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https://www.readbyqxmd.com/read/28097811/fc-silent-anti-cd154-domain-antibody-effectively-prevents-non-human-primate-renal-allograft-rejection
#1
Steven C Kim, Walter Wakwe, Laura B Higginbotham, David V Mathews, Cynthia P Breeden, Allison C Stephenson, Joe Jenkins, Elizabeth Strobert, Karen Price, Laura Price, Robert Kuhn, Haiqing Wang, Aaron Yamniuk, Suzanne Suchard, Alton B Farris, Thomas C Pearson, Christian P Larsen, Mandy L Ford, Anish Suri, Steven Nadler, Andrew B Adams
The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004)...
January 17, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28093524/age-associated-b-cells-express-a-diverse-repertoire-of-vh-and-v%C3%AE%C2%BA-genes-with-somatic-hypermutation
#2
Lisa M Russell Knode, Martin S Naradikian, Arpita Myles, Jean L Scholz, Yi Hao, Danya Liu, Mandy L Ford, John W Tobias, Michael P Cancro, Patricia J Gearhart
The origin and nature of age-associated B cells (ABCs) in mice are poorly understood. In this article, we show that their emergence required MHC class II and CD40/CD40L interactions. Young donor B cells were adoptively transferred into congenic recipients and allowed to remain for 1 mo in the absence of external Ag. B cells expressing the T-bet transcription factor, a marker for ABCs, were generated after multiple cell divisions from C57BL/6 donors but not from MHC class II- or CD40-deficient donors. Furthermore, old CD154 (CD40L)-deficient mice did not accrue ABCs, confirming that they arise primarily through T-dependent interactions...
January 16, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28058735/safe-use-of-anti-cd154-monoclonal-antibody-in-pig-islet-xenotransplantation-in-monkeys
#3
Rita Bottino, Michael F Knoll, Joshua Graeme-Wilson, Edwin C Klein, David Ayares, Massimo Trucco, David K C Cooper
Anti-CD154mAb is a powerful co-stimulation blockade agent that is efficacious in preventing rejection, even in xenogeneic settings. It has been used in the majority of successful long-term pig-to-non-human primate islet transplantation models. However, its clinical use was halted as a result of thromboembolic complications that were also observed in preclinical and clinical organ transplantation models. An anti-CD154mAb was administered to 14 streptozotocin-induced diabetic cynomolgus monkey recipients of porcine islets, some of which received the agent for many months...
January 6, 2017: Xenotransplantation
https://www.readbyqxmd.com/read/27989689/cd40-signaling-and-hepatic-steatosis-unanticipated-links
#4
Sébastien Lepreux, Julien Villeneuve, Antoine Dewitte, Annie M Bérard, Alexis Desmoulière, Jean Ripoche
Obesity predisposes to an increased risk of nonalcoholic fatty liver disease (NAFLD). Hepatic steatosis is the key pathological feature of NAFLD and has emerged as a metabolic disorder in which innate and adaptive arms of the immune response play a central role in disease pathogenesis. Recent studies have revealed unexpected relationships between CD40 signaling and hepatic steatosis in high fat diet rodent models. CD154, the ligand of CD40, is a mediator of inflammation and controls several critical events of innate and adaptive immune responses...
December 15, 2016: Clinics and Research in Hepatology and Gastroenterology
https://www.readbyqxmd.com/read/27893093/ligation-of-cd40-in-human-m%C3%A3-ller-cells-induces-p2x7-receptor-dependent-death-of-retinal-endothelial-cells
#5
Jose-Andres C Portillo, Yalitza Lopez Corcino, George R Dubyak, Timothy S Kern, Shigemi Matsuyama, Carlos S Subauste
Purpose: Cluster of differentiation 40 (CD40) is required for retinal capillary degeneration in diabetic mice, a process mediated by the retinal endothelial cells (REC) death. However, CD40 activates prosurvival signals in endothelial cells. The purpose of this study was to identify a mechanism by which CD40 triggers programmed cell death (PCD) of RECs and address this paradox. Methods: Human RECs and Müller cells were incubated with CD154 and L-N6-(1-Iminoethyl)lysine (L-Nil, nitric oxide synthase 2 inhibitor), α-lipoic acid (inhibitor of oxidative stress), anti-Fas ligand antibody, or A-438079 (P2X7 adenosine triphosphate [ATP] receptor inhibitor)...
November 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27829285/immunomodulation-of-cell-penetrating-tat-metallothionein-for-successful-outcome-of-xenotransplanted-pancreatic-islet
#6
Min Jun Kim, Yong Hwa Hwang, Yong Hee Kim, Dong Yun Lee
Pancreatic islet transplantation is a promising treatment for treatment of type 1 diabetes; however, transplantation outcomes have been disappointing due to early graft loss that is mediated by many immune responses. Immune cells not only directly damaged islet but also produced reactive oxygen species (ROS), which is highly toxic to islet cells. Metallothionein (MT) can provide protection against oxidative stress by scavenging various range of ROS including superoxide, hydroxyl radical, hydrogen peroxide, and nitric oxide...
November 10, 2016: Journal of Drug Targeting
https://www.readbyqxmd.com/read/27758933/mpges-1-deletion-affects-platelet-functions-in-mice
#7
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-)
https://www.readbyqxmd.com/read/27753080/cd40l-is-transferred-to-antigen-presenting-b-cells-during-delivery-of-t-cell-help
#8
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. By adding 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...
January 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/27693003/electronic-cigarettes-increase-endothelial-progenitor-cells-in-the-blood-of-healthy-volunteers
#9
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...
December 2016: Atherosclerosis
https://www.readbyqxmd.com/read/27692094/macrophage-effector-responses-of-horses-are-influenced-by-expression-of-cd154
#10
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
https://www.readbyqxmd.com/read/27634759/posttranscriptional-upregulation-of-p53-by-reactive-oxygen-species-in-chronic-lymphocytic-leukemia
#11
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
https://www.readbyqxmd.com/read/27631893/heterogeneity-of-specific-cd4-and-cd8-t-cells-stimulated-by-cmv-pp65-and-ie1-antigens
#12
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
https://www.readbyqxmd.com/read/27630283/cd40-expression-in-human-esophageal-squamous-cell-carcinoma-is-associated-with-tumor-progression-and-lymph-node-metastasis
#13
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...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27607533/short-term-pharmacological-inhibition-of-myd88-homodimerization-by-a-novel-inhibitor-promotes-robust-allograft-tolerance-in-mouse-cardiac-and-skin-transplantation
#14
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
https://www.readbyqxmd.com/read/27576126/human-circulating-group-2-innate-lymphoid-cells-can-express-cd154-and-promote-ige-production
#15
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
https://www.readbyqxmd.com/read/27566833/cmv-induces-expansion-of-highly-polyfunctional-cd4-t-cell-subset-coexpressing-cd57-and-cd154
#16
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
https://www.readbyqxmd.com/read/27521364/functional-diversity-of-cmv-specific-t-cells-is-maintained-in-older-people-and-significantly-associated-with-protein-specificity-and-response-size
#17
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
https://www.readbyqxmd.com/read/27517501/genetic-strategies-to-bring-islet-xenotransplantation-to-the-clinic
#18
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
https://www.readbyqxmd.com/read/27517137/current-status-of-costimulatory-blockade-in-renal-transplantation
#19
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
https://www.readbyqxmd.com/read/27511303/molecular-immunology-profiles-of-monkeys-following-xenografting-with-the-islets-and-heart-of-%C3%AE-1-3-galactosyltransferase-knockout-pigs
#20
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
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