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https://www.readbyqxmd.com/read/28730633/pd-1-expression-on-cd8-t-cells-regulates-their-differentiation-within-lung-allografts-and-is-critical-for-tolerance-induction
#1
T Takahashi, H M Hsiao, S Tanaka, W Li, R Higashikubo, D Scozzi, A Bharat, J H Ritter, A S Krupnick, A E Gelman, D Kreisel
Immunological requirements for rejection and tolerance induction differ between various organs. While memory CD8(+) T cells are considered a barrier to immunosuppression-mediated acceptance of most tissues and organs, tolerance induction after lung transplantation is critically dependent on central memory CD8(+) T lymphocytes. Here we demonstrate that costimulation blockade-mediated tolerance after lung transplantation is dependent on PD-1 expression on CD8(+) T cells. In the absence of PD-1 expression, CD8(+) T cells form prolonged interactions with graft-infiltrating CD11c(+) cells, their differentiation is skewed towards an effector memory phenotype and grafts are rejected acutely...
July 20, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28713380/targeting-the-human-t-cell-inducible-costimulator-molecule-with-a-monoclonal-antibody-prevents-graft-vs-host-disease-and-preserves-graft-vs-leukemia-in-a-xenograft-murine-model
#2
Aude Burlion, Simon Brunel, Nicolas Y Petit, Daniel Olive, Gilles Marodon
BACKGROUND: Graft-vs-host disease (GVHD) is a major complication of allogenic bone marrow transplantation (BMT). Targeting costimulatory molecules with antagonist antibodies could dampen the excessive immune response that occurs, while preserving the beneficial graft vs leukemia (GVL) of the allogeneic response. Previous studies using a mouse model of GVHD have shown that targeting the T-cell Inducible COStimulator (ICOS, CD278) molecule is beneficial, but it is unclear whether the same applies to human cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28697888/regulated-expansion-and-survival-of-chimeric-antigen-receptor-modified-t-cells-using-small-molecule-dependent-inducible-myd88-cd40
#3
Aaron E Foster, Aruna Mahendravada, Nicholas P Shinners, Wei-Chun Chang, Jeannette Crisostomo, An Lu, Mariam Khalil, Eva Morschl, Joanne L Shaw, Sunandan Saha, MyLinh T Duong, Matthew R Collinson-Pautz, David L Torres, Tania Rodriguez, Tsvetelina Pentcheva-Hoang, J Henri Bayle, Kevin M Slawin, David M Spencer
Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4(+) and CD8(+) T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function...
July 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28691954/maintenance-belatacept-based-immunosuppression-in-lung-transplantation-recipients-who-failed-calcineurin-inhibitors
#4
Carlo J Iasella, Ryan J Winstead, Cody A Moore, Bruce A Johnson, Ayelet T Feinberg, Matthew R Morrell, J W Awori Hayanga, Elizabeth A Lendermon, Adriana Zeevi, John F McDyer, Christopher R Ensor
BACKGROUND: Traditional immunosuppressive regimens (ISR) used in lung transplantation rely on calcineurin inhibitors (CNI) that occasionally cause severe adverse reactions necessitating discontinuation. Belatacept is a novel costimulation antagonist approved for use in renal transplantation which lacks data in lung transplantation. This series aims to describe the response to belatacept ISR in 11 lung transplantation recipients after CNI failure. METHODS: Single center, retrospective medical record review of adult lung transplant recipients (LTR) before and after conversion to belatacept-based ISR...
July 6, 2017: Transplantation
https://www.readbyqxmd.com/read/28650106/dok3-modulates-bone-remodeling-by-negatively-regulating-osteoclastogenesis-and-positively-regulating-osteoblastogenesis
#5
Xiaofeng Cai, Junjie Xing, Courtney L Long, Qisheng Peng, Mary Beth Humphrey
Osteoclastogenesis is essential for bone remodeling and normal skeletal maintenance. RANKL promotes osteoclast differentiation and function but requires costimulation of immunoreceptor tyrosine-based activation motif (ITAM)-coupled immunoreceptors. Triggering receptor expressed on myeloid cells-2 (TREM2) coupled to ITAM-adaptor protein DNAX activation protein 12kDA (DAP12) provides costimulation of intracellular calcium signaling during osteoclastogenesis. Previously, we found that downstream of kinase-3 (DOK3) physically associates with DAP12 to inhibit toll-like receptor (TLR)-induced inflammatory signaling in macrophages...
June 26, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28638849/refractory-t-cell-anergy-and-rapidly-fatal-progressive-multifocal-leukoencephalopathy-after-prolonged-ctla4-therapy
#6
Manon Dekeyser, Marie-Ghislaine de Goër de Herve, Houria Hendel-Chavez, Céline Labeyrie, David Adams, Ghaïdaa Adebs Nasser, Jacques Gasnault, Antoine Durrbach, Yassine Taoufik
Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to central nervous system replication of the human polyomavirus JC virus (JCV) in immunosuppressed patients. The only effective therapeutic approach is to restore anti-JCV T-cell responses. In this study, we describe a case of rapidly fatal PML with JCV T-cell anergy in a renal transplant patient treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). T-cell anergy could not be reversed despite several therapeutic approaches...
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/28637095/selective-cd28-blockade-results-in-superior-inhibition-of-donor-specific-t-follicular-helper-cell-and-antibody-responses-relative-to-ctla-4-ig
#7
I R Badell, G M La Muraglia, D Liu, M E Wagener, G Ding, M L Ford
Donor-specific antibodies (DSA) are a barrier to improved long-term outcomes following kidney transplantation. Costimulation blockade with CTLA-4-Ig has shown promise as a potential therapeutic strategy to control DSA. T follicular helper (Tfh) cells, a subset of CD4(+) T cells required for optimum antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8(+) T cells relative to CTLA-4-Ig, but the impact of CD28-specific blockade on CD4(+) Tfh cells is unknown...
June 21, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28636555/overcoming-resistance-to-targeted-therapy-with-immunotherapy-and-combination-therapy-for-metastatic-melanoma
#8
REVIEW
Hilary R Keller, Xin Zhang, Li Li, Helmut Schaider, James W Wells
Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28613437/t-cell-subsets-predicting-belatacept-resistant-rejection-finding-the-root-where-the-trouble-starts
#9
EDITORIAL
T Wekerle
No abstract text is available yet for this article.
June 14, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28612217/ox40-promotes-obesity-induced-adipose-inflammation-and-insulin-resistance
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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 and 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) with 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
#18
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
#19
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
#20
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
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