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A K S Salama, S J Moschos
BACKGROUND: Cancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well characterized at preclinical and clinical levels...
October 13, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
David Wojciechowski, Flavio Vincenti
Kidney transplantation immunosuppression relies on a calcineurin inhibitor backbone. Calcineurin inhibitors have reduced early-acute rejection rates but failed to improve long-term allograft survival. Their nephrotoxicity has shifted the focus of investigation to calcineurin inhibitor-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of CTLA4-Ig, has emerged as part of a calcineurin inhibitor-free regimen. Belatacept has demonstrated superior glomerular filtration rate compared with calcineurin inhibitors albeit with an increased risk of early and histologically severe rejection...
September 2016: Advances in Chronic Kidney Disease
Lisa S Thomas, Stephan R Targan, Masato Tsuda, Qi T Yu, Brenda C Salumbides, Talin Haritunians, Emebet Mengesha, Dermot P B McGovern, Kathrin S Michelsen
TL1A contributes to the pathogenesis of several chronic inflammatory diseases, including those of the bowel by enhancing TH1, TH17, and TH2 responses. TL1A mediates a strong costimulation of these TH subsets, particularly of mucosal CCR9(+) T cells. However, the signaling pathways that TL1A induces in different TH subsets are incompletely understood. We investigated the function of TL1A on human TH17 cells. TL1A, together with TGF-β, IL-6, and IL-23, enhanced the secretion of IL-17 and IFN-γ from human CD4(+) memory T cells...
October 12, 2016: Journal of Leukocyte Biology
Yueshui Zhao, Xue Gu, Ningyan Zhang, Mikhail G Kolonin, Zhiqiang An, Kai Sun
Endotrophin is a cleavage product of collagen 6 (Col6) in adipose tissue (AT). Previously, we demonstrated that endotrophin serves as a costimulator to trigger fibrosis and inflammation within the unhealthy AT milieu. However, how endotrophin affects lipid storage and breakdown in AT and how different cell types in AT respond to endotrophin stimulation remain unknown. In the current study, by using a doxycycline (Dox)-inducible mouse model, we observed significant upregulation of adipogenic genes in the WAT of endotrophin Tg mice...
October 11, 2016: American Journal of Physiology. Endocrinology and Metabolism
Judith Fraussen, Nele Claes, Bart Van Wijmeersch, Jack van Horssen, Piet Stinissen, Raymond Hupperts, Veerle Somers
Antibody-independent B cell functions play an important role in multiple sclerosis (MS) pathogenesis. In this study, B cell antigen presentation and costimulation in MS were studied. Peripheral blood B cells of MS patients showed increased expression of costimulatory CD86 and CD80 molecules compared with healthy controls (HC). In MS cerebrospinal fluid (CSF), 12-fold and 2-fold increases in CD86(+) and CD80(+) B cells, respectively, were evidenced compared with peripheral blood. Further, B cells from MS patients induced proinflammatory T cells in response to myelin basic protein (MBP)...
October 4, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Diamanda Rigas, Gavin Lewis, Jennifer L Aron, Bowen Wang, Homayon Banie, Ishwarya Sankaranarayanan, Lauriane Galle-Treger, Hadi Maazi, Richard Lo, Gordon J Freeman, Arlene H Sharpe, Pejman Soroosh, Omid Akbari
BACKGROUND: Atopic diseases including asthma exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T cells (Tregs) and the emerging group 2 innate lymphoid cells (ILC2s). While ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. OBJECTIVE: In the present study, we evaluate for the first time how Tregs interact with pulmonary ILC2s and control their function...
October 4, 2016: Journal of Allergy and Clinical Immunology
Maria-Luisa Del Rio, Ana Maria Bravo Moral, Carlos Fernandez-Renedo, Leo Buhler, Jose-Antonio Perez-Simon, Olivier Chaloin, Rafael Alvarez Nogal, Maximino Fernandez-Caso, Jose-Ignacio Rodriguez-Barbosa
CD160 is a glycosylphosphatidylinositol-anchored protein of the immunoglobulin superfamily. It exhibits a pattern of expression coincident in humans and mice that is mainly restricted to cytotoxic cells and to all intestinal intraepithelial T lymphocytes. B- and T-lymphocyte attenuator (BTLA) and CD160 interact with cysteine-rich domain 1 of the extracellular region of Herpesvirus entry mediator (HVEM). CD160 engagement by HVEM can deliver inhibitory signals to a small subset of human CD4 T cells and attenuate its proliferation and cytokine secretion, but can also costimulate natural killer cells or intraepithelial lymphocytes...
September 15, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
Julien Leconte, Sahar Bagherzadeh Yazdchi, Vincent Panneton, Woong-Kyung Suh
The inducible costimulator (ICOS) is a T cell costimulatory receptor that plays crucial roles in T cell differentiation and function. So far, ICOS has been shown to activate three signaling components: phosphoinositide 3-kinase (PI3K), intracellular calcium mobilization, and TANK binding kinase 1 (TBK1). By generating a knock-in strain of mice in which the ICOS gene is modified such that the ICOS-mediated PI3K pathway is selectively abrogated while the capacity of ICOS to mobilize intracellular calcium remains intact, we have shown that ICOS-mediated PI3K activation is required for some but not all T cell responses...
September 29, 2016: Molecular Immunology
Maria Sole Chimenti, Paola Conigliaro, Paola Triggianese, Eleonora Baffari, Ettore Squillaci, Francesca Bolacchi, Roberto Perricone, Alberto Bergamini
OBJECTIVES: To investigate the ability of synovial fluid from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) to modulate cell-surface phenotype, function and viability of monocytes. METHODS: Monocytes from healthy donors were incubated with synovial fluid from patients with RA or OA. These were then cultured with autologous healthy CD4+ T-cells. Immunoglobulin-like transcript 4 (ILT4) and CD86 were evaluated on stimulated monocytes and CD4+ T-cells via fluorescence activated cell sorting...
September 2016: Journal of International Medical Research
Shinsuke Oshima, Yasutomo Fujii, Erik E Karrer, Fujiko Takamura, Steven J Chapin, Margaret Neighbors, Sridhar Viswanathan, Bruce H Devens, Yasuyuki Higashi, Hidekazu Mizuhara
The CTLA4-Ig fusion proteins abatacept and belatacept inhibit CD28-mediated T cell activation by binding CD80 (B7-1) and CD86 (B7-2) costimulatory ligands and are clinically proven immunosuppressants used for rheumatoid arthritis and renal transplantation, respectively. Abatacept and belatacept preferentially bind CD80, yet CD86 has been implicated as the dominant ligand for CD28-mediated costimulation of T cells. We investigated the immunosuppressive effects of ASP2408, a novel CTLA4-Ig with CD86 selectivity and high potency created by directed evolution methods...
September 19, 2016: International Immunopharmacology
Joerg U Schmohl, Martin Felices, Deborah Todhunter, Elizabeth Taras, Jeffrey S Miller, Daniel A Vallera
BACKGROUND: The design of a highly effective anti-cancer immune-engager would include targeting of highly drug refractory cancer stem cells (CSC). The design would promote effective antibody-dependent cell-mediated cytotoxicity (ADCC) and simultaneously promote costimulation to expand and self-sustain the effector NK cell population. Based on our bispecific NK cell engager platform we constructed a tetraspecific killer engager (TetraKE) comprising single-chain variable fragments (scFvs) binding FcγRIII (CD16) on NK cells, EpCAM on carcinoma cells and CD133 on cancer stem cells in order to promote ADCC...
September 16, 2016: Oncotarget
Tünde Mester, Nupur Raychaudhuri, Erin F Gillespie, Hong Chen, Terry J Smith, Raymond S Douglas
CONTEXT: Fibrocytes appear to participate in inflammation and tissue remodeling in patients with thyroid-associated ophthalmopathy (TAO). These patients have increased frequencies of circulating TSH receptor (TSHR)- and CD40-positive fibrocytes, suggesting TSHR and CD40 may play roles in proinflammatory cytokine production, which ultimately leads to orbital inflammation and tissue remodeling. OBJECTIVE: To investigate the potential interactions between the TSHR and CD40 signaling pathways and their roles in IL-6 and TNF-α production...
2016: PloS One
Jia Wen Yin, Mao Ping Huang, Bei Zhong
BACKGROUND: The entire disease spectrum of chronic HBV infection (CHB) includes asymptomatic carriers (AC), active chronic hepatitis (ACH), cirrhosis (Cir), and hepatocellular carcinoma (HCC). Previous study have demonstrated that the costimulation profiles from the livers of patients influenced immune responses and played various immunological roles in AC, ACH, Cir, and HCC. In addition, activation of TLR3 signaling in the liver may contribute to HBV clearance, although some HBV components are able to block TLR3 signaling and counteract HBV clearance through positive or negative feedback loops...
June 2016: Hepatitis Monthly
Hiroyuki Sumi, Masakazu Inazuka, Kentaro Hashimoto, Tomoyasu Ishikawa, Sei Yoshida, Masato Yabuki
Inhibitors of apoptosis proteins (IAPs) are a family of antiapoptotic regulators that have attracted attention as potential targets for cancer therapeutics. Although recent studies have revealed that small-molecule IAP antagonists induce tumor selective cell death in an autocrine tumor necrosis factor (TNF)α-dependent manner, the single-agent efficacy of IAP antagonists is restricted to a small subset of cancer cells. In this study, we showed that the single-agent activity of T-3256336 was limited to a few cancer cell lines in vitro, and these cell lines were defined by relatively high levels of TNFα mRNA expression...
October 14, 2016: Biochemical and Biophysical Research Communications
Ana Paula Benaduce, Randall Brenneman, Brett Schrand, Alan Pollack, Eli Gilboa, Adrian Ishkanian
PURPOSE: To report a novel strategy using oligonucleotide aptamers to 4-1BB as an alternate method for costimulation, and show that combinatorial therapy with radiation improves the therapeutic ratio over equivalent monoclonal antibodies. METHODS AND MATERIALS: Subcutaneous 4T1 (mouse mammary carcinoma) tumors were established (approximately 100 mm(3)), and a radiation therapy (RT) dose/fractionation schedule that optimally synergizes with 4-1BB monoclonal antibody (mAb) was identified...
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Andrew B Adams, Mandy L Ford, Christian P Larsen
T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Blanca Homet Moreno, Jesse M Zaretsky, Angel Garcia-Diaz, Jennifer Tsoi, Giulia Parisi, Lidia Robert, Katrina Meeth, Abibatou Ndoye, Marcus Bosenberg, Ashani T Weeraratna, Thomas G Graeber, Begoña Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAF(V600E)-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAF(V600E) mutation and PTEN loss (BRAF(V600E)/PTEN(-/-))...
October 2016: Cancer Immunology Research
Tzu-Yu Shao, Ling-Hui Hsu, Chien-Hui Chien, Bor-Luen Chiang
Recent studies have revealed various Foxp3(-) regulatory T (Treg) cell subsets effectively protect mice from colitis. In the present study, we demonstrated that B cells induced a particular subset of regulatory T (Treg-of-B) cells, expressing programmed cell death 1 (PD-1), inducible costimulator (ICOS), lymphocyte-activation gene 3 (LAG3), glucocorticoid-induced tumor necrosis factor receptor (GITR), and OX-40, did not express Foxp3. Treg-of-B cells produced abundant levels of IL-10 and low levels of IL-4 and TGF-β...
2016: Scientific Reports
Guozhi Xia, Xin Sun, Xiaopu Zheng, Junkui Wang
Peripartum cardiomyopathy (PPCM) is a disease of unknown pathogenesis. Programmed death 1 (PD1) has been postulated to modulate immune response through potential mechanisms that remain elusive. This study aimed to elaborate the expression and function of PD1 on peripheral blood lymphocytes (PBLs) in the development of PPCM. Specimens of PBLs were performed to determine the expression of PD1 mRNA using fluorescence quantitative RT-PCR, and Th cytokines by ELISA. Immune homeostasis was evaluated with T lymphocyte phenotypes and immunoglobulin (Ig) isotypes as well as complement factors (C)...
November 15, 2016: International Journal of Cardiology
Sarita Rani Jaiswal, Shamsuz Zaman, Aditi Chakrabarti, Amit Sehrawat, Satish Bansal, Mahesh Gupta, Suparno Chakrabarti
The outcome of hyperacute grade 3-4 steroid-refractory graft-versus-host-disease (SR-GVHD) remains dismal despite a plethora of agents being tried alone or in combination. Following T replete haploidentical transplantation with post-transplantation cyclophosphamide on 75 patients, 10 patients (13%) aged 2-20years, developed hyperacute SR-GVHD. We report on the outcome of two different regimens for treatment of SR-GVHD on the outcome of these patients. Five patients were treated in Regimen A consisting of anti-thymocyte globulin, Etanercept and Basiliximab...
August 27, 2016: Transplant Immunology
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