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https://www.readbyqxmd.com/read/28613437/t-cell-subsets-predicting-belatacept-resistant-rejection-finding-the-root-where-the-trouble-starts
#1
EDITORIAL
T Wekerle
The potential of costimulation blockade to revolutionize post-transplant immunosuppression has remained largely unfulfilled to date. Belatacept, the only costimulation blocker approved in organ transplant recipients, has not replaced the 30-plus-year-old CNIs as the mainstay of immunosuppression and is currently used infrequently. Modulating pathogenic immune responses through the interruption of costimulatory signals, which a naïve T cell requires for its full activation, has captivated immunologists since the demonstration that such costimulation blockade leads to antigen-specific immunomodulation (at least in vitro)...
June 14, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28612217/ox40-promotes-obesity-induced-adipose-inflammation-and-insulin-resistance
#2
Bing Liu, Hengchi Yu, Guangyong Sun, Xiaojing Sun, Hua Jin, Chunpan Zhang, Wen Shi, Dan Tian, Kai Liu, Hufeng Xu, Xinmin Li, Jie Yin, Xu Hong, Dong Zhang
Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4(+) T cells, were observed in the adipose tissues of mice with diet-induced obesity. OX40-KO mice exhibited significantly less weight gain and lower fasting glucose levels than those of WT mice, without obvious adipose tissue inflammation...
June 13, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28600286/lipopolysaccharide-tlr4-stimulates-il-13-production-through-a-myd88-blt2-linked-cascade-in-mast-cells-potentially-contributing-to-the-allergic-response
#3
A-Jin Lee, MyungJa Ro, Kyung-Jin Cho, Jae-Hong Kim
In an experimental asthma model, the activation of TLR4 by bacterial LPS occasionally exacerbates allergic inflammation through the production of Th2 cytokines, and mast cells have been suggested to play a central role in this response. However, the detailed mechanism underlying how LPS/TLR4 stimulates the production of Th2 cytokines, especially IL-13, remains unclear in mast cells. In the current study, we observed that the expression levels of leukotriene B4 receptor-2 (BLT2) and the synthesis of its ligands were highly upregulated in LPS-stimulated bone marrow-derived mast cells and that BLT2 blockade with small interfering RNA or a pharmacological inhibitor completely abolished IL-13 production, suggesting a mediatory role of the BLT2 ligand-BLT2 axis in LPS/TLR4 signaling to IL-13 synthesis in mast cells...
June 9, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28580358/belatacept-as-an-alternative-to-calcineurin-inhibitors-in-patients-with-solid-organ-transplants
#4
REVIEW
Dhiren Kumar, Spencer LeCorchick, Gaurav Gupta
The goal of immunosuppression in transplantation has shifted to improving long-term outcomes, reducing drug-induced toxicities while preserving the already excellent short-term outcomes. Long-term gains in solid organ transplantation have been limited at least partly due to the nephrotoxicity and metabolic side effects of calcineurin inhibitors (CNIs). The alloimmune response requires activation of the costimulatory pathway for T cell proliferation and amplification. Belatacept is a molecule that selectively blocks T cell costimulation...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28564491/abatacept-attenuates-t-follicular-helper-cell-dependent-b-cell-hyperactivity-in-primary-sj%C3%A3-gren-s-syndrome
#5
Gwenny M Verstappen, Petra M Meiners, Odilia B J Corneth, Annie Visser, Suzanne Arends, Wayel H Abdulahad, Rudi W Hendriks, Arjan Vissink, Frans G M Kroese, Hendrika Bootsma
Objective To assess the effect of abatacept (CTLA-4-Ig), which limits T-cell activation, on homeostasis of CD4(+) T-cell subsets and T-cell-dependent B-cell hyperactivity in patients with primary Sjögren's syndrome (pSS). Methods Fifteen pSS patients treated with abatacept were included. Circulating CD4(+) T-cell and B-cell subsets were analyzed by flow cytometry at baseline, on treatment and off treatment. CD4(+) effector T-cell subsets and T regulatory (Treg)-cells were identified based on expression of CD45RA, CXCR3, CCR6, CCR4, CXCR5, programmed death-1 (PD-1), inducible costimulator (ICOS) and FoxP3...
May 31, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28557955/comparative-evaluation-of-%C3%AE-cd40-2c10r4-and-%C3%AE-cd154-5c8h1-and-idec-131-in-a-nonhuman-primate-cardiac-allotransplant-model
#6
Natalie A O'Neill, Tianshu Zhang, Gheorghe Braileanu, Wenji Sun, Xiangfei Cheng, Alena Hershfeld, Christopher T Laird, Anthony Kronfli, Lindsay A Hock, Sia Dahi, Natalia Kubicki, Evelyn Sievert, Wessam Hassanein, Arielle Cimeno, Richard N Pierson, Agnes M Azimzadeh
BACKGROUND: Specific blockade of T cell costimulation pathway is a promising immunomodulatory approach being developed to replace our current clinical immunosuppression therapies. The goal of this study is to compare results associated with 3 monoclonal antibodies directed against the CD40/CD154 T cell costimulation pathway. METHODS: Cynomolgus monkey heterotopic cardiac allograft recipients were treated with either IDEC-131 (humanized αCD154, n=9), 5C8H1 (mouse-human chimeric αCD154, n=5), or 2C10R4 (mouse-rhesus chimeric αCD40, n=6) monotherapy using a consistent, comparable dosing regimen for 3 months after transplant...
May 27, 2017: Transplantation
https://www.readbyqxmd.com/read/28555136/oncolytic-immunotherapy-conceptual-evolution-current-strategies-and-future-perspectives
#7
REVIEW
Zong Sheng Guo, Zuqiang Liu, Stacy Kowalsky, Mathilde Feist, Pawel Kalinski, Binfeng Lu, Walter J Storkus, David L Bartlett
The concept of oncolytic virus (OV)-mediated cancer therapy has been shifted from an operational virotherapy paradigm to an immunotherapy. OVs often induce immunogenic cell death (ICD) of cancer cells, and they may interact directly with immune cells as well to prime antitumor immunity. We and others have developed a number of strategies to further stimulate antitumor immunity and to productively modulate the tumor microenvironment (TME) for potent and sustained antitumor immune cell activity. First, OVs have been engineered or combined with other ICD inducers to promote more effective T cell cross-priming, and in many cases, the breaking of functional immune tolerance...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28547807/tnfsf9-exerts-an-inhibitory-effect-on-hepatocellular-carcinoma
#8
Yuling Shen, Yu Gan, Haifeng Gao, Yingchao Fan, Qing Wang, Hui Yuan, Yanfang Song, Jiadong Wang, Hong Tu
AIM: Tumor necrosis factor superfamily member 9 (TNFSF9), also known as 4-1BBL and CD137L, has been implicated in cancer immunotherapy due to its function as a T cell costimulator. However, little is known about its direct impact on cancer development, particularly for solid tumors. METHODS: The TNFSF9 expression was examined by immunohistochemistry in 106 pairs of hepatocellular carcinoma (HCC) and the adjacent non-HCC tissues, and by quantitative PCR and Western blot in HCC cell lines...
May 26, 2017: Journal of Digestive Diseases
https://www.readbyqxmd.com/read/28544101/belatacept-combined-with-transient-calcineurin-inhibitor-therapy-prevents-rejection-and-promotes-improved-long-term-renal-allograft-function
#9
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/28539453/epigenetic-metabolite-acetate-inhibits-class-i-ii-histone-deacetylases-promotes-histone-acetylation-and-increases-hiv-1-integration-in-cd4-t-cells
#10
Jean-François Bolduc, Laurent Hany, Corinne Barat, Michel Ouellet, Michel J Tremblay
In this study, we investigated the effect of acetate, the most concentrated short-chain fatty acid (SCFA) in the gut and bloodstream, on the susceptibility of primary human CD4(+) T cells to HIV-1 infection. We report that HIV-1 replication is increased in CD3/CD28-costimulated CD4(+) T cells upon acetate treatment. This enhancing effect correlates with an increased expression of the early activation marker CD69 and impaired class I/II histone deacetylase (HDAC) activity. In addition, acetate enhances acetylation of histones H3 and H4 and augments HIV-1 integration in the genome of CD4(+) T cells...
May 24, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28511719/interleukin-10-producing-lag3-regulatory-t-cells-are-associated-with-disease-activity-and-abatacept-treatment-in-rheumatoid-arthritis
#11
Shinichiro Nakachi, Shuji Sumitomo, Yumi Tsuchida, Haruka Tsuchiya, Masanori Kono, Rika Kato, Keiichi Sakurai, Norio Hanata, Yasuo Nagafuchi, Shoko Tateishi, Hiroko Kanda, Tomohisa Okamura, Kazuhiko Yamamoto, Keishi Fujio
BACKGROUND: Regulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4(+)CD25(-)LAG3(+) T cells (LAG3(+) Tregs) and their association with rheumatoid arthritis (RA). METHODS: LAG3(+) Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects...
May 16, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28502128/belatacept-resistant-rejection-is-associated-with-cd28-memory-cd8-t-cells
#12
D V Mathews, W C Wakwe, S C Kim, M C Lowe, C Breeden, M E Roberts, A B Farris, E A Strobert, J B Jenkins, C P Larsen, M L Ford, R Townsend, A B Adams
Recently newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28-CD80/86 specific reagent is associated with superior patient survival and graft function than traditional therapy but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely employed...
May 14, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28502091/increased-pre-transplant-frequency-of-cd28-cd4-tem-predicts-belatacept-resistant-rejection-in-human-renal-transplant-recipients
#13
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/28494200/a-new-therapeutic-potential-for-cancers-one-car-with-2-different-engines
#14
Abdolkarim Sheikhi, Abdollah Jafarzadeh
Tumor cells escape from immune recognition by several mechanisms such as down-regulating of MHC class I molecules, losing of tumor antigens, etc. The purpose of cancer immunotherapy is to robust or reconstruct the capacity of the immune system to recognize and kill tumor cells by overwhelming the mechanisms by which tumors escape the immune response. One of the novel immunotherapeutic strategies were used to potentiate NK- and T cell functions is chimeric antigen receptor (CAR). CARs are composed of an antigen-binding domain of a molecule such as an antibody (that binds to a tumor associated antigens expressed on the surface of tumor cells) and an intracellular T cell activation domain...
May 11, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28489338/regulatory-t-cells-promote-natural-killer-cell-education-in-mixed-chimeras
#15
B Mahr, N Pilat, S Maschke, N Granofszky, C Schwarz, L Unger, K Hock, A M Farkas, C Klaus, H Regele, T Wekerle
Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in nonirradiated recipient mice conditioned with costimulation blockade and mammalian target of rapamycin inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation led to BM engraftment and persistent chimerism without Treg transfer but failed to induce skin graft tolerance...
May 10, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28483987/innate-control-of-adaptive-immunity-beyond-the-three-signal-paradigm
#16
REVIEW
Aakanksha Jain, Chandrashekhar Pasare
Activation of cells in the adaptive immune system is a highly orchestrated process dictated by multiples cues from the innate immune system. Although the fundamental principles of innate control of adaptive immunity are well established, it is not fully understood how innate cells integrate qualitative pathogenic information to generate tailored protective adaptive immune responses. In this review, we discuss complexities involved in the innate control of adaptive immunity that extend beyond TCR engagement, costimulation, and priming cytokine production but are critical for the generation of protective T cell immunity...
May 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28479601/b7-dc-pd-l2-costimulation-of-cd4-t-helper-1-response-via-rgmb
#17
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/28473423/efficacy-and-safety-of-abatacept-a-t-cell-modulator-in-a-randomised-double-blind-placebo-controlled-phase-iii-study-in-psoriatic-arthritis
#18
Philip J Mease, Alice B Gottlieb, Désirée van der Heijde, Oliver FitzGerald, Alyssa Johnsen, Marleen Nys, Subhashis Banerjee, Dafna D Gladman
OBJECTIVES: To assess the efficacy and safety of abatacept, a selective T-cell costimulation modulator, in a phase III study in psoriatic arthritis (PsA). METHODS: This study randomised patients (1:1) with active PsA (~60% with prior exposure to a tumour necrosis factor inhibitor) to blinded weekly subcutaneous abatacept 125 mg (n=213) or placebo (n=211) for 24 weeks, followed by open-label subcutaneous abatacept. Patients without ≥20% improvement in joint counts at week 16 were switched to open-label abatacept...
May 4, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28460546/an-update-on-chemical-pharmacotherapy-options-for-the-prevention-of-kidney-transplant-rejection-with-a-focus-on-costimulation-blockade
#19
Florian Kälble, Matthias Schaier, Sebastian Schäfer, Caner Süsal, Martin Zeier, Claudia Sommerer, Christian Morath
The introduction of calcineurin inhibitors (CNI) has greatly improved graft survival in the past three decades. However, long-term graft survival is still limited due to chronic allograft injury and side-effects of immunosuppressive medication. Areas covered: The present overview gives an update on pharmacotherapeutic strategies after kidney transplantation. The main focus is on CNI-sparing regimens using co-stimulatory blockade and on new substances on the horizone. Expert opinion: CNI sparing regimens are well-established...
June 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28446317/-research-progress-on-relationship-between-cd58-molecule-and-all-and-lymphoma-review
#20
Ye-Jian Lu, Lan-Lan Qiu, Li-Li Wang
Lymphocyte function-associated antigen-3 (LFA-3/CD58) is a cell-surface glycoprotein, it can bind to CD2 and activate the costimulation pathways of T lymphocytes and natural killer (NK) cells, maximizing the cytolysis of target cells by cytotoxic T lymphocytes (CTL) and NK cells. Some studies have demonstrated that in acute lymphoblastic leukemia(ALL) and lymphomas, lack of CD58 on the tumor cells may fail to activate the T lymphocytes and NK cells, resulting in feeble cytotoxic effect and subsequently escape from immune surveillance, making the disease become more complicated and liable to relapse...
April 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
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