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CD8 tolerance

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https://www.readbyqxmd.com/read/27933315/immunogenicity-of-self-tumor-associated-proteins-is-enhanced-through-protein-truncation
#1
Tim Kottke, Kevin G Shim, Vanesa Alonso-Camino, Shane Zaidi, Rosa Maria Diaz, Jose Pulido, Jill Thompson, Karishma R Rajani, Laura Evgin, Elizabeth Ilett, Hardev Pandha, Kevin Harrington, Peter Selby, Alan Melcher, Richard Vile
We showed previously that therapy with Vesicular Stomatitis Virus (VSV) expressing tumor-associated proteins eradicates established tumors. We show here that when cellular cDNA were cloned into VSV which retained their own poly-A signal, viral species emerged in culture which had deleted the cellular poly-A signal and also contained a truncated form of the protein coding sequence. Typically, the truncation occurred such that a Tyrosine-encoding codon was converted into a STOP codon. We believe that the truncation of tumor-associated proteins expressed from VSV in this way occurred to preserve the ability of the virus to replicate efficiently...
2016: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/27925187/depletion-of-cd52-positive-cells-inhibits-the-development-of-cns-autoimmune-disease-but-deletes-an-immune-tolerance-promoting-cd8-t-cell-population-implications-for-secondary-autoimmunity-of-alemtuzumab-in-multiple-sclerosis
#2
Stephanie von Kutzleben, Gareth Pryce, Gavin Giovannoni, David Baker
The objective was to determine whether CD52 lymphocyte depletion can act to promote immunological tolerance induction via intravenous antigen administration such that it could be used to either: improve efficiency of inhibition of MS or to inhibit secondary autoimmunities that may occur following alemtuzumab use in multiple sclerosis. Relapsing experimental autoimmune encephalomyelitis was induced in ABH mice and immune cell depletion was therapeutically applied using mouse CD52 or CD4 (in conjunction with CD8 or CD20) depleting monoclonal antibodies...
December 7, 2016: Immunology
https://www.readbyqxmd.com/read/27922687/immature-myeloid-derived-suppressor-cells-a-bridge-between-inflammation-and-cancer-review
#3
Caterina Musolino, Alessandro Allegra, Govanni Pioggia, Sebastiano Gangemi
Chronic inflammation is considered to be one of the hallmarks of tumor initiation and progression. Changes occurring in the microenvironment of progressing tumors resemble the process of chronic inflammation, which begins with ischemia followed by interstitial and cellular edema, appearance of immune cells, growth of blood vessels and tissue repair, and development of inflammatory infiltrates. Moreover, long‑term production and accumulation of inflammatory factors lead to local and systemic immunosuppression associated with cancer progression...
December 5, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27920091/interferon-gamma-limits-diabetogenic-cd8-t-cell-effector-responses-in-type-1-diabetes
#4
John P Driver, Jeremy J Racine, Cheng Ye, Deanna J Lamont, Brittney N Newby, Caroline G McPhee-Leeth, Harold D Chapman, Todd M Brusko, Yi-Guang Chen, Clayton E Mathews, David V Serreze
Type 1 diabetes development in the NOD mouse model is widely reported to be dependent on high-level production by autoreactive CD4(+) and CD8(+) T-cells of IFNγ, generally considered a pro-inflammatory cytokine. However, IFNγ can also participate in tolerance induction pathways, indicating it is not solely pro-inflammatory. This study addresses how IFNγ can suppress activation of diabetogenic CD8(+) T-cells. CD8(+) T-cells transgenically expressing the diabetogenic AI4 T-cell receptor (TCR) adoptively transferred disease to otherwise unmanipulated NOD...
December 5, 2016: Diabetes
https://www.readbyqxmd.com/read/27919957/simultaneous-administration-of-statins-and-pioglitazone-limits-tumor-growth-in-a-rat-model-of-malignant-glioma
#5
Jorge Humberto Tapia-Pérez, Robert Preininger, Elmar Kirches, Annegret Reinhold, Jana Butzmann, Sylvia Prilloff, Christian Mawrin, Thomas Schneider
BACKGROUND/AIM: Statins are cholesterol reducers with considerable dose-dependent effect against glioma cells. The apoptotic effect could be increased by combining statins or by adding pioglitazone (PGZ). The last one is an anti-diabetic drug, an agonist of the peroxisome proliferator-activated receptor-gamma (PPARG). We used an animal model to test the effect of such combination in vivo and we investigated the changes on immunological processes. MATERIALS AND METHODS: Thirty-three rats (F344/DuCrl) were anesthetized and glioblastoma (F98) cells were implanted stereotactically...
December 2016: Anticancer Research
https://www.readbyqxmd.com/read/27914923/alloantigen-gene-transfer-to-hepatocytes-promotes-tolerance-to-pancreatic-islet-graft-by-inducing-cd8-regulatory-t-cells
#6
Valentin Le Guen, Jean-Paul Judor, Françoise Boeffard, Vanessa Gauttier, Nicolas Ferry, Jean-Paul Soulillou, Sophie Brouard, Sophie Conchon
BACKGROUND & AIM: Induction of donor-specific immune tolerance is a good alternative to chronic life-long immunosuppression for transplant patients. Donor major histocompatibility complex (MHC) molecules represent the main targets of the allogeneic immune response of transplant recipients. Liver-targeted gene transfer with viral vectors induces tolerance toward the encoded antigen. The aim of this work was to determine whether alloantigen gene transfer to hepatocytes induces tolerance and promotes graft acceptance...
November 30, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27911371/development-of-stem-cell-derived-antigen-specific-regulatory-t-cells-against-autoimmunity
#7
Mohammad Haque, Kristin Fino, Praneet Sandhu, Jianxun Song
Autoimmune diseases arise due to the loss of immunological self-tolerance. Regulatory T cells (Tregs) are important mediators of immunologic self-tolerance. Tregs represent about 5 - 10% of the mature CD4(+) T cell subpopulation in mice and humans, with about 1 - 2% of those Tregs circulating in the peripheral blood. Induced pluripotent stem cells (iPSCs) can be differentiated into functional Tregs, which have a potential to be used for cell-based therapies of autoimmune diseases. Here, we present a method to develop antigen (Ag)-specific Tregs from iPSCs (i...
November 8, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27903649/structural-mechanism-underpinning-cross-reactivity-of-a-cd8-t-cell-clone-that-recognises-a-peptide-derived-from-human-telomerase-reverse-transcriptase
#8
David K Cole, Hugo A van den Berg, Angharad Lloyd, Michael D Crowther, Konrad Beck, Julia Ekeruche-Makinde, John J Miles, Anna M Bulek, Garry Dolton, Andrea J Schauenburg, Aaron Wall, Anna Fuller, Mathew Clement, Bruno Laugel, Pierre J Rizkallah, Linda Wooldridge, Andrew K Sewell
T-cell cross-reactivity is essential for effective immune surveillance, but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT)...
November 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27898463/transplantation-tolerance-after-allograft-rejection
#9
Michelle L Miller, Maria-Luisa Alegre, Anita S Chong
PURPOSE OF REVIEW: Although elusive for many decades, transplantation tolerance can now be achieved in the clinic. This has prompted follow-up investigations into its stability and longevity, as well as into barriers to its induction, which include memory T and B cells. RECENT FINDINGS: Clinical observations reveal that transplantation tolerance can be induced in adult recipients and that even episodes of acute rejection do not preclude successful weaning from immunosuppression to reveal tolerance...
November 24, 2016: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/27891502/diacylglycerol-kinases-in-t-cell-tolerance-and-effector-function
#10
REVIEW
Shelley S Chen, Zhiming Hu, Xiao-Ping Zhong
Diacylglycerol kinases (DGKs) are a family of enzymes that regulate the relative levels of diacylglycerol (DAG) and phosphatidic acid (PA) in cells by phosphorylating DAG to produce PA. Both DAG and PA are important second messengers cascading T cell receptor (TCR) signal by recruiting multiple effector molecules, such as RasGRP1, PKCθ, and mTOR. Studies have revealed important physiological functions of DGKs in the regulation of receptor signaling and the development and activation of immune cells. In this review, we will focus on recent progresses in our understanding of two DGK isoforms, α and ζ, in CD8 T effector and memory cell differentiation, regulatory T cell development and function, and invariant NKT cell development and effector lineage differentiation...
2016: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/27872951/immunogenicity-and-efficacy-of-a-rationally-designed-vaccine-against-vascular-endothelial-growth-factor-in-mouse-solid-tumor-models
#11
Aizhang Xu, Li Zhang, Yangyang Chen, Zhibing Lin, Rongxiu Li
Vascular endothelial growth factor (VEGF) plays an important role in the progression of various cancers. The VEGF-specific antibody bevacizumab combined with chemotherapy was shown to significantly improve progression-free survival in certain cancers. However, repeated administration is necessary for effective suppression of VEGF, thereby making the therapy expensive and cumbersome. Thus, it is urgent to develop alternative reagents such as VEGF vaccines. Here we report that DTT-VEGF, a VEGF-based antigen consisting of the receptor-binding domain of VEGF and diphtheria toxin T domain (DTT), not only stimulated neutralizing antibody response, but also induced type 1 immune response as well as anti-tumor cytotoxic T lymphocytes in mice when administered with aluminum hydroxide adjuvant...
November 21, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27872621/combining-theoretical-and-experimental-techniques-to-study-murine-heart-transplant-rejection
#12
Julia C Arciero, Andrew Maturo, Anirudh Arun, Byoung Chol Oh, Gerald Brandacher, Giorgio Raimondi
The quality of life of organ transplant recipients is compromised by complications associated with life-long immunosuppression, such as hypertension, diabetes, opportunistic infections, and cancer. Moreover, the absence of established tolerance to the transplanted tissues causes limited long-term graft survival rates. Thus, there is a great medical need to understand the complex immune system interactions that lead to transplant rejection so that novel and effective strategies of intervention that redirect the system toward transplant acceptance (while preserving overall immune competence) can be identified...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27872087/tim-3-expression-on-tumor-infiltrating-pd-1-cd8-t-cells-correlates-with-poor-clinical-outcome-in-renal-cell-carcinoma
#13
Clémence Granier, Charles Dariane, Pierre Combe, Virginie Verkarre, Saik Urien, Cecile Badoual, Hélène Roussel, Marion Mandavit, Patrice Ravel, Mathilde Sibony, Lucie Biard, Camelia Radulescu, Emeline Vinatier, Nadine Benhamouda, Michael Peyromaure, Stephane Oudard, Arnaud Méjean, Marc Olivier Timsit, Alain Gey, Eric Tartour
Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis...
November 21, 2016: Cancer Research
https://www.readbyqxmd.com/read/27868139/clinical-genetic-and-innate-immunity-characteristics-of-melanoma-in-organ-transplant-recipients
#14
Anabelle Brocard, Anne-Chantal Knol, Céline Bossard, Marc G Denis, Gaëlle Quéreux, Mélanie Saint-Jean, Lucie Peuvrel, Amir Khammari, Gilles Blancho, Jacques Dantal, Brigitte Dréno
The aims of this study were to determine the clinical and histological characteristics of melanoma in transplant recipients, the mutation profile (BRAF, NRAS and c-KIT genes), and the immune tolerance of the tumour microenvironment by immunohistochemical study of the expression of IDO, PD1, PD-L1, CD8 and FoxP3. The study population comprised patients who had undergone a renal transplant in Nantes University Hospital who developed post-transplantation melanoma. Twenty cases of melanoma out of 4,663 transplant recipients were studied...
November 10, 2016: Acta Dermato-venereologica
https://www.readbyqxmd.com/read/27867515/the-cd8-t-cell-response-during-tolerance-induction-in-liver-transplantation
#15
REVIEW
Yik Chun Wong, Geoffrey W McCaughan, David G Bowen, Patrick Bertolino
Both experimental and clinical studies have shown that the liver possesses unique tolerogenic properties. Liver allografts can be spontaneously accepted across complete major histocompatibility mismatch in some animal models. In addition, some liver transplant patients can be successfully withdrawn from immunosuppressive medications, developing 'operational tolerance'. Multiple mechanisms have been shown to be involved in inducing and maintaining alloimmune tolerance associated with liver transplantation. Here, we focus on CD8 T-cell tolerance in this setting...
October 2016: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/27864347/human-pancreatic-cancer-cells-induce-a-myd88-dependent-stromal-response-to-promote-a-tumor-tolerant-immune-microenvironment
#16
Daniel Delitto, Andrea E Delitto, Bayli B DiVita, Kien Pham, Song Han, Emily R Hartlage, Brittney N Newby, Michael H Gerber, Kevin E Behrns, Lyle L Moldawer, Ryan M Thomas, Thomas George, Todd Brusko, Clayton E Mathews, Chen Liu, Jose G Trevino, Steven J Hughes, Shannon Wallet
Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the crosstalk between pancreatic cancer (PC) and its TAS in primary human cell culture models. Upon exposure of TAS to PC cell-conditioned media, we documented robust secretion of IL-6 and IL-8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T cell proliferation, inducing Th17 polarization at the expense of Th1...
November 18, 2016: Cancer Research
https://www.readbyqxmd.com/read/27863194/pomalidomide-for-symptomatic-kaposi-s-sarcoma-in-people-with-and-without-hiv-infection-a-phase-i-ii-study
#17
Mark N Polizzotto, Thomas S Uldrick, Kathleen M Wyvill, Karen Aleman, Cody J Peer, Margaret Bevans, Irini Sereti, Frank Maldarelli, Denise Whitby, Vickie Marshall, Priscila H Goncalves, Vikram Khetani, William D Figg, Seth M Steinberg, Jerome B Zeldis, Robert Yarchoan
Purpose Kaposi's sarcoma (KS) is a multicentric tumor caused by Kaposi's sarcoma-associated herpesvirus. Unmet needs include therapies that are oral, anthracycline sparing, and deliverable in resource-limited settings. We evaluated pomalidomide, an oral immune modulatory agent, in patients with symptomatic KS. Methods The primary objectives were to assess tolerability, pharmacokinetics, and activity. Initial dosage level was 5 mg once per day for 21 days per 28-day cycle, with a de-escalated level of 3 mg if not tolerable, and aspirin 81 mg once per day thromboprophylaxis...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27862343/human-anti-pig-nk-cell-and-cd8-t-cell-responses-in-the-presence-of-regulatory-dendritic-cells
#18
Natacha Madelon, Gisella L Puga Yung, Jörg D Seebach
BACKGROUND: Dendritic cells (DC) play a major role in natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activation leading to cell-mediated xenogeneic responses. In contrast, the use of in vitro differentiated regulatory DC may represent an attractive approach to protect porcine endothelial cells (pEC) from human cell-mediated immune responses. In this study, we evaluated the potential of human regulatory DC to reduce xenogeneic NK cell and CTL responses to pEC. METHODS: Human monocytes were differentiated into DC with GM-CSF and IL-4 in the absence or presence of rapamycin or IL-10...
November 13, 2016: Xenotransplantation
https://www.readbyqxmd.com/read/27861804/cd103-cd11b-salivary-gland-dendritic-cells-have-antigen-cross-presenting-capacity
#19
Lu Lu, Yukinori Tanaka, Naoto Ishii, Takashi Sasano, Shunji Sugawara
Dendritic cells (DCs) in lymphoid and non-lymphoid tissues are professional antigen-presenting cells that are essential for effective immunity and tolerance. However, the presence and characteristics of DCs in steady-state salivary glands (SGs) currently remain unknown. We herein identified CD64(-) CD11c(+) classical DCs (cDCs) as well as CD64(+) macrophages among CD45(+) MHC class II(+) antigen-presenting cells in steady-state murine SGs. SG cDCs were divided into CD103(+) CD11b(-) and CD103(-) CD11b(+) cDCs...
November 11, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27861263/mechanisms-of-graft-rejection-after-lung-transplantation
#20
Hsi-Min Hsiao, Davide Scozzi, Jason M Gauthier, Daniel Kreisel
PURPOSE OF REVIEW: To date, outcomes after lung transplantation are far worse than after transplantation of other solid organs. New insights into mechanisms that contribute to graft rejection and tolerance after lung transplantation remain of great interest. This review examines the recent literature on the role of innate and adaptive immunity in shaping the fate of lung grafts. RECENT FINDINGS: Innate and adaptive immune cells orchestrate allograft rejection after transplantation...
November 17, 2016: Current Opinion in Organ Transplantation
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