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https://www.readbyqxmd.com/read/28012568/improved-survival-after-induction-of-sepsis-by-cecal-slurry-in-pd-1-knockout-murine-neonates
#1
Whitney A Young, Eleanor A Fallon, Daithi S Heffernan, Philip A Efron, William G Cioffi, Alfred Ayala
BACKGROUND: Sepsis and the ensuing immune dysfunction continue to be major contributors to neonatal morbidity and mortality. Neonatal sepsis also is associated with profound immune dysfunction. We have recently identified a role for a family of coinhibitory molecules that are altered in murine sepsis and in critically ill adult patients, which may be a target for development of novel therapies. There is, however, a paucity of data pertaining to the role of coinhibitory checkpoint proteins in the control and modulation of neonatal sepsis...
December 21, 2016: Surgery
https://www.readbyqxmd.com/read/27993215/anti-pd-l1-peptide-improves-survival-in-sepsis
#2
Yuichiro Shindo, Jacquelyn S McDonough, Katherine C Chang, Murali Ramachandra, Pottayil G Sasikumar, Richard S Hotchkiss
BACKGROUND: Sepsis remains a leading cause of death in most intensive care units. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival...
February 2017: Journal of Surgical Research
https://www.readbyqxmd.com/read/27956634/brief-treatment-with-a-highly-selective-immunoproteasome-inhibitor-promotes-long-term-cardiac-allograft-acceptance-in-mice
#3
Esilida Sula Karreci, Hao Fan, Mayuko Uehara, Albana B Mihali, Pradeep K Singh, Ahmed T Kurdi, Zhabiz Solhjou, Leonardo V Riella, Irene Ghobrial, Teresina Laragione, Sujit Routray, Jean Pierre Assaker, Rong Wang, George Sukenick, Lei Shi, Franck J Barrat, Carl F Nathan, Gang Lin, Jamil Azzi
Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving autoimmunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit β5i that has thousands-fold selectivity over constitutive β5c...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27941003/efficacy-of-pd-1-blockade-is-potentiated-by-metformin-induced-reduction-of-tumor-hypoxia
#4
Nicole E Scharping, Ashley V Menk, Ryan D Whetstone, Xue Zeng, Greg M Delgoffe
Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy...
January 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/27898465/the-intragraft-microenvironment-as-a-central-determinant-of-chronic-rejection-or-local-immunoregulation-tolerance
#5
Johannes Wedel, Hironao Nakayama, Nora M Kochupurakkal, Josephine Koch, Michael Klagsbrun, Diane R Bielenberg, David M Briscoe
PURPOSE OF REVIEW: Chronic rejection is associated with persistent mononuclear cell recruitment, endothelial activation and proliferation, local tissue hypoxia and related biology that enhance effector immune responses. In contrast, the tumor microenvironment elicits signals/factors that inhibit effector T cell responses and rather promote immunoregulation locally within the tissue itself. The identification of immunoregulatory check points and/or secreted factors that are deficient within allografts is of great importance in the understanding and prevention of chronic rejection...
February 2017: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/27849166/first-in-human-study-in-healthy-subjects-with-fr104-a-pegylated-monoclonal-antibody-fragment-antagonist-of-cd28
#6
Nicolas Poirier, Gilles Blancho, Maryvonne Hiance, Caroline Mary, Tim Van Assche, Jos Lempoels, Steven Ramael, Weirong Wang, Virginie Thepenier, Cecile Braudeau, Nina Salabert, Regis Josien, Ian Anderson, Ian Gourley, Jean-Paul Soulillou, Didier Coquoz, Bernard Vanhove
FR104 is a monovalent pegylated Fab' Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27829150/programmed-death-1-culls-peripheral-accumulation-of-high-affinity-autoreactive-cd4%C3%A2-t-cells-to-protect-against-autoimmunity
#7
Tony T Jiang, Tijana Martinov, Lijun Xin, Jeremy M Kinder, Justin A Spanier, Brian T Fife, Sing Sing Way
Self-reactive CD4 T cells are incompletely deleted during thymic development, and their peripheral seeding highlights the need for additional safeguards to avert autoimmunity. Here, we show an essential role for the coinhibitory molecule programmed death-1 (PD-1) in silencing the activation of high-affinity autoreactive CD4 T cells. Each wave of self-reactive CD4 T cells that escapes thymic deletion autonomously upregulates PD-1 to maintain self-tolerance. By tracking the progeny derived from individual autoreactive CD4 T cell clones, we demonstrate that self-reactive cells with the greatest autoimmune threat and highest self-antigen affinity express the most PD-1...
November 8, 2016: Cell Reports
https://www.readbyqxmd.com/read/27803740/antagonizing-programmed-death-1-and-programmed-death-ligand-1-as-a-therapeutic-approach-for-gastric-cancer
#8
REVIEW
Xiaojun Liu, Zhongxia Yang, Olivier Latchoumanin, Liang Qiao
Malignant tumor cells are equipped with mechanisms that can help them escape the surveillance by host immune system. Immune checkpoint molecules can transduce coinhibitory signals to immunocompetent cells and exert immunosuppressive roles in antitumor immunity. Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are the two important checkpoint molecules with great potential in targeted cancer therapy. Several antibodies targeting PD-1 and PD-L1 have been approved for clinical use. In this review, we focus on the recent development of targeting PD-1 and PD-L1 in gastric cancer (GC) therapy...
November 2016: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/27802341/acute-malaria-induces-pd1-ctla4-effector-t-cells-with-cell-extrinsic-suppressor-function
#9
Maria Sophia Mackroth, Annemieke Abel, Christiane Steeg, Julian Schulze Zur Wiesch, Thomas Jacobs
In acute Plasmodium falciparum (P. falciparum) malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4+ T cell functions in malaria, blood samples were obtained from patients with acute P...
November 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27731324/unique-b7-h1-expression-on-masticatory-mucosae-in-the-oral-cavity-and-trans-coinhibition-by-b7-h1-expressing-keratinocytes-regulating-cd4-t-cell-mediated-mucosal-tissue-inflammation
#10
S Kang, C Zhang, T Ohno, M Azuma
The PD-1/B7-H1 pathway regulates immune responses and maintains homeostasis. Here, we identified a unique expression of B7 homolog 1 (B7-H1) on masticatory mucosae in the oral cavity. B7-H1 was physiologically expressed on the dorsal surface of the tongue, gingiva, and hard palate. Other squamous epithelia and other structures of the epithelia did not express B7-H1 in the steady state. Physiological B7-H1 expression on masticatory mucosae was limited on prickle cells, and its expression on basal keratinocytes (KCs) was strictly regulated...
October 12, 2016: Mucosal Immunology
https://www.readbyqxmd.com/read/27617403/hepatitis-b-core-antigen-upregulates-b7-h1-on-dendritic-cells-by-activating-the-akt-erk-p38-pathway-a-possible-mechanism-of-hepatitis-b-virus-persistence
#11
Man Li, Zhen-Hua Zhou, Xue-Hua Sun, Xin Zhang, Xiao-Jun Zhu, Shu-Gen Jin, Ya-Ting Gao, Yun Jiang, Yue-Qiu Gao
B7-H1 binding to programmed death-1 may deliver a coinhibitory signal to T cells that is involved in the regulation of T-cell activation and tolerance. B7-H1 plays a key role in dysfunction of dendritic cells (DCs) during chronic HBV infection, but the expression mechanism of B7-H1 remains unclear. One hundred and twenty-nine patients with chronic HBV infection were categorized into either the immune tolerance phase (HBV-IT), the immune clearance phase (HBV-IC), or the inactive carrier phase (HBV-IA). Twenty healthy volunteers were enrolled as controls...
September 12, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/27591335/costimulation-blockade-in-autoimmunity-and-transplantation-the-cd28-pathway
#12
Andrew B Adams, Mandy L Ford, Christian P Larsen
T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27587467/complementing-t-cell-function-an-inhibitory-role-of-the-complement-system-in-t-cell-mediated-antitumor-immunity
#13
Weiyi Peng, Jodi A McKenzie, Patrick Hwu
New data from Wang and colleagues show that complement C3 suppresses the function of CD8(+) tumor-infiltrating T cells by inhibiting IL10 production, and targeting the complement receptors C3aR and C5aR enhances the antitumor activity of immune checkpoint blockade. Their results not only define a new role of complement receptors as T-cell coinhibitory receptors, but also are useful in the development of novel strategies to improve the effectiveness of cancer immunotherapy. Cancer Discov; 6(9); 953-5. ©2016 AACR...
September 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27454297/human-car-t-cells-with-cell-intrinsic-pd-1-checkpoint-blockade-resist-tumor-mediated-inhibition
#14
Leonid Cherkassky, Aurore Morello, Jonathan Villena-Vargas, Yang Feng, Dimiter S Dimitrov, David R Jones, Michel Sadelain, Prasad S Adusumilli
Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication...
August 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27443896/current-status-of-immunotherapy-for-non-small-cell-lung-cancer
#15
Martina Imbimbo, Giuseppe Lo Russo, Fiona Blackhall
In the last few years, the introduction of novel immunotherapeutic agents has represented a treatment shift for a subset of patients with non-small-cell lung cancer (NSCLC). Checkpoint inhibitors have been demonstrated to improve survival in advanced stage disease with very good tolerability. This success follows many years of scientific effort to manipulate the human immune system to attack cancer cells. With a variety of approaches ranging from vaccines to administration of interleukin or interferon-γ, the results in NSCLC were unsuccessful, with the view that it is a scarcely immunogenic cancer, unlike melanoma or renal cell carcinoma...
August 3, 2016: Tumori
https://www.readbyqxmd.com/read/27242794/modulation-of-innate-immune-mechanisms-to-enhance-leishmania-vaccine-induced-immunity-role-of-coinhibitory-molecules
#16
REVIEW
Sreenivas Gannavaram, Parna Bhattacharya, Nevien Ismail, Amit Kaul, Rakesh Singh, Hira L Nakhasi
No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MΦ). Furthermore, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs and to condition the infected MΦ toward anti-inflammatory/alternative/M2 phenotype...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27236554/therapeutic-antibodies-in-cancer-therapy
#17
Martin Gasser, Ana Maria Waaga-Gasser
The therapeutic arsenal in solid tumors comprises different anticancer strategies with diverse chemotherapeutic agents and a growing number of biological substances. Large clinical study-based chemotherapeutic protocols combined with biologicals have become an important component in (neo-) adjuvant therapy alongside surgery in solid cancers as well as radiation therapy in some instances. In recent years, monoclonal antibodies have entered the mainstream of cancer therapy. Their first use was as antagonists of oncogenic receptor tyrosine kinases, but today monoclonal antibodies have emerged as long-sought vehicles for the targeted delivery of potent chemotherapeutic agents and as powerful tools to manipulate anticancer immune responses...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27234378/association-of-3-nearby-gene-btla-polymorphisms-with-the-risk-of-renal-cell-carcinoma-in-the-polish-population
#18
Anna Partyka, Krzysztof Tupikowski, Anna Kolodziej, Romuald Zdrojowy, Agnieszka Halon, Bartosz Malkiewicz, Janusz Dembowski, Irena Frydecka, Lidia Karabon
OBJECTIVE: T cells play an important role in antitumor immunity, and molecules regulating T-cell activity could influence cancer susceptibility. The distinct role of coinhibitory receptors in immunosurveillance has been considered. B- and T-lymphocyte attenuator (BTLA) is one of these receptors, which negatively regulate immune responses. The aim of this study was to investigate the association between BTLA gene polymorphisms and susceptibility to renal cell carcinoma (RCC) in the Polish population...
September 2016: Urologic Oncology
https://www.readbyqxmd.com/read/27197539/epigenetic-modifiers-in-immunotherapy-a-focus-on-checkpoint-inhibitors
#19
Manuela Terranova-Barberio, Scott Thomas, Pamela N Munster
Immune surveillance should be directed to suppress tumor development and progression, involving a balance of coinhibitory and costimulatory signals that amplify immune response without overwhelming the host. Immunotherapy confers durable clinical benefit in 'immunogenic tumors', whereas in other tumors the responses are modest. Thus, immune checkpoint inhibitors may need to be combined with strategies to boost immune response or increase the tumor immune profile. Epigenetic aberrations contribute significantly to carcinogenesis...
June 2016: Immunotherapy
https://www.readbyqxmd.com/read/27193453/the-role-of-surgical-pathology-in-guiding-cancer-immunotherapy
#20
Scott B Lovitch, Scott J Rodig
The recognition that the immune system can identify and destroy tumor cells has driven a paradigm shift in our understanding of human cancer. Therapies designed to enhance this capacity, including cancer vaccines and coinhibitory receptor blockade, have demonstrated clinical efficacy in treating tumors refractory to conventional therapy. In this review, we discuss how the analysis of the immune microenvironment in primary tissue biopsy samples can be used to stratify patients according to clinical outcome, identify patients likely to benefit from specific immunotherapies, and tailor combination immunotherapy to individual patients and tumor types...
May 23, 2016: Annual Review of Pathology
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