells are involved in the development of renal hemorrhage in the mouse model. At 2 days before virus inoculation, CD4+ or CD8+ T cells in 6-week-old BALB/c mice were depleted by administration of antibodies...
February 27, 2018: Archives of Virology
Yu Akazawa, Toshihiro Suzuki, Tetsuya Nakatsura
Recently, with the rapid development of elucidating the tumor immunological status, it has become clear that various lymphocytes, which are infiltrating tumor, are deeply involved in not only tumor growth but also its elimination. The interest and importance of cytotoxic T cells(CTLs)for cancer immunotherapy has been further increased, since CTLs play an important role in eliminating cancer cells by having high cytotoxic activity and high proliferation ability. To achieve potent antitumor effects, in addition to the anti-tumor immune response induced by various methods such as cancer peptide vaccine and immune checkpoint inhibitor, it is thought to be essential that CTLs should migrate and invade into localized cancer tissues...
February 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Hyunjoon Kim, Lin Niu, Peter Larson, Tamara A Kucaba, Katherine A Murphy, Britnie R James, David M Ferguson, Thomas S Griffith, Jayanth Panyam
Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds...
February 17, 2018: Biomaterials
Debby W Tsuang, Tiffany A Greenwood, Suman Jayadev, Marie Davis, Andrew Shutes-David, Thomas D Bird
BACKGROUND: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. OBJECTIVE: To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. METHODS: DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1...
2018: Journal of Huntington's Disease
Maryam Esmailbeig, Abbas Ghaderi
Interleukin (IL)-18, structurally similar to IL-1β, is a member of IL-1 superfamily of cytokines. This cytokine, which is expressed by many human lymphoid and nonlymphoid cells, has an important role in inflammatory processes. The main function of IL-18 is mediated through induction of interferon-γ (IFN-γ) secretion from T helper (Th1) cells. This cytokine synergistically with IL-12 contributes to Th1 differentiation and, therefore, is important in host defense mechanisms against intracellular bacteria, viruses, and fungi...
November 1, 2017: European Cytokine Network
Xiaoyuan Wei, Limin Wang, Wanwei Sun, Ming Zhang, Hongyu Ma, Yueling Zhang, Xinxu Zhang, Shengkang Li
As pattern recognition receptors, C-type lectins (CTLs) play important roles in immune system of crustaceans through identifying and binding to the conservative pathogen-associated molecular patterns (PAMPs) on pathogen surfaces. In this study, a new CTL, SpCTL-B, was identified from the hemocytes of mud crab Scylla paramamosain. The full-length of SpCTL-B cDNA was 1278 bp with an open reading frame (ORF) of 348 bp. The predicted SpCTL-B protein contains a single carbohydrate-recognition domain (CRD). SpCTL-B transcripts were distributed in all examined tissues with the highest levels in hepatopancreas...
February 21, 2018: Developmental and Comparative Immunology
Yiding Yang, Vitaly V Ganusov
Cytotoxic T lymphocytes (CTLs) have been suggested to play an important role in controlling human immunodeficiency virus (HIV-1 or simply HIV) infection. HIV, due to its high mutation rate, can evade recognition of T cell responses by generating escape variants that cannot be recognized by HIV-specific CTLs. Although HIV escape from CTL responses has been well documented, factors contributing to the timing and the rate of viral escape from T cells have not been fully elucidated. Fitness costs associated with escape and magnitude of the epitope-specific T cell response are generally considered to be the key in determining timing of HIV escape...
2018: Frontiers in Immunology
Shuang Wang, Dezhi Ni, Hua Yue, Nana Luo, Xiaobo Xi, Yugang Wang, Min Shi, Wei Wei, Guanghui Ma
Therapeutic vaccines possess particular advantages and show promising potential to combat burdening diseases, such as acquired immunodeficiency syndrome, hepatitis, and even cancers. An efficient therapeutic vaccine would strengthen the immune system and eventually eliminate target cells through cytotoxic T lymphocytes (CTLs). Unfortunately, insufficient efficacy in triggering such an adaptive immune response is a problem that remains unsolved. To achieve efficient cellular immunity, antigen-presenting cells must capture and further cross-present disease-associated antigens to CD8 T cells via major histocompatibility complex I molecules...
February 22, 2018: Small
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