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https://www.readbyqxmd.com/read/28325871/progression-of-type-1-diabetes-from-the-prediabetic-stage-is-controlled-by-interferon-%C3%AE-signaling
#1
Brett S Marro, Brian C Ware, Jaroslav Zak, Juan Carlos de la Torre, Hugh Rosen, Michael B A Oldstone
Blockade of IFN-α but not IFN-β signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "antiself" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing β cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28321813/harnessing-the-immune-system-against-leukemia-monoclonal-antibodies-and-checkpoint-strategies-for-aml
#2
Lucia Masarova, Hagop Kantarjian, Guillermo Garcia-Mannero, Farhad Ravandi, Padmanee Sharma, Naval Daver
Acute myeloid leukemia (AML) is the most common leukemia among adults and is associated with a poor prognosis, especially in patients with adverse prognostic factors, older age, or relapsed disease. The last decade has seen a surge in successful immune-based therapies in various solid tumors; however, the role of immune therapies in AML remains poorly defined. This chapter describes the rationale, clinical data, and toxicity profiles of immune-based therapeutic modalities in AML including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, chimeric antigen receptor (CAR)-T cells, and checkpoint blockade via blockade of PD1/PDL1 or CTLA4...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28321130/effective-combinatorial-immunotherapy-for-castration-resistant-prostate-cancer
#3
Xin Lu, James W Horner, Erin Paul, Xiaoying Shang, Patricia Troncoso, Pingna Deng, Shan Jiang, Qing Chang, Denise J Spring, Padmanee Sharma, John A Zebala, Dean Y Maeda, Y Alan Wang, Ronald A DePinho
A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance...
March 20, 2017: Nature
https://www.readbyqxmd.com/read/28320831/interference-of-the-t-cell-and-antigen-presenting-cell-costimulatory-pathway-using-ctla4-ig-abatacept-prevents-staphylococcal-enterotoxin-b-pathology
#4
Sarah J C Whitfield, Chris Taylor, Jane E Risdall, Gareth D Griffiths, James T A Jones, E Diane Williamson, Sjoerd Rijpkema, Luisa Saraiva, Sandrine Vessillier, A Christopher Green, Alun J Carter
Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology...
March 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28297658/multiscale-modeling-of-complex-formation-and-cd80-depletion-during-immune-synapse-development
#5
István P Sugár, Jayajit Das, Ciriyam Jayaprakash, Stuart C Sealfon
The mechanisms that discriminate self- and foreign antigen before T cell activation are unresolved. As part of the immune system's adaptive response to specific infections or neoplasms, antigen-presenting cells (APC) and effector T cells form transcellular molecular complexes. CTLA4 expression on regulatory or effector T cells reduces T cell activation. The CTLA4 transendocytosis hypothesis proposes that CTLA4 depletes CD80 and CD86 proteins from the APC membrane, rendering the APC incapable of activating T cells...
March 14, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28291636/correlation-between-messenger-rna-expression-and-protein-expression-of-immune-checkpoint-associated-molecules-in-bladder-urothelial-carcinoma-a-retrospective-study
#6
Constance Le Goux, Diane Damotte, Sophie Vacher, Mathilde Sibony, Nicolas Barry Delongchamps, Anne Schnitzler, Benoit Terris, Marc Zerbib, Ivan Bieche, Géraldine Pignot
OBJECTIVES: Immunotherapy for bladder cancer seems to have promising results. Here, we evaluated the association between messenger RNA (mRNA) and protein levels and possible prognostic value of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) immune checkpoint pathways during bladder carcinogenesis. METHODS AND MATERIALS: Tumor samples were obtained from 155 patients (84 with muscle-invasive bladder cancer [MIBC], and 71 non-muscle-invasive bladder cancer [NMIBC]) and normal bladder tissue from 15 patients...
March 10, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28276698/the-role-of-checkpoint-inhibitors-immunotherapy-in-advanced-non-small-cell-lung-cancer-in-the-elderly
#7
Assunta Sgambato, Francesca Casaluce, Cesare Gridelli
Immune checkpoint inhibition is a novel treatment modality that has brought a new hope to patients with advanced NSCLC. Several molecules targeting cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 receptor/programmed death ligand-1 (PD1/PD-L1) pathways are under evaluation in NSCLC and three of them are currently approved: nivolumab and atezolizumab for advanced NSCLC after prior chemotherapy and pembrolizumab for advanced NSCLC expressing PD-L1 ≥ 1% after at least one prior chemotherapy regimen and > 50% as a first-line response...
February 20, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28274366/pemphigus-vulgaris-and-pemphigus-foliaceus-determined-by-cd86-and-ctla4-polymorphisms
#8
Srdjan Tanasilovic, Svetlana Popadic, Ljiljana Medenica, Dusan Popadic
Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare autoimmune blistering diseases with presumed T-cell-dependent pathology. Activation of naïve T cells is dependent on antigen recognition, subsequent signaling through the T-cell receptor complex (signal 1), and various other interactions of T cells with antigen presenting cells that may be collectively designated as signal 2, which is unconditionally required for T-cell activation both in response to infection and to autoantigens. Among the best described interactions contributing to signal 2 are those mediated by B7 family molecules, such as CD80 and CD86 with their ligands; CD28, providing activation signals; and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), conferring inhibition...
March 2017: Clinics in Dermatology
https://www.readbyqxmd.com/read/28270700/growth-arrest-specific-6-enhances-the-suppressive-function-of-cd4-cd25-regulatory-t-cells-mainly-through-axl-receptor
#9
Guang-Ju Zhao, Jia-Yi Zheng, Jia-Lan Bian, Long-Wang Chen, Ning Dong, Yan Yu, Guang-Liang Hong, Arvine Chandoo, Yong-Ming Yao, Zhong-Qiu Lu
Background. Growth arrest-specific (Gas) 6 is one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), and its role as an immune modulator has been recently emphasized. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study was designed to investigate whether Tregs express TAM receptors and the potential role of Gas6-TAM signal in regulating the suppressive function of Tregs. Methods. The protein and mRNA levels of TAM receptors were determined by using Western blot, immunofluorescence, flow cytometry, and RT-PCR...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28264025/both-anti-tnf-and-ctla4-ig-treatments-attenuate-the-disease-severity-of-staphylococcal-dermatitis-in-mice
#10
Manli Na, Wanzhong Wang, Ying Fei, Elisabet Josefsson, Abukar Ali, Tao Jin
BACKGROUND: RA patients being treated with biologics are known to have an increased risk of infections. We recently demonstrated that both CTLA4 Ig and anti-TNF treatment aggravate systemic Staphylococcus aureus (S. aureus) infection in mice, but with distinct clinical manifestations. However, the effects of CTLA4 Ig and anti-TNF treatments on a local S. aureus infection (e.g., skin infection) might differ from their effects on a systemic infection. AIMS: The aim of this study was to examine the differential effects of anti-TNF versus CTLA4 Ig treatment on S...
2017: PloS One
https://www.readbyqxmd.com/read/28262800/the-influence-of-population-stratification-on-genetic-markers-associated-with-type-1-diabetes
#11
Karla Fabiana Brasil Gomes, Aritânia Sousa Santos, Cintia Semzezem, Márcia Regina Correia, Luciano Abreu Brito, Marcelo Ortega Ruiz, Rosa Tsuneshiro Fukui, Sergio Russo Matioli, Maria Rita Passos-Bueno, Maria Elizabeth Rossi da Silva
Ethnic admixtures may interfere with the definition of type 1 diabetes (T1D) risk determinants. The role of HLA, PTPN22, INS-VNTR, and CTLA4 in T1D predisposition was analyzed in Brazilian T1D patients (n = 915), with 81.7% self-reporting as white and 789 controls (65.6% white). The results were corrected for population stratification by genotyping 93 ancestry informative markers (AIMs) (BeadXpress platform). Ancestry composition and structural association were characterized using Structure 2.3 and STRAT...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28258692/lag3-cd223-as-a-cancer-immunotherapy-target
#12
REVIEW
Lawrence P Andrews, Ariel E Marciscano, Charles G Drake, Dario A A Vignali
Despite the impressive impact of CTLA4 and PD1-PDL1-targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene-3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity...
March 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28257599/immunosuppressive-drugs-affect-ifn%C3%AE-and-pd1-kinetics-in-patients-with-newly-diagnosed-autoimmune-hepatitis
#13
Charlotte R Grant, Beth S Holder, Rodrigo Liberal, Michael A Heneghan, Yun Ma, Giorgina Mieli-Vergani, Diego Vergani, Maria Serena Longhi
Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs). Several lines of evidence indicate CD4 as the main effectors involved in the autoimmune liver damage. Herein we investigate the in vitro effects of prednisolone, 6-mercaptopurine, cyclosporine, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of pro-inflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4(+) CD25(-) cells, isolated from the peripheral blood of treatment-naïve patients with AIH...
March 3, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28252315/checkpoint-blockade-in-lung-cancer-and-mesothelioma
#14
Lysanne A Lievense, Daniel H Sterman, Robin Cornelissen, Joachim G Aerts
In the past decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors; antibodies which unleash the anti-tumor immune response. Following the success in melanoma, numerous clinical trials are being conducted investigating checkpoint inhibitors in lung cancer and mesothelioma. The programmed death protein 1-protein death ligand 1/2 (PD-1 - PD-L1/2) pathway and cytotoxic T-lymphocyte associated protein 4 (CTLA4) are currently the most studied immunotherapeutic targets in these malignancies...
March 2, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28250252/association-of-il10-il4-ifng-and-ctla4-gene-polymorphisms-with-efavirenz-hypersensitivity-reaction-in-patients-infected-with-human-immunodeficiency-virus
#15
Raphael de Oliveira Rodrigues, Silvia Helena Barem Rabenhorst, Paulo Germano de Carvalho, Greyce Luri Sasahara, Luciana Mabel Ferreira Vasconcelos, Érico Antônio Gomes de Arruda, Silvia Fernandes Ribeiro da Silva, Ilana Farias Ribeiro, E Aparecida Tiemi Nagao-Dias
We evaluated IL-10 -592 C/A, IL-4 -589 C/T, IFN-γ +874 A/T, CTLA-4 +49 A/G gene polymorphisms in efavirenz hypersensitivity reaction. A total of 63 HIV-positive patients under treatment at a public hospital were included in the study, of which 21 presented efavirenz hypersensitivity. Patients who presented efavirenz hypersensitivity reaction showed a higher frequency of the IL-10 -592A allele than the controls (p = 0.028). The allele A was associated with increased risk to efavirenz hypersensitivity (OR = 2...
February 28, 2017: Japanese Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28236768/survival-of-patients-with-melanoma-brain-metastasis-treated-with-stereotactic-radiosurgery-and-active-systemic-drug-therapies
#16
Ee Siang Choong, Serigne Lo, Martin Drummond, Gerald B Fogarty, Alexander M Menzies, Alexander Guminski, Brindha Shivalingam, Kathryn Clarke, Georgina V Long, Angela M Hong
INTRODUCTION: With new systemic therapies demonstrating activity in melanoma brain metastasis, most of the previously reported stereotactic radiosurgery (SRS) data are superseded. In this study, we report the outcomes (overall survival [OS] and brain control [BC]) and identify factors that associate with such outcomes in the era of modern systemic therapy. METHOD: A total of 108 patients treated with SRS from 2010 to 2015 were included. Systemic treatment use within 6 weeks of SRS was noted...
February 22, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28230715/a-multireferral-centre-retrospective-cohort-analysis-on-the-experience-in-treatment-of-metastatic-uveal-melanoma-and-utilization-of-sequential-liver-directed-treatment-and-immunotherapy
#17
Malinda Itchins, Paolo A Ascierto, Alexander M Menzies, Meredith Oatley, Serigne Lo, Dariush Douraghi-Zadeh, Timmothy Harrington, Richard Maher, Antonio M Grimaldi, Alexander Guminski
Metastatic uveal melanoma is a rare malignancy with a poor prognosis. To date, systemic therapy has been ineffective; however, there are few data on the benefits of anti-CTLA4 or anti-PD-1 antibodies in sequence with liver-directed therapy. A retrospective cohort analysis was carried out on 37 consecutive patients managed in a tertiary referral centre examining the safety and efficacy of treatment; patterns of care; and impact on survival. The sequential treatment with transarterial chemotherapy (TAC), systemic immunotherapy (IT) and systemic chemotherapy was reviewed...
February 22, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28220815/cbx3-hp1%C3%AE-deficiency-confers-enhanced-tumor-killing-capacity-on-cd8-t-cells
#18
Michael Sun, Ngoc Ha, Duc-Hung Pham, Megan Frederick, Bandana Sharma, Chie Naruse, Masahide Asano, Matthew E Pipkin, Rani E George, To-Ha Thai
Cbx3/HP1γ is a histone reader whose function in the immune system is not completely understood. Here, we demonstrate that in CD8(+) T cells, Cbx3/HP1γ insufficiency leads to chromatin remodeling accompanied by enhanced Prf1, Gzmb and Ifng expression. In tumors obtained from Cbx3/HP1γ-insufficient mice or wild type mice treated with Cbx3/HP1γ-insufficient CD8(+) T cells, there is an increase of CD8(+) effector T cells expressing the stimulatory receptor Klrk1/NKG2D, a decrease in CD4(+) CD25(+) FOXP3(+) regulatory T cells (Treg cells) as well as CD25(+) CD4(+) T cells expressing the inhibitory receptor CTLA4...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28216262/efis-lecture-understanding-the-ctla-4-checkpoint-in-the-maintenance-of-immune-homeostasis
#19
REVIEW
Lucy S K Walker
The past 20 years have heralded fascinating developments in the field of CTLA-4 biology. The CTLA-4 protein is a critical negative regulator of T cell immunity and its absence provokes severe lymphoproliferative disease. In a surprising twist, the generation of mixed bone marrow chimeric mice revealed that CTLA-4 predominantly functions in a cell-extrinsic manner, suggesting that CTLA-4 expressed on one cell can modify the behaviour of another cell. This was followed by the demonstration that CTLA-4 is highly expressed in regulatory T cells and can contribute to their suppressive activity...
February 16, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28214651/a-review-on-the-evolution-of-pd-1-pd-l1-immunotherapy-for-bladder-cancer-the-future-is-now
#20
REVIEW
Joaquin Bellmunt, Thomas Powles, Nicholas J Vogelzang
The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated...
March 2017: Cancer Treatment Reviews
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