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https://www.readbyqxmd.com/read/28544101/belatacept-combined-with-transient-calcineurin-inhibitor-therapy-prevents-rejection-and-promotes-improved-long-term-renal-allograft-function
#1
A B Adams, J Goldstein, C Garrett, R Zhang, R E Patzer, K A Newell, N A Turgeon, A S Chami, A Guasch, A D Kirk, S O Pastan, T C Pearson, C P Larsen
Belatacept, a T cell costimulation-blocker demonstrated superior renal function, lower cardiovascular risk, and improved graft/patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011 we have utilized belatacept-based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n=535) to a historical cohort receiving a tacrolimus-based protocol (n=205)...
May 23, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28539278/-construction-of-specific-artificial-antigen-presenting-cells-for-in-vitro-activation-of-cd19-chimeric-antigen-receptor-t-cells
#2
Yao-Jun Peng, Qi-Yan Wu, Hong-Yu Liu, Jian Zhao, Hua-Feng Wei
OBJECTIVE: To construct CD19-specific artificial antigen-presenting cells (aAPCs) for in vitro activation and expansion of CD19 chimeric antigen receptor (CAR)-modified T cells (CD19-CAR-T) and investigate their cytotoxic effect. METHODS: CD19-specific aAPCs (NIH3T3-CD19/86, NIH3T3-CD19/86/137L) expressing costimulatory molecules CD86 and/or CD137L were prepared on the basis of NIH3T3 backbone cells by lentivirus-mediated gene transfer. Irradiated CD19-specific aAPCs were co-cultured with CD19-CAR-T cells to activate and amplify CD19-CAR-T cells...
May 20, 2017: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
https://www.readbyqxmd.com/read/28528521/myeloid-populations-in-systemic-autoimmune-diseases
#3
REVIEW
María Morell, Nieves Varela, Concepción Marañón
Systemic autoimmune diseases (SADs) encompass a wide spectrum of clinical signs as a reflection of their complex physiopathology. A variety of mechanisms related with the innate immune system are in the origin of the loss of self-tolerance in these diseases, and for most of them, the myeloid leukocytes are key actors. Monocytes, macrophages, dendritic cells, and neutrophils are first-line immune effectors located in the interface between innate and adaptive immunity. They are crucial in the organization of the local and systemic responses to damage-associated molecular patterns (DAMPs) and determine the intensity, orientation, and duration of the local immune response through the expression of chemokines, costimulatory or protolerogenic factors...
May 20, 2017: Clinical Reviews in Allergy & Immunology
https://www.readbyqxmd.com/read/28526137/cellular-and-molecular-mechanisms-of-autoimmunity-and-lupus-nephritis
#4
S K Devarapu, G Lorenz, O P Kulkarni, H-J Anders, S R Mulay
Autoimmunity involves immune responses directed against self, which are a result of defective self/foreign distinction of the immune system, leading to proliferation of self-reactive lymphocytes, and is characterized by systemic, as well as tissue-specific, inflammation. Numerous mechanisms operate to ensure the immune tolerance to self-antigens. However, monogenetic defects or genetic variants that weaken immune tolerance render susceptibility to the loss of immune tolerance, which is further triggered by environmental factors...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28525959/challenges-and-opportunities-in-targeting-the-cd28-ctla-4-pathway-in-transplantation-and-autoimmunity
#5
Rebecca L Crepeau, Mandy L Ford
Introduction T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. Areas Covered This review discusses past, current and future biological therapies that have been utilized to block the CD28/CTLA-4 cosignaling pathway in the settings of autoimmunity and transplantation, as well the challenges facing successful implementation of these therapies...
May 19, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28513775/adiponectin-inhibits-oxidization-induced-differentiation-of-t-helper-cells-through-inhibiting-costimulatory-cd40-and-cd80
#6
Y Xiao, T Deng, Z Shang, D Wang
Adiponectin is a multifunctional adipokine that has several oligomeric forms in the blood stream, which broadly regulates innate and acquired immunity. Therefore, in this study, we aimed to observe the differentiation of T helper (Th) cells and expression of costimulatory signaling molecules affected by adiponectin. The mRNA and protein expression levels of adiponectin and its receptors in oxidized low density lipoprotein cholesterol-treated endothelial cells were assayed by real time PCR and immunofluorescence...
May 15, 2017: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/28502091/increased-pre-transplant-frequency-of-cd28-cd4-tem-predicts-belatacept-resistant-rejection-in-human-renal-transplant-recipients
#7
Miriam Cortes-Cerisuelo, Sonia J Laurie, David V Mathews, Pamela D Winterberg, Christian P Larsen, Andrew B Adams, Mandy L Ford
While most human T cells express the CD28 costimulatory molecule constitutively, it is well-known that age, inflammation, and viral infection can drive the generation of CD28(null) T cells. In vitro studies have demonstrated that CD28(null) cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28(null) cells may precipitate costimulation blockade-resistant rejection. However, CD28(+) cells possess more proliferative and multi-functional capacity, factors that may increase their ability to successfully mediate rejection...
May 14, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28501941/paracrine-release-of-il-2-and-anti-ctla-4-enhances-the-ability-of-artificial-polymer-antigen-presenting-cells-to-expand-antigen-specific-t-cells-and-inhibit-tumor-growth-in-a-mouse-model
#8
Lei Zhang, Limin Wang, Khawar Ali Shahzad, Tao Xu, Xin Wan, Weiya Pei, Chuanlai Shen
Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology...
May 13, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28495792/cd70-reverse-signaling-enhances-nk-cell-function-and-immunosurveillance-in-cd27-expressing-b-cell-malignancies
#9
Mohamad F Al Sayed, Carla A Ruckstuhl, Tamara Hilmenyuk, Christina Claus, Jean-Pierre Bourquin, Beat C Bornhauser, Ramin Radpour, Carsten Riether, Adrian F Ochsenbein
The interaction of the tumor necrosis factor receptor (TNFR) CD27 with its ligand CD70 is an emerging target to treat cancer. CD27 signaling provides costimulatory signals to cytotoxic T cells but also increases the frequency of regulatory T cells (Tregs). Similar to other TNFR-ligands, CD70 has been shown to initiate intracellular signaling pathways (CD70 reverse signaling). CD27 is expressed on a majority of B cell non-Hodgkin lymphoma (NHL), but its role in the immune control of lymphoma and leukemia is unknown...
May 11, 2017: Blood
https://www.readbyqxmd.com/read/28495139/high-yield-primary-microglial-cultures-using-granulocyte-macrophage-colony-stimulating-factor-from-embryonic-murine-cerebral-cortical-tissue
#10
Adam C Yu, Sarah E Neil, Jacqueline A Quandt
BACKGROUND: Microglia play vital roles in neurotrophic support and modulating immune or inflammatory responses to pathogens or damage/stressors during disease. This study describes the ability to establish large numbers of microglia from embryonic tissues with the addition of granulocyte-macrophage stimulating factor (GM-CSF) and characterizes their similarities to adult microglia examined ex vivo as well as their responses to inflammatory mediators. METHOD: Microglia were seeded from a primary embryonic mixed cortical suspension with the addition of GM-CSF...
June 15, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28491063/isa-2011b-a-phosphatidylinositol-4-phosphate-5-kinase-%C3%AE-inhibitor-impairs-cd28-dependent-costimulatory-and-pro-inflammatory-signals-in-human-t-lymphocytes
#11
Martina Kunkl, Nicla Porciello, Marta Mastrogiovanni, Cristina Capuano, Federica Lucantoni, Chiara Moretti, Jenny L Persson, Ricciarda Galandrini, Raffaella Buzzetti, Loretta Tuosto
Phosphatidylinositol 4,5-biphosphate (PIP2) is a membrane phospholipid that controls the activity of several proteins regulating cytoskeleton reorganization, cytokine gene expression, T cell survival, proliferation, and differentiation. Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are the main enzymes involved in PIP2 biosynthesis by phosphorylating phosphatidylinositol 4-monophosphate (PI4P) at the D5 position of the inositol ring. In human T lymphocytes, we recently found that CD28 costimulatory molecule is pivotal for PIP2 turnover by recruiting and activating PIP5Kα...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28488693/icos-protects-against-mortality-from-acute-lung-injury-through-activation-of-il-5-ilc2s
#12
C L Hrusch, S T Manns, D Bryazka, J Casaos, C A Bonham, M R Jaffery, K M Blaine, K A M Mills, P A Verhoef, A O Adegunsoye, J W Williams, M Y Tjota, T V Moore, M E Strek, I Noth, A I Sperling
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreversible lung scarring and loss of pulmonary function. IPF Patients suffer from a high rate of pulmonary infections and acute exacerbations of disease that further contribute to pulmonary decline. Low expression of the inducible T-cell costimulatory molecule (ICOS) in peripheral blood mononuclear cells predicts decreased survival of IPF patients, but the mechanisms by which ICOS protects are unclear. Using a model of bleomycin-induced lung injury and fibrosis, we now demonstrate that ICOS expression enhances survival from lung injury rather than regulating fibrogenesis...
May 10, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28487429/rationally-designed-tlr4-ligands-for-vaccine-adjuvant-discovery
#13
Kelsey A Gregg, Erin Harberts, Francesca M Gardner, Mark R Pelletier, Corinne Cayatte, Li Yu, Michael P McCarthy, Jason D Marshall, Robert K Ernst
Adjuvant properties of bacterial cell wall components like MPLA (monophosphoryl lipid A) are well described and have gained FDA approval for use in vaccines such as Cervarix. MPLA is the product of chemically modified lipooligosaccharide (LOS), altered to diminish toxic proinflammatory effects while retaining adequate immunogenicity. Despite the virtually unlimited number of potential sources among bacterial strains, the number of useable compounds within this promising class of adjuvants are few. We have developed bacterial enzymatic combinatorial chemistry (BECC) as a method to generate rationally designed, functionally diverse lipid A...
May 9, 2017: MBio
https://www.readbyqxmd.com/read/28483281/preclinical-data-support-leveraging-cs1-chimeric-antigen-receptor-t-cell-therapy-for-systemic-light-chain-amyloidosis
#14
Michael Rosenzweig, Ryan Urak, Miriam Walter, Laura Lim, James F Sanchez, Amrita Krishnan, Stephen Forman, Xiuli Wang
BACKGROUND AIMS: Light chain amyloidosis (AL) is a protein deposition disorder that is a result of a plasma cell dyscrasia, similar to multiple myeloma (MM). Immunotherapy is an attractive approach because of the low burden of disease, but the optimal target for AL is unclear. CS1 and B-cell maturation antigen (BCMA) are two potential targets because they are expressed on normal plasma cells and MM cells. METHODS: We performed a prospective study evaluating bone marrow specimens of 20 patients with plasma cell diseases, 10 with AL and 10 with MM...
May 5, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28479601/b7-dc-pd-l2-costimulation-of-cd4-t-helper-1-response-via-rgmb
#15
Xinxin Nie, Wenni Chen, Ying Zhu, Baozhu Huang, Weiwei Yu, Zhanshuai Wu, Sizheng Guo, Yiping Zhu, Liqun Luo, Shengdian Wang, Lieping Chen
The role of B7-DC in T-cell responses remains controversial because both coinhibitory and costimulatory functions have been reported in various experimental systems in vitro and in vivo. In addition to interacting with the coinhibitory receptor PD-1, B7-DC has also been shown to bind repulsive guidance molecule b (RGMb). The functional consequences of the B7-DC/RGMb interaction, however, remain unclear. More than a decade ago, we reported that replacement of a murine B7-DC mutant lysine with serine (K113S) at positive 113 resulted in a loss of binding capacity to PD-1...
May 8, 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28473831/il-7-and-cd4-t-follicular-helper-cells-in-hiv-1-infection
#16
Francesca Chiodi, Yonas Bekele, Rebecka Lantto Graham, Aikaterini Nasi
IL-7 was previously shown to upregulate the expression of molecules important for interaction of CD4+ T cells with B cells. It is poorly studied whether IL-7 has a role in the biology of T follicular helper (Tfh) cells and whether IL-7 dysregulates the expression of B-cell costimulatory molecules on Tfh cells. We review the literature and provide arguments in favor of IL-7 being involved in the biology of human Tfh cells. The CD127 IL-7 receptor is expressed on circulating Tfh and non-Tfh cells, and we show that IL-7, but not IL-6 or IL-21, upregulates the expression of CD70 and PD-1 on these cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28466476/numerical-and-functional-defects-in-cd8-cd28-t-suppressor-lymphocytes-from-patients-with-primary-immune-thrombocytopenia
#17
Huiyuan Li, Yating Hao, Donglei Zhang, Wenjie Liu, Yang Li, Mingen Lyu, Rongfeng Fu, Feng Xue, Xiaofan Liu, Renchi Yang
Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, and loss of immune tolerance has been implicated in ITP pathogenesis. CD8(+) CD28(-) suppressor (Ts) cells have an immunosuppression function and are involved in several autoimmune disorders. However, the role of Ts cells in ITP is currently not clear. Here, flow cytometry was used to detect the CD8(+) CD28(-) CD127(-) proportion, which was decreased in active ITP patients compared with that of controls. Function analysis showed that immunosuppression of CD8(+) CD28(-) Ts cells in ITP patients was impaired...
May 3, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28463985/palmitic-acid-is-a-toll-like-receptor-4-ligand-that-induces-human-dendritic-cell-secretion-of-il-1%C3%AE
#18
Dequina A Nicholas, Kangling Zhang, Christopher Hung, Shane Glasgow, Aruni Wilson Aruni, Juli Unternaehrer, Kimberly J Payne, William H R Langridge, Marino De Leon
Palmitic acid (PA) and other saturated fatty acids are known to stimulate pro-inflammatory responses in human immune cells via Toll-like receptor 4 (TLR4). However, the molecular mechanism responsible for fatty acid stimulation of TLR4 remains unknown. Here, we demonstrate that PA functions as a ligand for TLR4 on human monocyte derived dendritic cells (MoDCs). Hydrophobicity protein modeling indicated PA can associate with the hydrophobic binding pocket of TLR4 adaptor protein MD-2. Isothermal titration calorimetry quantified heat absorption that occurred during PA titration into TLR4/MD2, indicating that PA binds to TLR4/MD2...
2017: PloS One
https://www.readbyqxmd.com/read/28463630/safety-and-activity-of-varlilumab-a-novel-and-first-in-class-agonist-anti-cd27-antibody-in-patients-with-advanced-solid-tumors
#19
Howard A Burris, Jeffrey R Infante, Stephen M Ansell, John J Nemunaitis, Geoffrey R Weiss, Victor M Villalobos, Branimir I Sikic, Matthew H Taylor, Donald W Northfelt, William E Carson, Thomas R Hawthorne, Thomas A Davis, Michael J Yellin, Tibor Keler, Timothy Bullock
Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors...
May 2, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28454382/increased-b7-h4-expression-during-esophageal-squamous-cell-carcinogenesis-is-associated-with-il-6-stat3-signaling-pathway-activation-in-mice
#20
Xinran Chen, Wei Wang, Hongwei Man, Pengfei Li, Baoen Shan
B7-homolog 4 (B7-H4), one of the costimulatory molecules of the B7 family, has been reported to be widely expressed in multiple types of cancer tissues, and to be important in tumor progression and poor prognosis. However, the role of B7-H4 in esophageal precancerous lesions has not been elucidated yet. In the present study, a model of esophageal squamous cell carcinogenesis was established in 208 C57BL/6 mice by 4-nitroquinoline-1-oxide (4NQO) drinking water of mice, and the changes in the expression of B7-H4 during the whole pathological process were investigated...
April 2017: Oncology Letters
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