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TCR gene therapy

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https://www.readbyqxmd.com/read/28632753/mait-cells-launch-a-rapid-robust-and-distinct-hyperinflammatory-response-to-bacterial-superantigens-and-quickly-acquire-an-anergic-phenotype-that-impedes-their-cognate-antimicrobial-function-defining-a-novel-mechanism-of-superantigen-induced-immunopathology
#1
Christopher R Shaler, Joshua Choi, Patrick T Rudak, Arash Memarnejadian, Peter A Szabo, Mauro E Tun-Abraham, Jamie Rossjohn, Alexandra J Corbett, James McCluskey, John K McCormick, Olivier Lantz, Roberto Hernandez-Alejandro, S M Mansour Haeryfar
Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections...
June 2017: PLoS Biology
https://www.readbyqxmd.com/read/28599078/non-lesional-atopic-dermatitis-skin-shares-similar-t-cell-clones-with-lesional-tissues
#2
Patrick M Brunner, Ryan O Emerson, Christopher Tipton, Sandra Garcet, Saakshi Khattri, Israel Coats, James G Krueger, Emma Guttman-Yassky
BACKGROUND: Atopic dermatitis (AD) is characterized by robust immune activation. Various T-cell subsets, including Th2/Th22 cells, are increased in lesional and non-lesional skin. However, there is conflicting literature on the diversity of the T-cell receptor (TCR) repertoire in lesional AD, and its relation to non-lesional skin remains unclear. METHODS: We performed high-throughput deep sequencing of the β-TCR repertoire in 29 lesional and 19 non-lesional AD biopsies, compared to 6 healthy control and 6 cutaneous T-cell lymphoma (CTCL) samples from previously published cohorts...
June 9, 2017: Allergy
https://www.readbyqxmd.com/read/28507809/t-cell-therapy-targeting-a-public-neoantigen-in-microsatellite-instable-colon-cancer-reduces-in-vivo-tumor-growth
#3
Else M Inderberg, Sébastien Wälchli, Marit R Myhre, Sissel Trachsel, Hilde Almåsbak, Gunnar Kvalheim, Gustav Gaudernack
T-cell receptor (TCR) transfer is an attractive strategy to increase the number of cancer-specific T cells in adoptive cell therapy. However, recent clinical and pre-clinical findings indicate that careful consideration of the target antigen is required to limit the risk of off-target toxicity. Directing T cells against mutated proteins such as frequently occurring frameshift mutations may thus be a safer alternative to tumor-associated self-antigens. Furthermore, such frameshift mutations result in novel polypeptides allowing selection of TCRs from the non-tolerant T-cell repertoire circumventing the problem of low affinity TCRs due to central tolerance...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28482391/-two-families-of-x-linked-lymphoproliferative-disease-type-1-characterized-by-agammaglobulinemia
#4
W Y Li, J S Chen, Q Zhao, R X Dai, Y P Wang, H Y Zhao, X M Chen, X H Xue, X Y Sun, X M Tang, Y Zhang, Y Ding, X D Zhao, Z Y Zhang
Objective: To investigate the clinical and immunological laboratory features, mutations in SH2D1A gene and SAP protein expression in four children of two families with X-linked lymphoproliferative disease type 1(XLP-1). Method: Four patients (Family A including Patient 1 and Patient 2, Family B including Patient 3 and Patient 4) and their maternal relatives were enrolled in this study. The clinical manifestation, EBV infection status and chest CT scan were analyzed. The absolute and relative numbers of lymphocyte subsets, T lymphocyte proliferative response, SAP protein expression were assessed by flow cytometry...
May 4, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/28448599/simulation-of-the-dynamics-of-primary-immunodeficiencies-in-cd4-t-cells
#5
Gabriel N Teku, Mauno Vihinen
Primary immunodeficiencies (PIDs) form a large and heterogeneous group of mainly rare disorders that affect the immune system. T-cell deficiencies account for about one-tenth of PIDs, most of them being monogenic. Apart from genetic and clinical information, lots of other data are available for PID proteins and genes, including functions and interactions. Thus, it is possible to perform systems biology studies on the effects of PIDs on T-cell physiology and response. To achieve this, we reconstructed a T-cell network model based on literature mining and TPPIN, a previously published core T-cell network, and performed semi-quantitative dynamic network simulations on both normal and T-cell PID failure modes...
2017: PloS One
https://www.readbyqxmd.com/read/28441778/gene-expression-analysis-before-and-after-treatment-with-adalimumab-in-patients-with-ankylosing-spondylitis-identifies-molecular-pathways-associated-with-response-to-therapy
#6
Marzia Dolcino, Elisa Tinazzi, Andrea Pelosi, Giuseppe Patuzzo, Francesca Moretta, Claudio Lunardi, Antonio Puccetti
The etiology of Ankylosing spondylitis (AS) is still unknown and the identification of the involved molecular pathogenetic pathways is a current challenge in the study of the disease. Adalimumab (ADA), an anti-tumor necrosis factor (TNF)-alpha agent, is used in the treatment of AS. We aimed at identifying pathogenetic pathways modified by ADA in patients with a good response to the treatment. Gene expression analysis of Peripheral Blood Cells (PBC) from six responders and four not responder patients was performed before and after treatment...
April 24, 2017: Genes
https://www.readbyqxmd.com/read/28428503/-cancer-immunotherapy-utilizing-t-cell-receptor-gene-engineering
#7
Hiroaki Ikeda
Immune-checkpoint inhibitors have shown their efficacy in the treatment of patients with many kinds of progressive/relapsed cancers. However, the efficacy remains as 10-40%of the patients in most type of cancers, suggesting that the development of new therapy for patients resistant to the therapy is an urgent unmet need. Adoptive therapy with tumor-specific T cells is a promising therapy that can be effective in patients who are not benefited from the immune-checkpoint inhibitors. The T cell therapy with genetic engineering in T cell receptor(TCR)is expected to be a universal therapy because this therapy can be applicable for patients with many kinds of cancers...
April 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28424240/the-histone-acetyltransferase-gcn5-positively-regulates-t-cell-activation
#8
Beixue Gao, Qingfei Kong, Yana Zhang, Chawon Yun, Sharon Y R Dent, Jianxun Song, Donna D Zhang, Yiming Wang, Xuemei Li, Deyu Fang
Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of general control nonrepressed-protein 5 (Gcn5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. In this study, we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice, and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion, and differentiation...
May 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28422742/multi-omics-study-revealing-the-complexity-and-spatial-heterogeneity-of-tumor-infiltrating-lymphocytes-in-primary-liver-carcinoma
#9
Lijun Shi, Yang Zhang, Lin Feng, Liming Wang, Weiqi Rong, Fan Wu, Jianxiong Wu, Kaitai Zhang, Shujun Cheng
Intratumoral heterogeneity has been revealed in primary liver carcinoma (PLC). However, spatial heterogeneity of tumor-infiltrating lymphocytes (TILs), which reflects one dimension of a tumor's spatial heterogeneity, and the relationship between TIL diversity, local immune response and mutation burden remain unexplored in PLC. Therefore, we performed immune repertoire sequencing, gene expression profiling analysis and whole-exome sequencing in parallel on five regions of each tumor and on matched adjacent normal tissues and peripheral blood from five PLC patients...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28393253/recombinant-adenovirus-of-sea-and-cd80-genes-driven-by-mmre-and-mouse-tert-promoter-induce-effective-antitumor-immune-responses-against-different-types-of-tumor-cells-in%C3%A2-vitro-and-in%C3%A2-vivo
#10
Shao-Yan Si, Jun-Li Liu, Jun-Lian Liu, Bing-Xin Xu, Jian-Zhong Li, Ya-Ya Qin, Shu-Jun Song
Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant and can stimulate T cells bearing certain T-cell receptor β-chain variable regions when bound to major histocompatibility complex II molecules. SEA is widely used in research of antitumor therapy. The low affinity T-cell receptor (TCR) interaction with SEA in the absence of MHC class II antigens is sufficient for the induction of cytotoxicity but requires additional CD28/B7 signaling to result in proliferation of resting T cells. In this study, we constructed recombinant adenovirus (named as Ad-MMRE-mTERT-BIS) carrying membrane-expressing SEA (named as SEAtm) and CD80 driven by Myc-Max response elements (MMRE) and mouse telomerase reverse transcriptase (mTERT) promoter to reduce toxicity and to improve safety and efficiency...
May 2017: Oncology Reports
https://www.readbyqxmd.com/read/28348568/a-bacterial-artificial-chromosome-reporter-system-for-expression-of-the-human-foxp3-gene-in-mouse-regulatory-t-cells
#11
Masato Tsuda, Yukiko Tone, Chihiro Ogawa, Yoshiko Nagaoka, Makoto Katsumata, Andra Necula, Duncan Howie, Esteban Masuda, Herman Waldmann, Masahide Tone
The transcription factor FOXP3 plays key roles in the development and function of regulatory T cells (Treg) capable of preventing and correcting immunopathology. There has been much interest in exploiting Treg as adoptive cell therapy in man, but issues of lack of nominal antigen-specificity and stability of FoxP3 expression in the face of pro-inflammatory cytokines have been a concern. In order to enable fundamental studies of human FOXP3 (hFOXP3) gene regulation and to provide preclinical tools to guide the selection of drugs that might modulate hFOXP3 expression for therapeutic purposes, we generated hFOXP3/AmCyan bacterial artificial chromosome (BAC) transgenic mice and transfectants, wherein hFOXP3 expression was read out as AmCyan expression...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28346544/epigenetic-silencing-of-v-d-j-recombination-is-a-major-determinant-for-selective-differentiation-of-mucosal-associated-invariant-t-cells-from-induced-pluripotent-stem-cells
#12
Yutaka Saito, Chie Sugimoto, Toutai Mituyama, Hiroshi Wakao
Mucosal-associated invariant T cells (MAITs) are innate-like T cells that play a pivotal role in the host defense against infectious diseases, and are also implicated in autoimmune diseases, metabolic diseases, and cancer. Recent studies have shown that induced pluripotent stem cells (iPSCs) derived from MAITs selectively redifferentiate into MAITs without altering their antigen specificity. Such a selective differentiation is a prerequisite for the use of MAITs in cell therapy and/or regenerative medicine...
2017: PloS One
https://www.readbyqxmd.com/read/28345004/homology-directed-recombination-for-enhanced-engineering-of-chimeric-antigen-receptor-t-cells
#13
Malika Hale, Baeckseung Lee, Yuchi Honaker, Wai-Hang Leung, Alexandra E Grier, Holly M Jacobs, Karen Sommer, Jaya Sahni, Shaun W Jackson, Andrew M Scharenberg, Alexander Astrakhan, David J Rawlings
Gene editing by homology-directed recombination (HDR) can be used to couple delivery of a therapeutic gene cassette with targeted genomic modifications to generate engineered human T cells with clinically useful profiles. Here, we explore the functionality of therapeutic cassettes delivered by these means and test the flexibility of this approach to clinically relevant alleles. Because CCR5-negative T cells are resistant to HIV-1 infection, CCR5-negative anti-CD19 chimeric antigen receptor (CAR) T cells could be used to treat patients with HIV-associated B cell malignancies...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28330372/car-t-cell-therapy-progress-and-prospects
#14
REVIEW
Olivia Wilkins, Allison M Keeler, Terence R Flotte
Lentivirus-mediated transduction of autologous T cells with a chimeric antigen receptor (CAR) to confer a desired epitope specificity as a targeted immunotherapy for cancer has been among the first human gene therapy techniques to demonstrate widespread therapeutic efficacy. Other approaches to using gene therapy to enhance antitumor immunity have been less specific and less effective. These have included amplification, marking, and cytokine transduction of tumor infiltrating lymphocytes, recombinant virus-based expression of tumor antigens as a tumor vaccine, and transduction of antigen-presenting cells with tumor antigens...
April 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/28323276/open-capsule-budesonide-for-refractory-celiac-disease
#15
Saurabh S Mukewar, Ayush Sharma, Alberto Rubio-Tapia, Tsung-Teh Wu, Bana Jabri, Joseph A Murray
OBJECTIVES: Refractory celiac disease (RCD) is a rare condition often associated with poor prognosis. Various immunosuppressive medications (IMs) have been used with modest success. We describe outcomes in patients treated with open-capsule budesonide (OB), including those for whom IM treatment failed. METHODS: We identified RCD patients treated with OB at Mayo Clinic, Rochester, Minnesota from 2003 to 2015. Demographic, serologic, and clinical variables were analyzed...
June 2017: American Journal of Gastroenterology
https://www.readbyqxmd.com/read/28318808/t-cell-receptor-assessment-in-autoimmune-disease-requires-access-to-the-most-adjacent-immunologically-active-organ
#16
Bergithe E Oftedal, Brita Ardesjö Lundgren, David Hamm, Poh-Yi Gan, Stephen R Holdsworth, Christopher N Hahn, Andreas W Schreiber, Hamish S Scott
Next generation sequencing of T and B cell receptors is emerging as a valuable and effective method to diagnose and monitor hematopoietic malignancies. So far, this approach has not been fully explored in regard to autoimmune diseases. T cells develop in the thymus where they undergo positive and negative selection, and the autoimmune regulator (Aire) is central in the establishment of immunological tolerance. Loss of Aire leads to severe multiorgan autoimmune disease with infiltration of autoreactive T cells in affected organs...
July 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28259946/%C3%AE-%C3%AE-tcr-immunoglobulin-constant-region-domain-exchange-in-human-%C3%AE-%C3%AE-tcrs-improves-tcr-pairing-without-altering-tcr-gene-modified-t-cell-function
#17
Changli Tao, Hongwei Shao, Wenfeng Zhang, Huaben Bo, Fenglin Wu, Han Shen, Shulin Huang
The adoptive genetic transfer of T cell receptors (TCRs) has been shown to be overall feasible and offer clinical potential as a treatment for different types of cancer. However, this promising clinical approach is limited by the serious potential consequence that exogenous TCR mispairing with endogenous TCR chains may lead to the risk of self-reactivity. In the present study, domain‑exchange and three‑dimensional modeling strategies were used to create a set of chimeric TCR variants, which were used to exchange the partial or complete constant region of αβTCR with corresponding γδTCR domains...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28245368/-clinical-and-immunophenotypic-properties-of-small-cell-variant-of-t-cell-prolymphocytic-leukemia
#18
Ya-Ping Yu, Li-Ping Wang, Ping Song, Jian-Gang Mei, Zhi-Ming An, Xiao-Gang Zhou, Feng Li, Yu-Mei Tang, Yong-Ping Zhai
OBJECTIVE: To investigate the clinical, morphologic and immunophenotypic properties of the patients with small cell variant of T-cell prolymphocytic leukaemia(T-PLL). METHODS: Peripheral blood and bone marrow cytomorphologic and immunophenotypic examination, and T-cell receptor(TCR) gene rearrangement detection were used to verify the diagnosis for 2 patients with lymphocytosis. Two patients were treated with combined chemotherapeutic protocol based on fludarabine...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28237835/integration-of-a-cd19-car-into-the-tcr-alpha-chain-locus-streamlines-production-of-allogeneic-gene-edited-car-t-cells
#19
Daniel T MacLeod, Jeyaraj Antony, Aaron J Martin, Rachel J Moser, Armin Hekele, Keith J Wetzel, Audrey E Brown, Melissa A Triggiano, Jo Ann Hux, Christina D Pham, Victor V Bartsevich, Caitlin A Turner, Janel Lape, Samantha Kirkland, Clayton W Beard, Jeff Smith, Matthew L Hirsch, Michael G Nicholson, Derek Jantz, Bruce McCreedy
Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19(+) hematological malignancies, including durable complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells...
April 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28228595/hepatitis-c-virus-specific-t-cell-receptor-mrna-engineered-human-t-cells-impact-of-antigen-specificity-on-functional-properties
#20
Anangi Balasiddaiah, Haleh Davanian, Soo Aleman, Anna Pasetto, Lars Frelin, Matti Sällberg, Volker Lohmann, Sarene Koh, Antonio Bertoletti, Margaret Chen
Therapy with genetically modified autologous T cells has shown great promise in cancer therapy. For an efficient control of hepatitis C virus (HCV) infection, cytotoxic T cells (CTL) are pivotal, but persistence of activated T cells may lead to liver toxicity. Here, anti-HCV T cell receptors (TCRs) recognizing the HCV nonstructural (NS) NS3 or NS5 viral peptide target were examined by mRNA transfection of human peripheral blood lymphocytes (PBLs) derived from healthy donors as well as chronically infected HCV patients...
May 1, 2017: Journal of Virology
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