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https://www.readbyqxmd.com/read/27803044/pre-clinical-evaluation-of-chimeric-antigen-receptors-targeting-cd70-expressing-cancers
#1
Qiong J Wang, Zhiya Yu, Ken-Ichi Hanada, Krishna Patel, David Kleiner, Nicholas P Restifo, James Yang
PURPOSE: CD70 expression in normal tissues is restricted to activated lymphoid tissues. Targeting CD70 on CD70-expressing tumors could mediate "on-target, off-tumor" toxicity. This study was to evaluate the feasibility and safety of using anti-human CD70 CARs to treat cancer patients whose tumors express CD70. EXPERIMENTAL DESIGN: Seven anti-human CD70 CARs with binding moieties from human CD27 combined with CD3-zeta and different co-stimulatory domains from CD28 and/or 41BB were constructed...
November 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27384937/imaging-spatiotemporal-activities-of-zap-70-in-live-t-cells-using-a-fret-based-biosensor
#2
Kaitao Li, Xue Xiang, Jie Sun, Hai-Tao He, Jianhua Wu, Yingxiao Wang, Cheng Zhu
The zeta-chain-associated protein kinase 70 kDa (ZAP-70), a member of the spleen tyrosine kinase (Syk) family, plays an essential role in early T cell receptor (TCR) signaling. Defects in ZAP-70 lead to impaired thymocyte development and peripheral T cell activation. To better understand its activation dynamics and regulation, we visualized ZAP-70 activities in single live T cells with a Förster resonance energy transfer (FRET)-based biosensor, which was designed for probing kinase activities of the Syk family...
December 2016: Annals of Biomedical Engineering
https://www.readbyqxmd.com/read/27265873/a-novel-tcr-like-car-with-specificity-for-pr1-hla-a2-effectively-targets-myeloid-leukemia-in-vitro-when-expressed-in-human-adult-peripheral-blood-and-cord-blood-t-cells
#3
Qing Ma, Haven R Garber, Sijie Lu, Hong He, Eran Tallis, Xiaoling Ding, Anna Sergeeva, Michael S Wood, Gianpietro Dotti, Barbara Salvado, Kathryn Ruisaard, Karen Clise-Dwyer, Lisa St John, Katayoun Rezvani, Gheath Alatrash, Elizabeth J Shpall, Jeffrey J Molldrem
BACKGROUND AIMS: The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a T-cell receptor (TCR)-like monoclonal antibody (8F4) that binds the PR1/HLA-A2 complex on the surface of AML cells, efficiently killing them in vitro and eliminating them in preclinical models. Humanized 8F4 (h8F4) with high affinity for the PR1/HLA-A2 epitope was used to construct an h8F4- chimeric antigen receptor (CAR) that was transduced into T cells to mediate anti-leukemia activity...
August 2016: Cytotherapy
https://www.readbyqxmd.com/read/27177669/modification-of-expanded-nk-cells-with-chimeric-antigen-receptor-mrna-for-adoptive-cellular-therapy
#4
Yaya Chu, Allyson Flower, Mitchell S Cairo
NK cells are bone marrow-derived cytotoxic lymphocytes that play a major role in the rejection of tumors and cells infected by viruses. The regulation of NK activation vs inhibition is regulated by the expression of a variety of NK receptors (NKRs) and specific NKRs' ligands expressed on their targets. However, factors limiting NK therapy include small numbers of active NK cells in unexpanded peripheral blood and lack of specific tumor targeting. Chimeric antigen receptors (CAR) usually include a single-chain Fv variable fragment from a monoclonal antibody, a transmembrane hinge region, and a signaling domain such as CD28, CD3-zeta, 4-1BB (CD137), or 2B4 (CD244) endodimers...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/26606254/comprehensive-survey-of-mirna-mrna-interactions-reveals-that-ccr7-and-cd247-cd3-zeta-are-posttranscriptionally-controlled-in-pancreas-infiltrating-t-lymphocytes-of-non-obese-diabetic-nod-mice
#5
Thais A Fornari, Paula B Donate, Amanda F Assis, Claudia Macedo, Elza T Sakamoto-Hojo, Eduardo A Donadi, Geraldo A Passos
In autoimmune type 1 diabetes mellitus (T1D), auto-reactive clones of CD4+ and CD8+ T lymphocytes in the periphery evolve into pancreas-infiltrating T lymphocytes (PILs), which destroy insulin-producing beta-cells through inflammatory insulitis. Previously, we demonstrated that, during the development of T1D in non-obese diabetic (NOD) mice, a set of immune/inflammatory reactivity genes were differentially expressed in T lymphocytes. However, the posttranscriptional control involving miRNA interactions that occur during the evolution of thymocytes into PILs remains unknown...
2015: PloS One
https://www.readbyqxmd.com/read/26599209/il4i1-is-a-novel-regulator-of-m2-macrophage-polarization-that-can-inhibit-t-cell-activation-via-l-tryptophan-and-arginine-depletion-and-il-10-production
#6
Yinpu Yue, Wei Huang, Jingjing Liang, Jing Guo, Jian Ji, Yunliang Yao, Mingzhu Zheng, Zhijian Cai, Linrong Lu, Jianli Wang
Interleukin 4-induced gene-1 (IL4I1) was initially described as an early IL-4-inducible gene in B cells. IL4I1 protein can inhibit T cell proliferation by releasing its enzymatic catabolite, H2O2, and this effect is associated with transient down-regulation of T cell CD3 receptor-zeta (TCRζ) expression. Herein, we show that IL4I1 contributes to the regulation of macrophage programming. We found that expression of IL4I1 increased during bone marrow-derived macrophage (BMDM) differentiation, expression of IL4I1 is much higher in primary macrophages than monocytes, and IL4I1 expression in BMDMs could be induced by Th1 and Th2 cytokines in two different patterns...
2015: PloS One
https://www.readbyqxmd.com/read/26356787/theoretical-study-of-the-infrared-frequencies-of-crystalline-methyl-acetate-under-interstellar-medium-conditions
#7
Radhika Narayanan, Kensuke Inomata, Geetha Gopakumar, Bhalamurugan Sivaraman, Yasunari Zempo, Masahiko Hada
Identification of methyl acetate in the interstellar medium (ISM) and its spectroscopic studies have prompted us to investigate the structure of crystalline methyl acetate using numerical calculations. Here, we present a theoretical study of the structure of crystalline methyl acetate and its isotopologues and compare the calculated infrared (IR) spectra with the available experimental data. The optimized structure and vibrational properties were calculated using SIESTA software at 0 K. In the optimization process, the Perdew-Burke-Ernzerhof functional and conjugate gradient methods were used with double zeta polarization basis functions...
January 15, 2016: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/26134847/serine-arginine-rich-splicing-factor-1-srsf1-contributes-to-the-transcriptional-activation-of-cd3%C3%AE-in-human-t-cells
#8
Vaishali R Moulton, Andrew R Gillooly, Marcel A Perl, Anastasia Markopoulou, George C Tsokos
T lymphocytes from many patients with systemic lupus erythematosus (SLE) express decreased levels of the T cell receptor (TCR)-associated CD3 zeta (ζ) signaling chain, a feature directly linked to their abnormal phenotype and function. Reduced mRNA expression partly due to defective alternative splicing, contributes to the reduced expression of CD3ζ chain. We previously identified by oligonucleotide pulldown and mass spectrometry approaches, the serine arginine-rich splicing factor 1 (SRSF1) binding to the 3' untranslated region (UTR) of CD3ζ mRNA...
2015: PloS One
https://www.readbyqxmd.com/read/26110267/tumor-targeted-human-t-cells-expressing-cd28-based-chimeric-antigen-receptors-circumvent-ctla-4-inhibition
#9
Maud Condomines, Jon Arnason, Reuben Benjamin, Gertrude Gunset, Jason Plotkin, Michel Sadelain
Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway...
2015: PloS One
https://www.readbyqxmd.com/read/25956037/a-signaling-enhanced-chimeric-receptor-to-activate-the-icos-pathway-in-t-cells
#10
Christian Vettermann, Hannah P Victor, Yu Sun, Cherylene Plewa, Shalini Gupta
Activation of the inducible costimulator (ICOS) signaling pathway in T cells is difficult to assess with bioassays, because most T cell lines do not constitutively express ICOS. Additionally, engagement of ICOS by its natural ligand B7 related protein 1 (B7RP1) is insufficient to elicit ICOS signaling, but requires simultaneous costimulation of the T cell receptor (TCR) to be effective. Here we describe a genetically engineered human T cell line that expresses a chimeric receptor (ICOS-CD3) consisting of full-length human ICOS fused at its C-terminal end to the cytoplasmic domain of human CD3 zeta...
September 2015: Journal of Immunological Methods
https://www.readbyqxmd.com/read/25814225/increased-ptpn22-expression-and-defective-creb-activation-impair-regulatory-t-cell-differentiation-in-non-st-segment-elevation-acute-coronary-syndromes
#11
COMPARATIVE STUDY
Davide Flego, Anna Severino, Francesco Trotta, Marco Previtero, Sarassunta Ucci, Chiara Zara, Gianluca Massaro, Daniela Pedicino, Luigi M Biasucci, Giovanna Liuzzo, Filippo Crea
BACKGROUND: Critical impairment of adaptive immune response has been observed in patients with acute coronary syndromes (ACS) with reduced expansion of regulatory T cells (Treg) and enhanced effector T-cell responsiveness, both associated with poorer outcomes. OBJECTIVES: This study investigated the mechanisms underlying T-cell dysregulation in ACS. METHODS: We evaluated both early and downstream T-cell receptor activation pathways after ex vivo stimulation with anti-CD3 and anti-CD28 crosslink in CD4(+) T cells from 20 patients with non-ST-segment elevation myocardial infarction (NSTEMI), 20 with stable angina (SA), and 20 controls...
March 31, 2015: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/25804237/peripheral-blood-lymphocyte-phenotype-of-zap-70%C3%A2-%C2%BA-and-zap-70%C3%A2-patients-with-b-cell-chronic-lymphocytic-leukaemia
#12
A Rivkina, I Holodnuka-Kholodyuk, M Murovska, M Soloveichika, S Lejniece
BACKGROUND: Up to now, the immune status of chronic lymphocytic leukemia (CLL) patients in association with the expression of zeta-chain-associated protein kinase 70 (ZAP-70) in leukemic cells has not been evaluated. AIM: The aim of this work was the study of the peripheral blood (PB) T-lymphocyte phenotypes in ZAP-70-positive (ZAP-70(+)) and ZAP-70-negative (ZAP-70(-)) untreated patients with CLL. MATERIALS AND METHODS: ZAP-70-, CD25-, CD3-, CD4-, and CD8-positive lymphocytes were enumerated by flow cytometry in PB of 120 untreated CLL patients...
March 2015: Experimental Oncology
https://www.readbyqxmd.com/read/25563239/the-middle-ear-immune-defense-changes-with-age
#13
Michelle Christine Nielsen, Morten Friis, Tomas Martin-Bertelsen, Ole Winther, Lennart Friis-Hansen, Per Cayé-Thomasen
Otitis media is a common disease in childhood. In adults, the disease is relatively rare, but more frequently associated with complications. Possible reasons for this discrepancy are age-related differences in pathogen exposure, anatomy of the Eustachian tube and immune system. The objective of this study was to analyze the relationship between age and the mucosal immune system in the middle ear. It is hypothesized that genes involved in the middle ear immune system will change with age. A comprehensive assessment of these genetic differences using the techniques of complementary DNA has not been performed...
January 2016: European Archives of Oto-rhino-laryngology
https://www.readbyqxmd.com/read/25186600/cancer-cartography-charting-out-a-new-approach-to-cancer-immunotherapy
#14
COMMENT
Jaina M Patel, Gordon A Dale, Vincent F Vartabedian, Paulami Dey, Periasamy Selvaraj
Evaluation of: Davila ML, Riviere I, Wang X et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6(224), 224ra25 (2014). Recently, chimeric antigen receptor (CAR) T-cell immunotherapy has entered clinical trials in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. 19-28z CAR T cells express a fusion protein comprised of an anti-CD19 mAb fused with CD28 costimulatory and CD3-zeta-chain signaling domains. The current paper demonstrates that administration of 19-28z CAR T cells in patients with relapsed or refractory B-ALL in a Phase I clinical trial has led to 88% of patients undergoing complete remission...
2014: Immunotherapy
https://www.readbyqxmd.com/read/25084831/neutrophils-with-myeloid-derived-suppressor-function-deplete-arginine-and-constrain-t-cell-function-in-septic-shock-patients
#15
Christabelle J Darcy, Gabriela Minigo, Kim A Piera, Joshua S Davis, Yvette R McNeil, Youwei Chen, Alicia D Volkheimer, J Brice Weinberg, Nicholas M Anstey, Tonia Woodberry
INTRODUCTION: Impaired T cell function in sepsis is associated with poor outcome, but the mechanisms are unclear. In cancer, arginase-expressing myeloid derived suppressor cells (MDSCs) deplete arginine, impair T cell receptor CD3 zeta-chain expression and T cell function and are linked to poor clinical outcome, but their role during acute human infectious disease and in particular sepsis remains unknown. Hypoarginemia is prevalent in sepsis. This study aimed to determine whether neutrophils that co-purify with PBMC express arginase, and if arginine depletion constrains T cell CD3 zeta-chain expression and function in human sepsis...
2014: Critical Care: the Official Journal of the Critical Care Forum
https://www.readbyqxmd.com/read/24972704/type-ii-ptdins-4-kinase-%C3%AE-associates-with-cd4-p56lck-complex-and-is-involved-in-cd4-receptor-signaling
#16
Ranjeet Kumar Sinha, Naveen Bojjireddy, Deepak Kanojia, Gosukonda Subrahmanyam
Type II phosphatidylinositol (PtdIns) 4-kinases are involved in the synthesis of PtdIns 4-phosphates and modulate various cell functions like, intracellular signaling, cytoskeletal rearrangements, vesicular trafficking, and pathogen invasion. In CD3 receptor activated T cells, a type II PtdIns 4-kinase β is recruited to CD3 receptor zeta and plays a role in intracellular calcium release and probably in actin cytoskeleton reorganization. T cell receptor mediated activation is supported by CD4 receptor. The role of type II PtdIns 4-kinase β in CD4 receptor-mediated signaling was addressed in the present manuscript...
October 2014: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/24724418/-novel-therapy-for-malignant-lymphoma-adoptive-immuno-gene-therapy-using-chimeric-antigen-receptor-car-expressing-t-lymphocytes
#17
Keiya Ozawa
Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3 zeta receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in the clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL)...
March 2014: Nihon Rinsho. Japanese Journal of Clinical Medicine
https://www.readbyqxmd.com/read/24641274/thymopentin-nanoparticles-engineered-with-high-loading-efficiency-improved-pharmacokinetic-properties-and-enhanced-immunostimulating-effect-using-soybean-phospholipid-and-phbhhx-polymer
#18
Chengyu Wu, Mengtian Zhang, Zhirong Zhang, Ka-Wai Wan, Waqar Ahmed, David A Phoenix, Abdelbary M A Elhissi, Xun Sun
Formulation of protein and peptide drugs with sustained release properties is crucial to enhance their therapeutic effect and minimize administration frequency. In this study, immunomodulating polymeric systems were designed by manufacturing PHBHHx nanoparticles (NPs) containing thymopentin (TP5). The release profile of the drug was studied over a period of 7 days. The PHBHHx NPs containing TP5-phospholipid (PLC) complex (TP5-PLC) displayed a spherical shape with a mean size, zeta potential, and encapsulation efficiency of 238...
October 6, 2014: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/24120941/the-cytoplasmic-domain-of-the-t-cell-receptor-zeta-subunit-does-not-form-disordered-dimers
#19
Amanda Nourse, Tanja Mittag
Intrinsically disordered regions in proteins play active roles in recognition, signaling and molecular sorting. They often undergo coupled folding and binding giving rise to largely ordered interfaces with their binding partners. The cytoplasmic region of the T-cell receptor zeta subunit (ζcyt) has been previously proposed to specifically dimerize in the absence of a disorder-to-order transition, suggesting an intriguing dimerization mechanism that may involve multiple transient interfaces. We show here using analytical ultracentrifugation, NMR, size-exclusion chromatography (SEC) and multi-angle light scattering that neither ζcyt nor the cytoplasmic region of CD3ε significantly populates a dimeric state but that they are mostly monomers in solution up to millimolar concentrations...
January 9, 2014: Journal of Molecular Biology
https://www.readbyqxmd.com/read/24013589/spleen-tyrosine-kinase-syk-regulates-systemic-lupus-erythematosus-sle-t-cell-signaling
#20
Alexandros P Grammatikos, Debjani Ghosh, Amy Devlin, Vasileios C Kyttaris, George C Tsokos
Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules...
2013: PloS One
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