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immune tolerance OR anergy OR deletion

Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Keren Turjeman, Yechezkel Barenholz
BACKGROUND: Steroids are the most efficacious anti-inflammatory agents. However, their toxicities and side-effects compromise their clinical application. Various strategies and major efforts were dedicated for formulating viable liposomal glucocorticosteroids (GCs), so far none of these were approved. OBJECTIVES: To evaluate these approaches for formulating GC-delivery systems, especially liposomes, and with focus on the Barenholz Lab experience. METHODS: We developed PEGylated nano-liposomes (NSSL) remotely loaded with water-soluble amphipathic weak acid GC-prodrugs...
October 18, 2016: Journal of Drug Targeting
Hiroshi Yamazaki
Research over the past 30 years has elucidated the roles of polymorphic human liver cytochrome P450 (P450) enzymes associated with toxicological and/or pharmacological actions. Thalidomide exerts its various pharmacological and toxic actions in primates through multiple mechanisms, including nonspecific modification of many protein networks after bioactivation by autoinduced human P450 enzymes. To overcome species-differences between rodents, currently, nonhuman primates and/or mouse models with transplanted human hepatocytes are used...
October 17, 2016: Chemical Research in Toxicology
Aitor Nogales, Kai Huang, Caroline Chauché, Marta L DeDiego, Pablo R Murcia, Colin R Parrish, Luis Martínez-Sobrido
Canine Influenza Virus (CIV) H3N8 is the causative agent of canine influenza, a common and contagious respiratory disease of dogs. Currently, only inactivated influenza vaccines (IIVs) are available for the prevention of CIV H3N8. However, live-attenuated influenza vaccines (LAIVs) are known to provide better immunogenicity and protection efficacy than IIVs. Influenza NS1 is a virulence factor that offers an attractive target for the preparation of attenuated viruses as LAIVs. Here we generated recombinant H3N8 CIVs containing truncated or a deleted NS1 protein to test their potential as LAIVs...
October 14, 2016: Virology
Oladapo Yeku, Susan F Slovin
Immunotherapy for castration-resistant prostate cancer has continued to be an area of active research over the last several years. The enthusiasm of this approach has been based on the assumption of better tolerability and that using the body's own immune system may be more effective than either hormonal or chemotherapy. Sipuleucel-T, a dendritic cell-based vaccine, is the only approved agent in this class for the management of castrate-resistant prostate cancer. Although sipuleucel-T increases overall survival without any significant changes in progression-free survival, other forms of immunotherapy such as PSA-TRICOM, ipilimumab, and chimeric antigen receptor T cell therapy are in advanced stages of clinical development...
September 2016: Cancer Journal
G N Nguyen, L A George, J I Siner, R J Davidson, C B Zander, X L Zheng, V R Arruda, R M Camire, D E Sabatino
BACKGROUND: The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a Paired basic Amino acid Cleaving Enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function...
October 17, 2016: Journal of Thrombosis and Haemostasis: JTH
Xu Shi, Ying Tang, Xiguang Sun, Yufei Liu, Ying Sun, Munan Sun, Yanfang Jiang, Yulin Li
The current study aimed to investigate the distribution of memory and naïve T cell (TN) subsets in hepatitis B virus (HBV)‑infected patients at different immune stages and investigate the effect of interleukin 33 (IL‑33) on the regulation of the T‑cell subsets. The distributions of memory and naïve T cells were detected by flow cytometry. ELISA was conducted to assess the levels of IL‑4, IL‑5, IL‑10, IL‑12, interferon γ and tumor necrosis factor α. The expression levels of IL‑33 and HBV x protein (HBx) were measured by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively...
October 13, 2016: Molecular Medicine Reports
Sarah A Altınoğlu, Ming Wang, Kathleen Q Li, Yuyang Li, Qiaobing Xu
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor, mutated or inactive in a large percentage of human cancers. Restoring PTEN activity in cancer cells through gene therapy has shown to inhibit cell growth and induce apoptosis, particularly in cells with a PTEN deficiency. Gene therapy, however, comes with some inherent risks such as triggering an immune response and permanent off target effects. Nanoparticle assisted protein delivery could mitigate these liabilities while maintaining therapeutic integrity...
October 17, 2016: Biomaterials Science
Philip Mease, Iain B McInnes
INTRODUCTION: Psoriatic arthritis (PsA) is an immune-mediated chronic inflammatory arthropathy associated with impaired physical function and reduced quality of life. Biologic therapies that target tumor necrosis factor (anti-TNF) have significantly improved clinical outcomes. Partial, non- and transient responses remain common comprising significant unmet clinical need. New therapies with novel modes of action are urgently required. OBJECTIVES: The interleukin (IL)-17 pathway has recently been attributed a critical role in the pathogenesis of spondyloarthritides...
June 2016: Rheumatol Ther
Farhad Shahsavar, Shaghayegh Mapar, Seyyed Amir Yasin Ahmadi
Multiple sclerosis (MS) is a disease in which we can recognize destruction of the myelin that is around nerve cells of brain and spinal cord called as oligodendrocytes. Both genetic and environmental factors play roles in MS. One of these genes is the killer-cell immunoglobulin-like receptor (KIR) which expressed on surface of natural killer cells (NKs). These genes have loci (not locus) in human genome, so they inherit as haplotypes. The results of previous studies show that different genes of KIR may affect both susceptibility and resistance to such autoimmune disorders that their pathogenesis in MS is still unclear...
December 2016: Genomics Data
Vijay K Karra, Soumya J Chowdhury, Rajesh Ruttala, Sunil K Polipalli, Premashis Kar
BACKGROUND/OBJECTIVE: Quantification of serum hepatitis B antigen (HBsAg) is an important test that marks active infection with hepatitis B and helps in the prediction of the clinical outcome and management of hepatitis B virus (HBV) infection. Correlation with HBV DNA quantitative levels may help in developing strategies for antiviral treatment. This study is aimed to evaluate HBsAg titres in various phase of HBV infection in HBsAg positive patients, and its correlation with HBV DNA viral load levels...
September 2016: Journal of Clinical and Experimental Hepatology
Min Zhang, Zhongqi Zhou, Jinguang Wang, Shufa Li
Inflammatory pathways play an important role in impaired glucose metabolism and insulin production. Adipose tissue inflammation is characterized by infiltration and expansion of macrophages, leading to type 2 diabetes (T2D). Macrophage polarization contributes to various inflammatory responses and cytokine production profiles. MiR-130b is involved in regulating immune response and metabolism. However, the specific role in macrophage polarization and glucose metabolism of T2D has not been reported. In this study, C57BL/6 mice were fed a high-fat diet to induce T2D mice model...
October 13, 2016: Immunology Letters
Deborah M Hussey Freeland, Hua Fan-Minogue, Jonathan M Spergel, Talal A Chatila, Kari C Nadeau
The incidence of food allergy, a disease characterized by adverse immune responses that can render common foods life-threatening, is rising. Yet our current standard of care is simply avoidance of allergenic foods and administration of emergency medications upon accidental exposure. Significant advances have been made in food allergy oral immunotherapy, which is emerging as a potential preventive and curative treatment for this disease. The fundamental strategy of oral immunotherapy is to mitigate adverse immune responses to allergenic food proteins through repeated exposure; reduced reactivity to food allergens (desensitization) often results, but the establishment of sustained immune unresponsiveness or of permanent resolution (tolerance) is not certain...
October 13, 2016: Current Opinion in Immunology
Jianbin Wang, Michael C Holmes
The battle with human immunodeficiency virus (HIV) has been ongoing for more than 30 years, and although progress has been made, there are still significant challenges remaining. A few unique features render HIV to be one of the toughest viruses to conquer in the modern medicine era, such as the ability to target the host immune system, persist by integrating into the host genome and adapt to a hostile environment such as a single anti-HIV medication by continuously evolving. The finding of combination anti-retroviral therapy (cART) about 2 decades ago has transformed the treatment options for HIV-infected patients and significantly improved patient outcomes...
November 2016: Cytotherapy
Shanmuganathan Chandrakasan, Rebecca A Marsh, Gulbu Uzel, Steven M Holland, Kara N Shah, Jack Bleesing
Patients with NEMO deficiency tolerate myeloablative hematopoietic stem cell conditioning and transplant, and most patients achieve adequate immune reconstitution to correct the underlying immune deficiency.
October 12, 2016: Journal of Allergy and Clinical Immunology
Haleh Saber, Ramadevi Gudi, Michael Manning, Emily Wearne, John K Leighton
As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities...
October 12, 2016: Regulatory Toxicology and Pharmacology: RTP
Raul Elgueta, Dan Tse, Sophie J Deharvengt, Marcus R Luciano, Catherine Carriere, Randolph J Noelle, Radu V Stan
Plasmalemma vesicle-associated protein (Plvap) is an endothelial protein with roles in endothelial diaphragm formation and maintenance of basal vascular permeability. At the same time, Plvap has roles in immunity by facilitating leukocyte diapedesis at inflammatory sites and controlling peripheral lymph node morphogenesis and the entry of soluble Ags into lymph node conduits. Based on its postulated role in diapedesis, we have investigated the role of Plvap in hematopoiesis and show that deletion of Plvap results in a dramatic decrease of IgM(+)IgD(lo) B cells in both the spleen and the peritoneal cavity...
October 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
A K S Salama, S J Moschos
BACKGROUND: Cancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well characterized at preclinical and clinical levels...
October 13, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Vindhya Mohindra, Ratnesh Kumar Tripathi, Akanksha Singh, Ruchi Patangia, Rajeev Kumar Singh, Kuldeep Kumar Lal, Joy Krushna Jena
The Indian catfish, Clarias magur is an air breathing fish, inhabitant of aquatic bodies characterized by low dissolved oxygen levels. It is exposed to hypoxic conditions in its natural habitat. Thus, it can be useful model to study the mechanism of hypoxia stress tolerance. In C. magur, molecular processes facilitating its adaptation to hypoxia stress remain largely unexplored, in part due to unavailability of genomic resources. The suppression subtractive hybridization technique (SSH) was employed to compare the differential expression of transcripts under experimental hypoxic conditions, to that of normoxic conditions...
October 11, 2016: Fish & Shellfish Immunology
Jennifer Jurkin, Corinna Krump, René Köffel, Christina Fieber, Christopher Schuster, Patrick M Brunner, Izabela Borek, Gregor Eisenwort, Clarice Lim, Jörg Mages, Roland Lang, Wolfgang Bauer, Diana Mechtcheriakova, Anastasia Meshcheryakova, Adelheid Elbe-Bürger, Georg Stingl, Herbert Strobl
BACKGROUND: Langerhans cell (LC) networks play key roles in immunity and tolerance at body surfaces. LCs are established prenatally and can be replenished from blood monocytes. Unlike skin-resident dermal/interstitial-type DCs (d/intDCs) and inflammatory dendritic epidermal cells (IDECs) appearing in dermatitis/eczema lesions, LCs lack key monocyte-affiliated markers. Inversely, LCs express various epithelial genes critical for their long-term peripheral tissue residency. OBJECTIVE: DCs are functionally involved in inflammatory diseases; however, mechanisms remained poorly understood...
October 11, 2016: Journal of Allergy and Clinical Immunology
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