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Mireya Paulina Velasquez, Arpad Szoor, Abishek Vaidya, Aarohi Thakkar, Phuong Nguyen, Meng-Fen Wu, Hao Liu, Stephen Gottschalk
T cells expressing CD19-specific chimeric antigen receptors (CARs) with endodomains that encode a signaling domain derived from CD3ζ and CD28 or 41BB have potent antitumor activity in early-phase clinical studies for B-cell malignancies. Besides CD19-specific CARs, other approaches are actively being pursued to redirect T cells to CD19, including recombinant bispecific T-cell engager (BiTE) proteins or T cells genetically modified to express BiTEs [engager (ENG) T cells]. As BiTEs provide no costimulation, we investigated here if provision of costimulation through CD28 and 41BB enhances the effector function of CD19-ENG T cells...
October 2017: Cancer Immunology Research
Nelly Noraz, Iness Jaaoini, Camille Charoy, Chantal Watrin, Naura Chounlamountri, Aurélien Benon, Céline Malleval, Hélène Boudin, Jérôme Honnorat, Valérie Castellani, Véronique Pellier-Monnin
In the hematopoietic system, Syk family tyrosine kinases are essential components of immunoreceptor ITAM-based signaling. While there is increasing data indicating the involvement of immunoreceptors in neural functions, the contribution of Syk kinases remains obscure. Previously, we identified phosphorylated forms of Syk kinases in specialized populations of migrating neurons or projecting axons. Moreover, we identified ephrin/Eph as guidance molecules utilizing the ITAM-bearing CD3zeta (Cd247) and associated Syk kinases for the growth cone collapse response induced in vitro Here, we show that in the developing spinal cord, Syk is phosphorylated in navigating commissural axons...
June 15, 2016: Development
Xianqiang Liu, Meili Sun, Shui Yu, Kai Liu, Xirui Li, Huan Shi
PURPOSE: Despite advancements in its treatment, gastric cancer continues to be one of the leading causes of cancer deaths worldwide. Adoptive transfer of chimeric antigen receptor-modified T cells is a promising antitumor therapy for many cancers. The purpose of this study was to construct a chimeric receptor linking the extracellular domain of NKG2D to the CD28 and CD3zeta chain intracellular domains to target gastric cancers that expressed NKG2D ligands. METHODS: Expression of NKG2D ligands including MICA, MICB, and ULBP1-3 in a gastric cancer cell line and primary gastric cancer cells from ascites samples were analyzed using flow cytometry...
2015: OncoTargets and Therapy
Ming-Ru Wu, Tong Zhang, Andre Alcon, Charles L Sentman
Chimeric antigen receptor (CAR) T cell therapies hold great potential for treating cancers, and new CARs that can target multiple tumor types and have the potential to target non-hematological malignancies are needed. In this study, the tumor recognition ability of a natural killer cell-activating receptor, DNAM-1 was harnessed to design CARs that target multiple tumor types. DNAM-1 ligands, PVR and nectin-2, are expressed on primary human leukemia, myeloma, ovarian cancer, melanoma, neuroblastoma, and Ewing sarcoma...
April 2015: Cancer Immunology, Immunotherapy: CII
Sven Saussez, Barbara Laumbacher, Gilbert Chantrain, Alexandra Rodriguez, Songhai Gu, Rudolf Wank, Mia Levite
In previous studies we found that several Neurotransmitters and Neuropeptides among them: Glutamate, Dopamine, Gonadotropin-releasing-hormone (GnRH) I and II, Somatostatin, CGRP and Neuropeptide Y, can each by itself, at low physiological concentration (~10 nM) bind its receptors in human T cells and trigger several key T cell functions. These findings showed that the nervous system, via Neurotransmitters and Neuropeptides, can 'talk' directly to the immune system, and stimulate what we coined 'Nerve-Driven Immunity': immune responses dictated by the nervous system...
August 2014: Journal of Neural Transmission
Daniel Abate-Daga, Kiran H Lagisetty, Eric Tran, Zhili Zheng, Luca Gattinoni, Zhiya Yu, William R Burns, Anne M Miermont, Yaroslav Teper, Udo Rudloff, Nicholas P Restifo, Steven A Feldman, Steven A Rosenberg, Richard A Morgan
Despite advances in the understanding of its molecular pathophysiology, pancreatic cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA), a glycoprotein that is overexpressed in pancreatic cancer starting at early stages of malignant transformation. To optimize the CAR design, we used antigen-recognition domains derived from mouse or human antibodies, and intracellular signaling domains containing one or two T cell costimulatory elements, in addition to CD3zeta...
December 2014: Human Gene Therapy
Julie Angibaud, Antoine Louveau, Stéphane J Baudouin, Véronique Nerrière-Daguin, Sarah Evain, Virginie Bonnamain, Philippe Hulin, Zsolt Csaba, Pascal Dournaud, Reynald Thinard, Philippe Naveilhan, Nelly Noraz, Véronique Pellier-Monnin, Hélène Boudin
Recent studies have highlighted the key role of the immune protein CD3ζ in the maturation of neuronal circuits in the CNS. Yet, the upstream signals that might recruit and activate CD3ζ in neurons are still unknown. In this study, we show that CD3ζ functions early in neuronal development and we identify ephrinA1-dependent EphA4 receptor activation as an upstream regulator of CD3ζ. When newly born neurons are still spherical, before neurite extension, we found a transient CD3ζ aggregation at the cell periphery matching the initiation site of the future neurite...
November 2011: Journal of Neurochemistry
Nazanin Pirooznia, Sadegh Hasannia, Majid Taghdir, Fatemeh Rahbarizadeh, Morteza Eskandani
Adaptive cell immunotherapy with the use of chimeric receptors leads to the best and most specific response against tumors. Chimeric receptors consist of a signaling fragment, extracellular spacer, costimulating domain, and an antibody. Antibodies cause immunogenicity; therefore, VHH is a good replacement for ScFv in chimeric receptors. Since peptide sequences have an influence on chimeric receptors, the effect of peptide domains on each other's conformation were investigated. CD3Zeta, CD28, VHH and CD8α, and FcgIIα are used as signaling moieties, costimulating domain, antibody, and spacers, respectively...
2011: Journal of Biomedicine & Biotechnology
Julie Angibaud, Stéphane J Baudouin, Antoine Louveau, Véronique Nerrière-Daguin, Virginie Bonnamain, Zsolt Csaba, Pascal Dournaud, Philippe Naveilhan, Nelly Noraz, Véronique Pellier-Monnin, Hélène Boudin
Immune signaling and neuroinflammatory mediators have recently emerged as influential variables that regulate neural precursor/stem cell (NPC) behavior and function. In this study, we investigated whether the signaling adaptor protein CD3ζ, a transmembrane protein involved in T cell differentiation and function and recently shown to regulate neuronal development in the central nervous system (CNS), may have a role in NPC differentiation. We analyzed the expression profile of CD3ζ in embryonic rat brain during neurogenic periods and in neurosphere-derived neural cells, and we investigated the action of CD3ζ on cell differentiation...
February 2012: Journal of Molecular Neuroscience: MN
Yangqiu Li, Shaohua Chen, Lijian Yang, Si Chen, Chunlan Lin, Liang Wang, Yuhong Lu, Suxia Geng, Xin Du, Christian A Schmidt
In haematological malignancy, cell-mediated immunity has been shown to be suppressed in advanced disease. This immune dysfunction may be due, in part, to altered expression of the T cell receptor (TCR)-CD3 complex. The distribution and clonality of the TCR Vbeta repertoire and the expression levels of CD3gamma, CD3delta, CD3epsilon, and CD3zeta genes in T cells from patients with multiple myeloma (MM) were investigated. Specific Vbeta subfamily primers, reverse transcription polymerase chain reaction, and the GeneScan® technique were used to analyse the expression of the TCR Vbeta subfamily and the clonality of Vbeta T cells in 11 patients with MM...
May 2011: Hematology (Amsterdam, Netherlands)
Nobuyoshi Hanaoka, Bana Jabri, Zhenpeng Dai, Cezary Ciszewski, Anne M Stevens, Cassian Yee, Hideki Nakakuma, Thomas Spies, Veronika Groh
Deficiencies of the T cell and NK cell CD3ζ signaling adapter protein in patients with cancer and autoimmune diseases are well documented, but mechanistic explanations are fragmentary. The stimulatory NKG2D receptor on T and NK cells mediates tumor immunity but can also promote local and systemic immune suppression in conditions of persistent NKG2D ligand induction that include cancer and certain autoimmune diseases. In this paper, we provide evidence that establishes a causative link between CD3ζ impairment and chronic NKG2D stimulation due to pathological ligand expression...
November 15, 2010: Journal of Immunology: Official Journal of the American Association of Immunologists
Bin Yu, Wei Zhang
This work was done to establish a correlation between serum protein expression profiles and breast cancer. A high-density antibody microarray was used to identify serum protein expression profiles. Proteins up- or down-regulated by 2-fold compared with normal controls were used for hierarchical clustering analysis. ELISA and immunohistochemistry were used for validation of protein array data. The CD3zeta chain was one of the down-regulated molecules identified by the antibody array analysis and confirmed by ELISA and immunohistochemistry...
February 2011: Cell Biology International
Masasuke Ohno, Atsushi Natsume, Ken Ichiro Iwami, Hidetaka Iwamizu, Kana Noritake, Daiki Ito, Yuki Toi, Motokazu Ito, Kazuya Motomura, Jun Yoshida, Kazuhiro Yoshikawa, Toshihiko Wakabayashi
The isotype of epidermal growth factor receptor variant III (EGFRvIII) is often identified in glioblastomas. Previously, we created a mouse monoclonal antibody, 3C10 (IgG2b), that specifically recognized EGFRvIII, and a recombinant single-chain variable fragment of 3C10. The aim of the current study was to develop genetically engineered T cells, termed T-bodies, that express a chimeric receptor consisting of the 3C10 single-chain variable fragment coupled to signaling modules such as the CD3zeta (ζ) chain, for the treatment of tumors expressing mutant EGFR...
December 2010: Cancer Science
Yihu Zheng, Kang Yu, Jimei Du, Lei Jiang, Shenghui Zhang, Yixiang Han, Panpan Yu, Yingxia Tan
BACKGROUND: Anti-CD20 monoclonal antibody treatment has not only increased survival and cure rates in many non-Hodgkin lymphomas, but also has prompted an explosion in the development of novel antibodies and biologically active substances with specific cellular targets in the field of malignancies treatment. Since the robust immune responses are elicited by the gene-modified T cells, gene based T cell therapy may also provide a powerful tool for cancer immunotherapy. METHODS: In this study, we developed a vector construction encoding a chimeric T cell receptor that recognizes the CD20 antigen and delivers co-stimulatory signals to achieve T cell activation...
2010: Journal of Experimental & Clinical Cancer Research: CR
Naoto Shirasu, Hirotomo Shibaguci, Motomu Kuroki, Hiromi Yamada, Masahide Kuroki
BACKGROUND: Chimeric T-cell antigen receptors (CAR) provide a promising approach for adoptive T-cell immunotherapy of cancer. Extensive studies on CARs have been conducted, but the detailed molecular mechanisms of the activation of a CAR-grafted T-cell remain ambiguous. This study constructed a CAR bearing anti-carcinoembryonic antigen (CEA) derived from a human monoclonal antibody (clone C2-45), and investigated the molecular basis of the CAR-mediated activation in Jurkat T-cells. MATERIALS AND METHODS: A gene of a single chain fragment variable (scFv) specific for CEA was functionally cloned by the phage display method...
July 2010: Anticancer Research
Jaeyul Kwon, Kristen E Shatynski, Haiyan Chen, Stanislas Morand, Xavier de Deken, Françoise Miot, Thomas L Leto, Mark S Williams
Production of reactive oxygen species, often by NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidases, plays a role in the signaling responses of cells to many receptor stimuli. Here, we describe the function of the calcium-dependent, nonphagocytic NADPH oxidase Duox1 in primary human CD4(+) T cells and cultured T cell lines. Duox1 bound to inositol 1,4,5-trisphosphate receptor 1 and was required for early T cell receptor (TCR)-stimulated production of hydrogen peroxide (H(2)O(2)) through a pathway that was dependent on TCR-proximal kinases...
August 3, 2010: Science Signaling
Arnette Scavella, Lily Leiva, Hanh Monjure, Arnold H Zea, Renee V Gardner
BACKGROUND: L-arginine (L-Arg) is deficient in sickle cell disease (SSD) during vasoocclusion. We investigated possible causal relationship between L-Arg deficiency and immune dysfunction in SSD in steady-state. PROCEDURE: Fifteen patients with SSD in steady-state and 13 controls were studied. Plasma L-Arg levels were measured using liquid chromatography. T cell subsets and CD3zeta (CD3zeta) chain expression were analyzed using flow cytometry. Lymphocyte proliferative response to phytohemagglutinin (PHA) and production of IL-6 and interferon-gamma (IFN-gamma) were evaluated with and without L-Arg...
August 2010: Pediatric Blood & Cancer
John S Bridgeman, Robert E Hawkins, Steve Bagley, Morgan Blaylock, Mark Holland, David E Gilham
Chimeric Ag receptors (CARs) expressed in T cells permit the redirected lysis of tumor cells in an MHC-unrestricted manner. In the Jurkat T cell model system, expression of a carcinoembryonic Ag-specific CD3zeta CAR (MFEzeta) resulted in an increased sensitivity of the transduced Jurkat cell to generate cytokines when stimulated through the endogenous TCR complex. This effect was driven through two key characteristics of the MFEzeta CAR: 1) receptor dimerization and 2) the interaction of the CAR with the endogenous TCR complex...
June 15, 2010: Journal of Immunology: Official Journal of the American Association of Immunologists
Marie Lundholm, Sofia Mayans, Vinicius Motta, Anna Löfgren-Burström, Jayne Danska, Dan Holmberg
Tuning of TCR-mediated activation was demonstrated to be critical for lineage fate in T cell development, as well as in the control of autoimmunity. In this study, we identify a novel diabetes susceptibility gene, Idd28, in the NOD mouse and provide evidence that Cd3zeta (Cd247) constitutes a prime candidate gene for this locus. Moreover, we show that the allele of the Cd3zeta gene expressed in NOD and DBA/2 mouse strains confers lower levels of T cell activation compared with the allele expressed by C57BL/6 (B6), BALB/c, and C3H/HeJ mice...
May 15, 2010: Journal of Immunology: Official Journal of the American Association of Immunologists
William R Burns, Yangbing Zhao, Timothy L Frankel, Christian S Hinrichs, Zhili Zheng, Hui Xu, Steven A Feldman, Soldano Ferrone, Steven A Rosenberg, Richard A Morgan
Immunotherapy, particularly the adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL), is a very promising therapy for metastatic melanoma. Some patients unable to receive TIL have been successfully treated with autologous peripheral blood lymphocytes (PBL), genetically modified to express human leukocyte antigen (HLA) class I antigen-restricted, melanoma antigen-reactive T-cell receptors; however, substantial numbers of patients remain ineligible due to the lack of expression of the restricting HLA class I allele...
April 15, 2010: Cancer Research
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