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CD8 tolerance

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https://www.readbyqxmd.com/read/29784760/formation-of-the-intrathymic-dendritic-cell-pool-requires-ccl21-mediated-recruitment-of-ccr7-progenitors-to-the-thymus
#1
Emilie J Cosway, Izumi Ohigashi, Karin Schauble, Sonia M Parnell, William E Jenkinson, Sanjiv Luther, Yousuke Takahama, Graham Anderson
During αβ T cell development in the thymus, migration of newly selected CD4+ and CD8+ thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αβ TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα+ conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2...
May 21, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29782535/mycobacterium-tuberculosis-specific-cd4-and-cd8-t-cells-differ-in-their-capacity-to-recognize-infected-macrophages
#2
Jason D Yang, Daniel Mott, Rujapak Sutiwisesak, Yu-Jung Lu, Fiona Raso, Britni Stowell, Greg Hunter Babunovic, Jinhee Lee, Steve M Carpenter, Sing Sing Way, Sarah M Fortune, Samuel M Behar
Containment of Mycobacterium tuberculosis (Mtb) infection requires T cell recognition of infected macrophages. Mtb has evolved to tolerate, evade, and subvert host immunity. Despite a vigorous and sustained CD8+ T cell response during Mtb infection, CD8+ T cells make limited contribution to protection. Here, we ask whether the ability of Mtb-specific T cells to restrict Mtb growth is related to their capacity to recognize Mtb-infected macrophages. We derived CD8+ T cell lines that recognized the Mtb immunodominant epitope TB10...
May 21, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29782330/a-transgenic-mouse-model-for-hla-b-57-01-linked-abacavir-drug-tolerance-and-reactivity
#3
Marco Cardone, Karla Garcia, Mulualem E Tilahun, Lisa F Boyd, Sintayehu Gebreyohannes, Masahide Yano, Gregory Roderiquez, Adovi D Akue, Leslie Juengst, Elliot Mattson, Suryatheja Ananthula, Kannan Natarajan, Montserrat Puig, David H Margulies, Michael A Norcross
Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo...
May 21, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29780389/deep-surveying-of-the-transcriptional-and-alternative-splicing-signatures-for-decidual-cd8-t-cells-at-the-first-trimester-of-human-healthy-pregnancy
#4
Weihong Zeng, Xinmei Liu, Zhicui Liu, Ying Zheng, Tiantian Yu, Shaliu Fu, Xiao Li, Jing Zhang, Siming Zhang, Xiaoling Ma, Xiao-Rui Liu, Xiaoli Qin, Asma Khanniche, Yan Zhang, Fuju Tian, Yi Lin
Decidual CD8+ (dCD8) T cells have been proposed to play important roles in immune protection against the invading pathogens and in tolerance toward the growing semi-allogeneic fetus during early pregnancy. However, their phenotypic and functional characteristics remain poorly defined. Here, we performed the first analysis of the transcriptional and alternative splicing (AS) signatures for human first-trimester dCD8 T cells using high-throughput mRNA sequencing. Our data revealed that dCD8 T cells have distinct transcriptional and AS landscapes when compared with their autologous peripheral blood CD8+ (pCD8) T counterparts...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29772494/effects-of-ceftriaxone-induced-intestinal-dysbacteriosis-on-regulatory-t-cells-validated-by-anaphylactic-mice
#5
Xia Luo, Zengfeng Pan, Shuang Luo, Qi Liu, Shaowei Huang, Guanghua Yang, Feifei Nong, Yajun Fu, Xiangliang Deng, Lian Zhou
Both probiotics and pathogens in the human gut express pathogen-associated molecular patterns (PAMPs) and die with the release of endotoxin and bacterial DNA, which can stimulate our immune system and cause immune reaction. However, it's interesting and fascinating to address why the normal intestinal flora will not generate immunological rejection like the pathogen does. By investigating the changes in cells and molecules relevant to immune tolerance in mice with ceftriaxone-induced dysbacteriosis, our study discovered that both the Evenness indexes and Shannon Wiener index of intestinal flora showed a decrease in dysbacteriosis mice...
May 14, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29769207/mitigating-sox2-potentiated-immune-escape-of-head-and-neck-squamous-cell-carcinoma-with-a-sting-inducing-nanosatellite-vaccine
#6
Yee Sun Tan, Kanokwan Sansanaphongpricha, Yuying Xie, Christopher R Donnelly, Xiaobo Luo, Blake R Heath, Xinyi Zhao, Emily L Bellile, Hongxiang Hu, Hongwei Chen, Peter J Polverini, Qianming Chen, Simon Young, Thomas E Carey, Jacques E Nör, Robert L Ferris, Gregory Wolf, Duxin Sun, Yu L Lei
PURPOSE: The response rates of Head and Neck Squamous Cell Carcinoma (HNSCC) to checkpoint blockade are below 20%. We aim to develop a mechanism-based vaccine to prevent HNSCC immune escape. EXPERIMENTAL DESIGN: We performed RNA-Seq of sensitive and resistant HNSCC cells to discover central pathways promoting resistance to immune killing. Using biochemistry, animal models, HNSCC microarray and immune cell deconvolution, we assessed the role of SOX2 in inhibiting STING-type I interferon (IFN-I) signaling-mediated anti-tumor immunity...
May 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29760702/emerging-concepts-in-immune-thrombocytopenia
#7
REVIEW
Maurice Swinkels, Maaike Rijkers, Jan Voorberg, Gestur Vidarsson, Frank W G Leebeek, A J Gerard Jansen
Immune thrombocytopenia (ITP) is an autoimmune disease defined by low platelet counts which presents with an increased bleeding risk. Several genetic risk factors (e.g., polymorphisms in immunity-related genes) predispose to ITP. Autoantibodies and cytotoxic CD8+ T cells (Tc) mediate the anti-platelet response leading to thrombocytopenia. Both effector arms enhance platelet clearance through phagocytosis by splenic macrophages or dendritic cells and by induction of apoptosis. Meanwhile, platelet production is inhibited by CD8+ Tc targeting megakaryocytes in the bone marrow...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29752423/strong-homeostatic-tcr-signals-induce-formation-of-self-tolerant-virtual-memory-cd8-t-cells
#8
Ales Drobek, Alena Moudra, Daniel Mueller, Martina Huranova, Veronika Horkova, Michaela Pribikova, Robert Ivanek, Susanne Oberle, Dietmar Zehn, Kathy D McCoy, Peter Draber, Ondrej Stepanek
Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells...
May 11, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29752315/formation-of-immune-complexes-with-a-tetanus-derived-b-cell-epitope-boosts-human-t-cell-responses-to-covalently-linked-peptides-in-an-ex-vivo-blood-loop-system
#9
Erika A K Fletcher, Wendy van Maren, Robert Cordfunke, Jasper Dinkelaar, Jeroen D C Codee, Gijs van der Marel, Cornelis J M Melief, Ferry Ossendorp, Jan Wouter Drijfhout, Sara M Mangsbo
Enhancing T cell responses against both viral and tumor Ags requires efficient costimulation and directed delivery of peptide Ags into APCs. Long peptide vaccines are considered favorable vaccine moieties from a clinical perspective, as they can harbor more than one immunogenic epitope enabling treatment of a broader target population. In addition, longer peptides are not extracellularly loaded on MHC class I; rather, they require intracellular processing and will thereby be presented to T cells mainly by professional APCs, thereby avoiding the risk of tolerance induction...
May 11, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29743501/a-phase-i-clinical-trial-with-ex-vivo-expanded-recipient-regulatory-t-cells-in-living-donor-kidney-transplants
#10
James M Mathew, Jessica H-Voss, Ann LeFever, Iwona Konieczna, Cheryl Stratton, Jie He, Xuemei Huang, Lorenzo Gallon, Anton Skaro, Mohammed Javeed Ansari, Joseph R Leventhal
There is considerable interest in therapeutic transfer of regulatory T cells (Tregs) for controlling aberrant immune responses. Initial clinical trials have shown the safety of Tregs in hematopoietic stem cell transplant recipients and subjects with juvenile diabetes. Our hypothesis is that infusion(s) of Tregs may induce transplant tolerance thus avoiding long-term use of toxic immunosuppressive agents that cause increased morbidity/mortality. Towards testing our hypothesis, we conducted a phase I dose escalation safety trial infusing billions of ex vivo expanded recipient polyclonal Tregs into living donor kidney transplant recipients...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29739434/gastric-cancer-vaccines-synthesized-using-a-tlr7-agonist-and-their-synergistic-antitumor-effects-with-5-fluorouracil
#11
Xiaodong Wang, Yu Liu, Yuwen Diao, Ningning Gao, Yanyan Wan, Jingjing Zhong, Huali Zheng, Zhulin Wang, Guangyi Jin
BACKGROUND: Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. METHODS: Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 - ML (linear tetra-epitope) and T7 - MB (branched tetra-epitope)...
May 8, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29731752/resetting-the-t-cell-compartment-in-autoimmune-diseases-with-autologous-hematopoietic-stem-cell-transplantation-an-update
#12
REVIEW
Lisanne Lutter, Julia Spierings, Femke C C van Rhijn-Brouwer, Jacob M van Laar, Femke van Wijk
Autologous hematopoietic stem cell transplantation (aHSCT) for autoimmune diseases has been applied for two decades as a treatment for refractory patients with progressive disease. The rationale behind aHSCT is that high-dose immunosuppression eliminates autoreactive T and B cells, thereby resetting the immune system. Post-aHSCT the cytotoxic CD8+ T cells normalize via clonal expansion due to homeostatic proliferation within a few months. CD4+ T cells recover primarily via thymopoiesis resulting in complete renewal of the T cell receptor (TCR) repertoire which requires years or never normalize completely...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29729204/outcome-of-anti-viral-immunity-in-the-liver-is-shaped-by-the-level-of-antigen-expressed-in-infected-hepatocytes
#13
Katrin Manske, Nina Kallin, Verena König, Annika Schneider, Sandra Kurz, Miriam Bosch, Meike Welz, Ru-Lin Cheng, Bertram Bengsch, Katja Steiger, Ulrike Protzer, Robert Thimme, Percy A Knolle, Dirk Wohlleber
The liver bears unique immune-properties supporting both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus-infected hepatocytes remains unclear. Here, we dissect the factors determining the outcome of anti-viral immunity using novel recombinant adenoviruses reflecting the hepatropism and -trophism of hepatitis viruses. We generated replication-deficient adenoviruses with equimolar ovalbumin, luciferase and GFP-expression driven by strong ubiquitous CMV-promoter (Ad-CMV-GOL) or by 100-fold weaker, yet hepatocyte-specific Transthyretin(TTR)-promoter (Ad-TTR-GOL)...
May 5, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29721378/a-phase-ii-study-of-combined-therapy-with-a-braf-inhibitor-vemurafenib-and-interleukin-2-aldesleukin-in-patients-with-metastatic-melanoma
#14
Meghan J Mooradian, Alexandre Reuben, Peter A Prieto, Mehlika Hazar-Rethinam, Dennie T Frederick, Brandon Nadres, Adriano Piris, Vikram Juneja, Zachary A Cooper, Arlene H Sharpe, Ryan B Corcoran, Keith T Flaherty, Donald P Lawrence, Jennifer A Wargo, Ryan J Sullivan
Background : Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/- MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods : Patients with unresectable Stage III or IV BRAFV600E mutant melanoma were enrolled in a single-center prospective study (n = 6). Patients were eligible to receive two courses of HD-IL-2 and vemurafenib twice daily. The primary endpoint was progression-free survival (PFS) with secondary objectives including overall survival (OS), response rates (RR), and safety of combination therapy as compared to historical controls...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29713085/determinants-of-response-and-resistance-to-cd19-chimeric-antigen-receptor-car-t-cell-therapy-of-chronic-lymphocytic-leukemia
#15
Joseph A Fraietta, Simon F Lacey, Elena J Orlando, Iulian Pruteanu-Malinici, Mercy Gohil, Stefan Lundh, Alina C Boesteanu, Yan Wang, Roddy S O'Connor, Wei-Ting Hwang, Edward Pequignot, David E Ambrose, Changfeng Zhang, Nicholas Wilcox, Felipe Bedoya, Corin Dorfmeier, Fang Chen, Lifeng Tian, Harit Parakandi, Minnal Gupta, Regina M Young, F Brad Johnson, Irina Kulikovskaya, Li Liu, Jun Xu, Sadik H Kassim, Megan M Davis, Bruce L Levine, Noelle V Frey, Donald L Siegel, Alexander C Huang, E John Wherry, Hans Bitter, Jennifer L Brogdon, David L Porter, Carl H June, J Joseph Melenhorst
Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2 . We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response...
April 30, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29709495/morphological-changes-induced-by-intraprostatic-psa-based-vaccine-in-prostate-cancer-biopsies-phase-i-clinical-trial
#16
Maria J Merino, A Peter, Vanessa Moreno, Sara Gil, Jeffrey Schlom, James L Gulley
Immunotherapy is a novel treatment for many tumors including prostate cancer. Little is known about the histological changes in prostate biopsies caused by the prostatic-specific antigen (PSA)-based vaccine. This study evaluated the histopathological effects in prostate biopsies of recombinant fowlpox (rF) virus-based vaccine engineered to present the PSA and three costimulatory molecules (collectively labeled as PSA-TRICOM). This vaccine has shown that it can break tolerance of the PSA, and its administration directly into a tumor enables the affected tumor cells to act as antigen-presenting cells activating new T-cells, and broadening the immune response to recognize and kill tumor...
April 27, 2018: Human Pathology
https://www.readbyqxmd.com/read/29696366/genetic-interaction-between-two-insulin-dependent-diabetes-susceptibility-loci-idd2-and-idd13-in-determining-immunoregulatory-dn-t-cell-proportion
#17
Roxanne Collin, Kathy Doyon, Victor Mullins-Dansereau, Martin Karam, Geneviève Chabot-Roy, Erin E Hillhouse, Alexandre Orthwein, Sylvie Lesage
Several immune regulatory cell types participate in the protection against autoimmune diseases such as autoimmune diabetes. Of these immunoregulatory cells, we and others have shown that peripheral CD4- CD8- double negative (DN) T cells can induce antigen-specific immune tolerance. Particularly, we have described that diabetes-prone mice exhibit a lower number of peripheral DN T cells compared to diabetes-resistant mice. Identifying the molecular pathways that influence the size of the DN T cell pool in peripheral lymphoid organs may thus be of interest for maintaining antigen-specific immune tolerance...
April 25, 2018: Immunogenetics
https://www.readbyqxmd.com/read/29695766/vinorelbine-cyclophosphamide-and-5-fu-effects-on-the-circulating-and-intratumoural-landscape-of-immune-cells-improve-anti-pd-l1-efficacy-in-preclinical-models-of-breast-cancer-and-lymphoma
#18
Stefania Orecchioni, Giovanna Talarico, Valentina Labanca, Angelica Calleri, Patrizia Mancuso, Francesco Bertolini
BACKGROUND: Anti-PD-1 and anti-PD-L1 checkpoint inhibitors (CIs) are clinically active in many types of cancer. However, only a minority of patients achieve a complete and/or long-lasting clinical response. We studied the effects of different doses of three widely used, orally active chemotherapeutics (vinorelbine, cyclophosphamide and 5-FU) over local and metastatic tumour growth, and the landscape of circulating and tumour-infiltrating immune cells involved in CI activity. METHODS: Immunocompetent Balb/c mice were used to generate models of breast cancer (BC) and B-cell lymphoma...
April 26, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29688996/advances-on-cd8-tregs-and-their-potential-in-transplantation
#19
Séverine Bézie, Ignacio Anegon, Carole Guillonneau
Although CD8 Tregs have been in the last 20 years more studied since evidences of their role in tolerance as been demonstrated in transplantation, autoimmune diseases and cancer, their characteristics are still controversial. In this review, we will focus on recent advances on CD8 Tregs and description of a role for CD8 Tregs in tolerance in both solid organ transplantation and GVHD and their potential for clinical trials.
April 24, 2018: Transplantation
https://www.readbyqxmd.com/read/29684247/tr1-cell-immunotherapy-promotes-transplant-tolerance-via-de-novo-tr1-cell-induction-in-mice-and-is-safe-and-effective-during-acute-viral-infection
#20
Tatiana Jofra, Roberta Di Fonte, Giuseppe Galvani, Mirela Kuka, Matteo Iannacone, Manuela Battaglia, Georgia Fousteri
Tr1 cell therapy is considered an emerging approach to improve transplant tolerance and enhance allogeneic graft survival. However, it remains unclear how Tr1 cells promote transplant tolerance and whether they will be safe and stable in the face of an acute viral infection. By employing a mouse model of pancreatic islet transplantation, we report that Tr1 cell therapy promoted transplant tolerance via de novo induction of Tr1 cells in the recipients. Acute viral infection with lymphocytic choriomeningitis virus (LCMV) had no impact on Tr1 cell number and function, neither on the Tr1 cells infused nor on the ones induced, and that was reflected in the robust maintenance of the graft...
April 23, 2018: European Journal of Immunology
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