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Joan Raouf, Fariborz Mobarrez, Karin Larsson, Per-Johan Jakobsson, Marina Korotkova
Microsomal prostaglandin E2 synthase-1 (mPGES-1) constitutes an essential player of inflammation and is involved in the pathogenesis of rheumatoid arthritis (RA). Platelets participate in the regulation of inflammatory processes by the release of pro-inflammatory mediators and platelet-derived microparticles (PMPs). However, the role of the inducible mPGES-1/PGE2 pathway on platelet functions has not been investigated. Here we report a significant impact of mPGES-1 on platelet functions during inflammation...
October 7, 2016: Clinical Science (1979-)
Jennifer L Gardell, David C Parker
The delivery of T-cell help to B cells is antigen-specific, MHC-restricted, and CD40L (CD154) dependent. It has been thought that when a T cell recognizes an antigen-presenting B cell, CD40L expressed on the T-cell surface engages with CD40 on the surface of B cells as long as the cells remain conjugated. To study this, we added fluorescently labeled anti-CD40L antibody during overnight incubation of antigen-presenting B cells with antigen-specific T cells. We discovered that CD40L does not remain on the surface of the T cell, but it is transferred to and endocytosed by B cells receiving T-cell help...
October 18, 2016: European Journal of Immunology
Lukasz Antoniewicz, Jenny A Bosson, Jeanette Kuhl, Samy M Abdel-Halim, Anna Kiessling, Fariborz Mobarrez, Magnus Lundbäck
BACKGROUND AND AIMS: The use of electronic cigarettes is increasing dramatically on a global scale and its effects on human health remain uncertain. In the present study, we measured endothelial progenitor cells (EPCs) and microvesicles (MVs) in healthy young volunteers following short-term exposure to inhalation of e-cigarette vapor (ECV) to determine vascular changes. METHODS: Sixteen healthy seldom smokers were randomized into two groups either exposed or not exposed to 10 puffs of ECV for 10 min, in a crossover design...
September 22, 2016: Atherosclerosis
Brett A Sponseller, Sandra K Clark, Jessica Gilbertie, David M Wong, Kate Hepworth, Sarah Wiechert, Prashanth Chandramani, Beatrice T Sponseller, Cody J Alcott, Bryan Bellaire, Andrew C Petersen, Douglas E Jones
Reactive intermediates contribute to innate immunity by providing phagocytes with a mechanism of defense against bacteria, viruses and parasites. To better characterize the role of CD154 in the production of reactive intermediates, we cloned and expressed recombinant equine CD154 (reqCD154) in Chinese Hamster Ovary (CHO). In co-culture experiments, CHO cells ectopically expressing reqCD154 elicited superoxide production in monocyte-derived macrophages (MDM). Collectively, our results indicate that regulation of CD154 expression plays a role in innate host defenses...
November 1, 2016: Veterinary Immunology and Immunopathology
Jesvin Samuel, Sandrine Jayne, Yixiang Chen, Aneela Majid, Alice Wignall, Timothy Wormull, Hishyar Najeeb, JinLi Luo, Geroge D D Jones, Salvador Macip, Martin J S Dyer
Chronic lymphocytic leukemia (CLL) cells multiply and become more resistant to immunochemotherapy in 'proliferation centers' within tissues, whereas apoptosis occurs in the periphery. Various models recapitulate these microenvironments in vitro, such as stimulation with CD154 and IL-4. Using this system, we observed a 30-40 fold induction of wild-type p53 protein in 50 distinct human CLL specimens tested, without the induction of either cell cycle arrest or apoptosis. In contrast, the mRNA levels for p53 did not increase, indicating that its elevation occurred posttranscriptionally...
September 7, 2016: Cancer Research
Elena Albiero, Eliana Amati, Elke Baumeister, Hermann Einsele, Götz U Grigoleit, Francesco Rodeghiero
Characterization of human cytomegalovirus-specific T cells (CMV-T) is of critical importance for their potential use in adoptive immunotherapy after allogeneic hematopoietic stem cell transplantation. Background frequencies of CMV-T in peripheral blood mononuclear cells (PBMCs) of CMV-seropositive healthy subjects are usually very low, hence the requirement for prolonged culture time and multiple stimulations to expand them. The evaluation of the end-culture specificity and composition has sometimes been neglected or difficult to assess in these settings...
November 2016: Journal of Immunotherapy
Yoshiyuki Matsumura, Kei Hiraoka, Keidai Ishikawa, Yasuhito Shoji, Takehiro Noji, Koji Hontani, Tomoo Itoh, Toru Nakamura, Takahiro Tsuchikawa, Toshiaki Shichinohe, Satoshi Hirano
BACKGROUND: The co-stimulatory molecule cluster of differentiation 40 (CD40) is widely expressed in various types of malignant tumors, but its role remains unclear. The purpose of this study was to investigate the relationship between CD40 expression and clinicopathological variables in patients with esophageal squamous cell carcinoma (ESCC), as well as the function of CD40 expressed on ESCC tumor cells in vitro. MATERIALS AND METHODS: Tumor specimens of patients who underwent surgical resection for ESCC were immunohistochemically analyzed for CD40 expression...
September 2016: Anticancer Research
Chao Li, Li-Min Zhang, Xue Zhang, Xia Huang, Yong Liu, Ming-Qiang Li, Shuai Xing, Tao Yang, Lin Xie, Feng-Chao Jiang, Han-Ying Jiang, Wen-Tao He, Ping Zhou
BACKGROUND: Most strategies for anti-rejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. METHODS: We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models...
September 8, 2016: Transplantation
Laura Maggi, Gianni Montaini, Alessio Mazzoni, Beatrice Rossettini, Manuela Capone, Maria Caterina Rossi, Veronica Santarlasci, Francesco Liotta, Oliviero Rossi, Oreste Gallo, Raffaele De Palma, Enrico Maggi, Lorenzo Cosmi, Sergio Romagnani, Francesco Annunziato
BACKGROUND: Protection against helminths consists of adaptive responses by TH2 cells and innate responses by group 2 innate lymphoid cells (ILC2s), with these latter being well characterized in mice but less so in human subjects. OBJECTIVE: We sought to characterize human circulating ILC2s and compare their functional profile with that of autologous TH2 cells. METHODS: Circulating ILC2s and TH2 cells were isolated by means of fluorescence-activated cell sorting and magnetic cell sorting and expanded in vitro...
July 27, 2016: Journal of Allergy and Clinical Immunology
Alejandra Pera, Anusha Vasudev, Crystal Tan, Hassen Kared, Rafael Solana, Anis Larbi
CD4(+) T cells are essential for human CMV infection control. CMV-specific CD4(+) T cells possess antiviral functions and participate in anti-CMV humoral/cellular responses. In the elderly, CMV infection impairs immunity to other viruses and has been traditionally associated with T cell senescence; however, recent results suggest that, in younger people, CMV confers immune protection against other pathogens (heterologous immunity). To shed light on this controversy, we analyzed latent CMV infection effects on the quality of young individuals' immune response, specifically, the presence of polyfunctional T cells through an extensive phenotypic and functional characterization of the CD4(+) T cell subset...
August 26, 2016: Journal of Leukocyte Biology
Martha Bajwa, Serena Vita, Rosanna Vescovini, Martin Larsen, Paolo Sansoni, Nadia Terrazzini, Stefano Caserta, David Thomas, Kevin A Davies, Helen Smith, Florian Kern
BACKGROUND:  Parallel up-regulation of several T-cell effector functions ('polyfunctionality') is believed to be critical for the protection against viruses but thought to decrease in large T-cell expansions, in particular at older ages. The factors determining T-cell polyfunctionality are incompletely understood. Here we revisit the question of CMV-specific T-cell polyfunctionality, including a wide range of T-cell target proteins, response sizes, and participant ages. METHODS:  Polychromatic flow-cytometry was used to analyze the functional diversity (CD107, CD154, IL-2, TNF, IFN-γ) of CD4 and CD8 T-cell responses to 19 CMV proteins in a large group of young and older UK participants...
August 11, 2016: Journal of Infectious Diseases
Wayne J Hawthorne, Andrew M Lew, Helen E Thomas
PURPOSE OF REVIEW: Despite the benefits of islet and pancreas allotransplantation, their widespread use in type 1 diabetes is limited because of the paucity of suitable donors. Porcine xenotransplantation offers an alternative, and advances in genetic modification of pigs have opened up new potential for its clinical use. This review outlines the barriers to successful islet xenotransplantation, and genetic modifications that have been tested to overcome these. RECENT FINDINGS: Islets from pigs lacking α1,3-galactosyltransferase, to prevent hyperacute rejection, are now used as a background strain for further genetic modifications...
October 2016: Current Opinion in Organ Transplantation
David Wojciechowski, Flavio Vincenti
PURPOSE OF REVIEW: The review will focus on the impact and current status of costimulatory blockade in renal transplantation. RECENT FINDINGS: The mainstay of immunosuppression in kidney transplantation is calcineurin inhibitors (CNIs) which have reduced acute rejection rates but failed to improve long-term allograft survival. Their cardiometabolic side-effects and nephrotoxicity have shifted the focus of investigation to CNI-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of cytotoxic T-lymphocyte associated protein 4 has emerged as part of a CNI-free regimen...
November 2016: Current Opinion in Nephrology and Hypertension
Sun A Ock, Jungkyu Lee, Keon Bong Oh, Seongsoo Hwang, Ik Jin Yun, Curie Ahn, Hyun Keun Chee, Hwajung Kim, Jae Berm Park, Sung Joo Kim, Youngim Kim, Gi-Sun Im, EungWoo Park
Effective immunosuppression strategies and genetically modified animals have been used to prevent hyperacute and acute xenograft rejection; however, the underlying mechanisms remain unknown. In this study, we evaluated the expression of a comprehensive set of immune system-related genes (89 genes, including five housekeeping genes) in the blood of cynomolgus monkeys (~5 yr old) used as graft recipients, before and after the xenografting of the islets and heart from single and double α-1,3-galactosyltransferase (GalT) knockout (KO) pigs (<6 weeks old)...
September 2016: Xenotransplantation
Hengqi Betty Zheng, Benjamin Watkins, Victor Tkachev, Shan Yu, Dollnovan Tran, Scott Furlan, Katie Zeleski, Karnail Singh, Kelly Hamby, Charlotte Hotchkiss, Jennifer Lane, Sanjeev Gumber, Andrew Adams, Linda Cendales, Allan D Kirk, Amitinder Kaur, Bruce R Blazar, Christian P Larsen, Leslie S Kean
While stable mixed-hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC-matched NHP, a busulfan plus combined belatacept and anti-CD154 -based regimen could induce long-lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected and tolerance to skin allografts was not achieved. Here we describe an adaptation of this strategy, with the addition of low-dose total body irradiation (TBI) to our conditioning regimen...
August 8, 2016: American Journal of Transplantation
Abigail A Delaney, Zaraq Khan, Ye Zheng, Luiz F Correa, Valentina Zanfagnin, Chandra C Shenoy, John K Schoolmeester, Abdulrahman M Saadalla, Sherif El-Nashar, Abimbola O Famuyide, Malayannan Subramaniam, John R Hawse, Khashayarsha Khazaie, Gaurang S Daftary
Endometriosis is a highly prevalent, chronic, heterogeneous, fibro-inflammatory disease that remains recalcitrant to conventional therapy. We previously showed that loss of KLF11, a transcription factor implicated in uterine disease, results in progression of endometriosis. Despite extensive homology, co-expression, and human disease association, loss of the paralog Klf10 causes a unique inflammatory, cystic endometriosis phenotype in contrast to fibrotic progression seen with loss of Klf11. We identify here for the first time a novel role for KLF10 in endometriosis...
September 2016: Biology of Reproduction
S Wurster, P Weis, L Page, M Lazariotou, H Einsele, A J Ullmann
Fungal specific CD154(+) T-cells have been described as a biomarker in invasive aspergillosis. The influence of sample storage on the detection of these cells was assessed. Six-hour delay prior to PBMC isolation is associated with an 18% decrease of cell viability and alterations of the cellular composition of the sample. This results in 87% reduction of CD154(+) A. fumigatus specific cells due to reduced assay sensitivity and increased background values in unstimulated samples. If prompt cell measurement is not feasible, isolated PBMCs can be frozen (at -20°C and -80°C) and processed later with comparable assay reliability (mean value fresh vs...
August 2, 2016: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Nan Zhang, Jiandong Tai, Zhihui Qu, Zhihui Zhang, Songchen Zhao, Jiaxue He, Songling Zhang, Yanfang Jiang
BACKGROUND: T follicular helper (Tfh) cells are known to regulate humoral immune response. In this study we examined the correlation of different subsets of peripheral blood Tfh cells in patients with diabetic nephropathy (DN). METHODS: A total of 23 DN patients and 15 healthy controls (HC) were investigated for various subsets of Tfh cells by flow cytometry. The molecules ICOS(+), PD-1(+), CD28(+), CD154(+), IL-21(+), IFN-γ(+), IL-4(+), IL-17(+) Tfh cells were examined...
July 31, 2016: Autoimmunity
Malvezzi Paolo, Jouve Thomas, Rostaing Lionel
In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIsis associated with some degree of nephrotoxicity. This has led to exploring the blockadeof some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney-transplant patients is belatacept (Nulojix): a fusion protein that interferes with CTLA-4...
July 28, 2016: Transplantation
Jing J Wang, Cindy Macardle, Helen Weedon, Dimitra Beroukas, Tatjana Banovic
The frequencies, immunophenotype, and function of mucosal-associated invariant T (MAIT) cells were studied in patients with primary Sjögren syndrome (pSS) and healthy controls. MAIT cells were significantly decreased in the peripheral blood (PB) of patients with pSS. Vα7.2(+) MAIT cells were detected in the salivary gland tissue from pSS patients, but not in controls, indicating that the reduction of MAIT cells in PB might be due to migration into the target tissue. Furthermore, the residual peripheral blood MAIT cells in pSS patients showed altered immunophenotype and function...
October 2016: European Journal of Immunology
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