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Maxim Durand, Florian Dubois, Cécile Dejou, Eugénie Durand, Richard Danger, Mélanie Chesneau, Carole Brosseau, Pierrick Guerif, Jean-Paul Soulillou, Nicolas Degauque, Jean-François Eliaou, Magali Giral, Nathalie Bonnefoy, Sophie Brouard
Regulatory T cells were recently proposed as the central actor in operational tolerance after renal transplantation. Tolerant patients harbor increased FoxP3hi memory Treg frequency and increased demethylation in the Foxp3 Treg-specific demethylated region when compared to stable kidney recipients and exhibit greater memory Treg suppressive capacities and higher expression of the ectonucleotidase CD39. However, in this particular and unique situation the mechanisms of action of Tregs were not identified. Thus, we analyzed the ability of memory Tregs to degrade extracellular ATP in tolerant patients, healthy volunteers, and patients with stable graft function under immunosuppression and determined the role of immunosuppressive drugs on this process...
February 15, 2018: Kidney International
Kenneth A Newell, Andrew B Adams, Laurence A Turka
Studies of kidney transplant recipients who have developed spontaneous and sustained tolerance have revealed an association with B cells. Unexpectedly tolerant individuals are characterized by increased numbers and frequencies of B cells in the blood and increased expression of genes associated with B cells in the blood and urine. Comparisons of the B cell repertoires of tolerant individuals and those receiving immunosuppression reveal that not only are the B cells more numerous but developmental differences result in a repertoire comprised of more naïve and transitional B cells in the tolerant cohort...
February 12, 2018: Human Immunology
Anna Buermann, Stoyan Petkov, Björn Petersen, Rabea Hein, Andrea Lucas-Hahn, Wiebke Baars, Antje Brinkmann, Heiner Niemann, Reinhard Schwinzer
BACKGROUND: The programmed cell death-1 (PD-1, CD279)/PD-Ligand1 (PD-L1, CD274) receptor system is crucial for controlling the balance between immune activation and induction of tolerance via generation of inhibitory signals. Expression of PD-L1 is associated with reduced immunogenicity and renders cells and tissues to an immune-privileged/tolerogenic state. METHODS: To apply this concept for clinical xenotransplantation, we generated human (h)PD-L1 transgenic pigs and characterized expression and biological function of the transgene at the cellular level...
February 15, 2018: Xenotransplantation
Andrew W Taylor, Tat Fong Ng
The ocular microenvironment has adapted several negative regulators of inflammation to maintain immune privilege and health of the visual axis. Several constitutively produced negative regulators within the eye TGF-β2, α-melanocyte stimulating hormone (α-MSH), Fas ligand (FasL), and PD-L1 standout because of their capacity to influence multiple pathways of inflammation, and that they are part of promoting immune tolerance. These regulators demonstrate the capacity of immune privilege to prevent the activation of inflammation, and to suppress activation of effector immune cells even under conditions of ocular inflammation induced by endotoxin and autoimmune disease...
February 12, 2018: Journal of Leukocyte Biology
Tina A Nguyen, Daniel A Kahn, Andrea I Loewendorf
INTRODUCTION: Maternal-fetal chimerism is miniscule, a testament to the integrity of the uteroplacental interface. The soundness of this border region is potentially altered through cesarean delivery of prior babies with uncertain consequences for the following pregnancies. METHODS: Using multicolor flow cytometry and quantitative PCR of non-inherited maternal antigens we performed a retrospective case control pilot study and formulated the null hypothesis that placental implantation over a prior uterine scar does not result in the presence of memory Treg (CD45RO+) in the fetus...
February 12, 2018: Immunity, Inflammation and Disease
Gabriela Peron, Livia de Lima Thomaz, Larissa Camargo da Rosa, Rodolfo Thomé, Liana Maria Cardoso Verinaud
Dendritic cells (DCs) are essential players in the activation of T cells and in the development of adaptive immune response towards invading pathogens. Upon antigen (Ag) recognition of Pathogen Associated Molecular Patterns (PAMPs) by their receptors (PRRs), DCs are activated and acquire an inflammatory profile. DCs have the ability to direct the profile of helper T (Th) cells towards Th1, Th2, Th17, Th9 and regulatory (Treg) cells. Each subset of Th cells presents a unique gene expression signature and is endowed with the ability to conduct or suppress effector cells in inflammation...
February 7, 2018: Immunology Letters
Ashley L St John, Gladys W X Ang, Abhay P S Rathore, Soman N Abraham
A novel immune-modulatory therapy utilizing targeted delivery of cytokines to draining lymph nodes effectively reprograms Th2 allergic responses towards a Th1 and tolerogenic profile, resulting in protection from peanut antigen-induced anaphylaxis.
February 5, 2018: Journal of Allergy and Clinical Immunology
Nataša Ilic, Alisa Gruden-Movsesijan, Jelena Cvetkovic, Sergej Tomic, Dragana Bozidar Vucevic, Carmen Aranzamendi, Miodrag Colic, Elena Pinelli, Ljiljana Sofronic-Milosavljevic
Trichinella spiralis, as well as its muscle larvae excretory-secretory products (ES L1), given either alone or via dendritic cells (DCs), induce a tolerogenic immune microenvironment in inbred rodents and successfully ameliorate experimental autoimmune encephalomyelitis. ES L1 directs the immunological balance away from T helper (Th)1, toward Th2 and regulatory responses by modulating DCs phenotype. The ultimate goal of our work is to find out if it is possible to translate knowledge obtained in animal model to humans and to generate human tolerogenic DCs suitable for therapy of autoimmune diseases through stimulation with ES L1...
2018: Frontiers in Immunology
Byung Yi Ko, Yangyan Xiao, Flavia L Barbosa, Cintia S de Paiva, Stephen C Pflugfelder
Intestinal epithelial cells condition tolerogenic properties in DCs. Aqueous-deficient dry eye is associated with goblet cell (GC) loss and increased IFN-γ expression in the conjunctiva. We hypothesized that loss of GCs reduces tolerance-inducing properties of antigen presenting cells (APCs) in the conjunctiva and draining nodes. Mice lacking the SAM pointed domain containing ETS transcription factor (Spdef) that is required for GC differentiation had an increased frequency of macrophages in the conjunctiva and CD11b+CD11c+ DCs in the conjunctiva and draining nodes, and these cells had greater IL-12 expression than WT mice...
February 8, 2018: JCI Insight
Timo Castor, Nir Yogev, Thomas Blank, Christina Barwig, Marco Prinz, Ari Waisman, Matthias Bros, Angelika B Reske-Kunz
In this study we analysed the effects of prophylactic biolistic DNA vaccination with plasmids encoding the encephalitogenic protein myelin oligodendrocyte glycoprotein (MOG) on the severity of a subsequently MOGp35-55-induced EAE and on the underlying immune response. We compared the outcome of vaccination with MOG-encoding plasmids alone or in combination with vectors encoding the regulatory cytokines IL-10 and TGF-ß1, respectively. MOG expression was restricted to skin dendritic cells (DCs) by the use of the DC-specific promoter of the fascin1 gene (pFscn-MOG)...
2018: PloS One
Arianna Palladini, Susan Thrane, Christoph M Janitzek, Jessica Pihl, Stine B Clemmensen, Willem Adriaan de Jongh, Thomas M Clausen, Giordano Nicoletti, Lorena Landuzzi, Manuel L Penichet, Tania Balboni, Marianna L Ianzano, Veronica Giusti, Thor G Theander, Morten A Nielsen, Ali Salanti, Pier-Luigi Lollini, Patrizia Nanni, Adam F Sander
Overexpression of human epidermal growth factor receptor-2 (HER2) occurs in 20-30% of invasive breast cancers. Monoclonal antibody therapy is effective in treating HER2-driven mammary carcinomas, but its utility is limited by high costs, side effects and development of resistance. Active vaccination may represent a safer, more effective and cheaper alternative, although the induction of strong and durable autoantibody responses is hampered by immune-tolerogenic mechanisms. Using a novel virus-like particle (VLP) based vaccine platform we show that directional, high-density display of human HER2 on the surface of VLPs, allows induction of therapeutically potent anti-HER2 autoantibody responses...
2018: Oncoimmunology
Zhibo Chen, Dehao Yang, Xiao Peng, Jie Lin, Zhongqian Su, Jia Li, Xu Zhang, Yiyun Weng
It is well known that dendritic cells play a key role in producing antigen-specific responses. Inversely, tolerogenic dendritic cells (TolDCs), a specialized subset, induce immune tolerance and negatively regulate autoimmune responses. Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the mevalonate pathway for cholesterol biosynthesis, might be a promising inductive agent for inducing TolDCs. This study aimed to investigate the effectiveness of TolDCs induced by atorvastatin pulsed with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) in experimental autoimmune encephalomyelitis mice established by MOG35-55 immunization and to investigate the potential effects on Th17/Treg balance in the murine model of multiple sclerosis...
February 1, 2018: Neuroreport
Hao Wu, Jianping Gong, Yong Liu
Indoleamine 2, 3-dioxygenase (IDO) catalyzes the initial and rate‑limiting step in the degradation pathway of the essential amino acid tryptophan and is expressed by professional antigen presenting cells (APCs), epithelial cells, vascular endothelium and tumor cells. IDO‑mediated catabolic products, which are additionally termed 'kynurenines', exerts important immunosuppressive functions primarily via regulating T effector cell anergy and inducing the proliferation of T regulatory cells. This endogenous tolerogenic pathway has a critical effect on mediating the magnitude of immune responses under various stress conditions, including tumor, infection and transplantation...
February 1, 2018: Molecular Medicine Reports
Caixia Xi, Nan Liu, Fei Liang, Xiao Zhao, Juan Long, Fang Yuan, Song Yun, Yuying Sun, Yongzhi Xi
Effective treatment of rheumatoid arthritis can be mediated by native chicken type II collagen (nCCII), recombinant peptide containing nCCII tolerogenic epitopes (CTEs), or a therapeutic DNA vaccine encoding the full-length CCOL2A1 cDNA. As recombinant CCII (rCCII) might avoid potential pathogenic virus contamination during nCCII preparation or chromosomal integration and oncogene activation associated with DNA vaccines, here we evaluated the importance of propeptide and telopeptide domains on rCCII triple helix molecular assembly...
January 9, 2018: Science China. Life Sciences
Azza Abdel-Gadir, Amir H Massoud, Talal A Chatila
Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen...
2018: F1000Research
Adam Kim, Rebecca L McCullough, Kyle L Poulsen, Carlos Sanz-Garcia, Megan Sheehan, Abram B Stavitsky, Laura E Nagy
Both the innate and adaptive immune systems are critical for the maintenance of healthy liver function. Immune activity maintains the tolerogenic capacity of the liver, modulates hepatocellular response to various stresses, and orchestrates appropriate cellular repair and turnover. However, in response to heavy, chronic alcohol exposure, the finely tuned balance of pro- and anti-inflammatory functions in the liver is disrupted, leading to a state of chronic inflammation in the liver. Over time, this non-resolving inflammatory response contributes to the progression of alcoholic liver disease (ALD)...
January 28, 2018: Handbook of Experimental Pharmacology
William S Bowen, Abhishek K Svrivastava, Lalit Batra, Hampartsoum Barsoumian, Haval Shirwan
Although much progress has been made in the last decade(s) toward development of effective cancer vaccines, there are still important obstacles to therapeutic successes. New generations of cancer vaccines will benefit from a combination adjuvant approach that targets multiple branches of the immune response. Areas covered: Herein we describe how combinatorial adjuvant strategies can help overcome important obstacles to cancer vaccine development, including antigen immunogenicity and tumor immune suppression...
January 26, 2018: Expert Review of Vaccines
Daphne E DeTemple, Felix Oldhafer, Christine S Falk, Chen Chen-Wacker, Constanca Figueiredo, Moritz Kleine, Wolf Ramackers, Kai Timrott, Frank Lehner, Juergen Klempnauer, Michael Bock, Florian W R Vondran
Hepatocyte transplantation is a promising therapeutic approach for various liver diseases. Despite the liver's tolerogenic potential, early immune-mediated loss of transplanted cells is observed and long-term acceptance has not been achieved, yet. Patients deemed tolerant after liver transplantation presented an increased frequency of regulatory T cells (Treg ), which therefore also might enable reduction of posttransplant cell-loss and enhance long-term allograft-acceptance. We hence characterised hepatocyte-induced immune reactions and evaluated the immunomodulatory potential of Treg applying mixed lymphocyte cultures and mixed lymphocyte hepatocyte cultures...
January 24, 2018: Liver Transplantation
Javeed Ahmad, Aisha Farhana, Rita Pancsa, Simran Kaur Arora, Alagiri Srinivasan, Anil Kumar Tyagi, Madan Mohan Babu, Nasreen Zafar Ehtesham, Seyed Ehtesham Hasnain
Pathogens frequently employ eukaryotic linear motif (ELM)-rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection. Mycobacterium tuberculosis has a relatively high percentage of IDPs in its proteome, the significance of which is not known. The Mycobacterium-specific PE-PPE protein family has several members with unusually high levels of structural disorder and disorder-promoting Ala/Gly residues. PPE37 protein, a member of this family, carries an N-terminal PPE domain capable of iron binding, two transmembrane domains, and a disordered C-terminal segment harboring ELMs and a eukaryotic nuclear localization signal (NLS)...
January 23, 2018: MBio
Dominik Filipp, Tomáš Brabec, Matouš Vobořil, Jan Dobeš
The gut is the biggest immune organ in the body that encloses commensal microbiota which aids in food digestion. Paneth cells, positioned at the frontline of host-microbiota interphase, can modulate the composition of microbiota. Paneth cells achieve this via the delivery of microbicidal substances, among which enteric α-defensins play the primary role. If microbiota is dysregulated, it can impact the function and fitness of the local mucosal immune system. Importantly, this system is also exposed to an enormous number of antigens which are derived from the gut-resident microbiota and processed food, and may potentially trigger undesirable local inflammatory responses...
January 16, 2018: Seminars in Cell & Developmental Biology
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