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Immune mechanics

Alexandra M Nicaise, Kasey M Johnson, Cory M Willis, Rosa M Guzzo, Stephen J Crocker
The extracellular protein tissue inhibitor of metalloproteinase (TIMP)-1 is both a matrix metalloproteinase (MMP) inhibitor and a trophic factor. Mice lacking TIMP-1 exhibit delayed central nervous system myelination during postnatal development and impaired remyelination following immune-mediated injury in adulthood. We have previously determined that the trophic action of TIMP-1 on oligodendrocyte progenitor cells (OPCs) to mature into oligodendrocytes is independent of its MMP inhibitory function. However, the mechanism by which TIMP-1 promotes OPC differentiation is not known...
August 18, 2018: Molecular Neurobiology
I V Kholodenko, R V Kholodenko, A Yu Lupatov, K N Yarygin
Transplantation of solid organs, including liver, induces a number of serious complications related to immune incompatibility and requiring long-term use of immunosuppressive drugs. Finding the ways to inducing recipient immunological tolerance to the grafts is a top priority in organ transplantation and immunology. Along with the search for immunosupressive therapy, the development of alternative approaches to induction of immunological tolerance based on cell technologies is now in progress. In this regard, studies of the so-called spontaneous operational tolerance observed in ~20% patients after orthotopic liver transplantation is a promising trend...
August 18, 2018: Bulletin of Experimental Biology and Medicine
Ting Chen, Qing Li, Jiao Wu, Yaxin Wu, Wei Peng, Huan Li, Jianmei Wang, Xiaowei Tang, Yan Peng, Xiangsheng Fu
Fusobacterium nucleatum (Fn) has been shown to promote colorectal cancer (CRC) development by inhibiting host anti-tumour immunity. However, the impact of Fn infection on macrophage polarization and subsequent intestinal tumour formation as well as the underlying molecular pathways has not been investigated. We investigated the impact of Fn infection on macrophage polarization in human CRCs and cultured macrophages as well as the effects on macrophage phenotype and intestinal tumour formation in ApcMin/+ mice...
August 18, 2018: Cancer Immunology, Immunotherapy: CII
Keiko Igaki, Yoshiki Nakamura, Yusaku Komoike, Keiko Uga, Akira Shibata, Yoshimasa Ishimura, Masashi Yamasaki, Yasuhiro Tsukimi, Noboru Tsuchimori
IL-17-producing Th17 cells and IFN-γ and IL-17 double-producing Th1/17 cells have been identified as the pathogenic cells in inflammatory bowel disease (IBD). Retinoic acid-related orphan receptor γt (RORγt) is a master regulator for the differentiation and activation of Th17 and Th1/17 cells. We discovered a novel orally available TAK-828F, a strong and selective RORγt inverse agonist. To assess the potential of RORγt blockade in the therapy for IBD, the efficacy of TAK-828F in activated T cell transfer mouse colitis model was investigated...
August 18, 2018: Inflammation
Laura Kranaster, Carolin Hoyer, Suna S Aksay, J Malte Bumb, Norbert Müller, Peter Zill, Markus J Schwarz, Natalie Moll, Beat Lutz, Laura Bindila, Inga Zerr, Matthias Schmitz, Kaj Blennow, Henrik Zetterberg, Dieter Haffner, Maren Leifheit-Nestler, Cagakan Ozbalci, Christoph Janke, Manfred Thiel, Alexander Sartorius
BACKGROUND: No candidate biomarkers based on cerebrospinal fluid (CSF) have been identified as prognostic factors in patients with major depression treated with electroconvulsive therapy (ECT), yet. METHOD: Following different underlying hypotheses, we analysed baseline CSF levels of markers of neurodegeneration (tau proteins, β-amyloids and neurogranin), elements of the innate immune system (interleukin [IL]-6, neopterin, soluble CD14, soluble CD163, migration inhibitory factor and monocyte chemotactic protein 1), endocannabinoids, sphingolipids and Klotho before ECT in patients with depression (n = 12) to identify possible correlations with the clinical antidepressant response to ECT...
August 17, 2018: Neuropsychobiology
Richard P Tobin, Kimberly R Jordan, William A Robinson, Dana Davis, Virginia F Borges, Rene Gonzalez, Karl D Lewis, Martin D McCarter
BACKGROUND: Immune checkpoint inhibitors have improved overall survival rates for many cancers, yet the majority of patients do not respond to treatment and succumb to disease progression. One tumor-related mechanism limiting the efficacy of immunotherapies in melanoma is the recruitment and expansion of myeloid-derived suppressor cells (MDSCs). Therefore, targeting MDSCs in combination with immunotherapies is an attractive strategy to improve response rates and effectiveness. METHODS: We tested this strategy by designing a randomized phase II clinical trial treating advanced melanoma patients with either Ipilimumab monotherapy or Ipilimumab plus all-trans retinoic acid (ATRA)...
August 16, 2018: International Immunopharmacology
Saliha Esenboga, Can Akal, Betül Karaatmaca, Baran Erman, Sibel Dogan, Diclehan Orhan, Kaan Boztug, Deniz Ayvaz, İlhan Tezcan
V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections...
August 16, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Georgia Kaidonis, Anand N Rao, Yi-Bing Ouyang, Creed M Stary
Cerebral ischemia remains a major cause of death and disability worldwide, yet therapeutic options remain limited. Differences in sex and age play an important role in the final outcome in response to cerebral ischemia in both experimental and clinical studies: males have a higher risk and worse outcome than females at younger ages and this trend reverses in older ages. Although the molecular mechanisms underlying sex dimorphism are complex and are still not well understood, studies suggest steroid hormones, sex chromosomes, differential cell death and immune pathways, and sex-specific microRNAs may contribute to the outcome following cerebral ischemia...
August 16, 2018: Progress in Neurobiology
Afsane Bahrami, Negin Parsamanesh, Stephen L Atkin, Maciej Banach, Amirhossein Sahbekar
The toll-like receptors (TLRs) are a class of transmembrane-spanning receptors that are sentinels of both innate and adaptive immunity. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the most commonly prescribed therapeutic agents for treating hypercholesterolemia globally. However, statin therapy appears to have pleiotropic effects including attenuation of chronic low-grade inflammation and modulation of TLR activity. Statins through abolition of TLR4 expression and regulation of the TLR4/Myd88/NF-κB signaling pathway may slow the progression of atherosclerosis and other inflammatory diseases...
August 15, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Rongying Zhou, Gaofeng Wang, Dongwon Kim, Sooah Kim, Nasif Islam, Ruosi Chen, Zixiao Wang, Ang Li, Edward F McCarthy, Li Li, Zhiqi Hu, Luis A Garza
How cell and tissue identity persist despite constant cell turnover is an important biologic question with cell therapy implications. While many mechanisms exist, we investigated the controls for site-specific gene expression in skin given its diverse structures and functions. For example, the transcriptome of in vivo palmoplantar (i.e. volar) epidermis is globally unique including Keratin 9 (KRT9). While volar fibroblasts have the capacity to induce KRT9 in non-volar keratinocytes, we demonstrate here that volar keratinocytes continue to express KRT9 in vitro solo-cultures...
August 15, 2018: Journal of Investigative Dermatology
Michael C Comiskey, Matthew C Dallos, Charles G Drake
Immunotherapy is rapidly transforming cancer care across a range of tumor types. Although Sipuleucel-T represented the first successful vaccine for the treatment of established cancer, other immunotherapeutic approaches for prostate cancer such as checkpoint inhibitors have been relatively disappointing to date. However, significant promise is on the horizon as there is a wide array trials evaluating immunotherapy in prostate cancer patients. These include both immune checkpoint inhibitors and antigen-specific approaches including vaccines, antibody-drug conjugates, and antitumor antibodies...
August 18, 2018: Current Oncology Reports
Anh Cao, Nouf Alluqmani, Fatima Hifza Mohammed Buhari, Laabiah Wasim, Logan K Smith, Andrew T Quaile, Michael Shannon, Zaki Hakim, Hossai Furmli, Dylan M Owen, Alexei Savchenko, Bebhinn Treanor
The galectin family of secreted lectins have emerged as important regulators of immune cell function; however, their role in B-cell responses is poorly understood. Here we identify IgM-BCR as a ligand for galectin-9. Furthermore, we show enhanced BCR microcluster formation and signaling in galectin-9-deficient B cells. Notably, treatment with exogenous recombinant galectin-9 nearly completely abolishes BCR signaling. We investigated the molecular mechanism for galectin-9-mediated inhibition of BCR signaling using super-resolution imaging and single-particle tracking...
August 17, 2018: Nature Communications
N Giovannone, J Liang, A Antonopoulos, J Geddes Sweeney, S L King, S M Pochebit, N Bhattacharyya, G S Lee, A Dell, H R Widlund, S M Haslam, C J Dimitroff
Leukocytes are coated with a layer of heterogeneous carbohydrates (glycans) that modulate immune function, in part by governing specific interactions with glycan-binding proteins (lectins). Although nearly all membrane proteins bear glycans, the identity and function of most of these sugars on leukocytes remain unexplored. Here, we characterize the N-glycan repertoire (N-glycome) of human tonsillar B cells. We observe that naive and memory B cells express an N-glycan repertoire conferring strong binding to the immunoregulatory lectin galectin-9 (Gal-9)...
August 17, 2018: Nature Communications
Giuseppe Lofano, Matthew J Gorman, Ashraf S Yousif, Wen-Han Yu, Julie M Fox, Anne-Sophie Dugast, Margaret E Ackerman, Todd J Suscovich, Joshua Weiner, Dan Barouch, Hendrik Streeck, Susan Little, Davey Smith, Douglas Richman, Douglas Lauffenburger, Bruce D Walker, Michael S Diamond, Galit Alter
HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC...
August 17, 2018: Science Immunology
Blanca E Ruiz-Medina, Denisse A Cadena-Medina, Edmundo Esparza, Amy J Arrieta, Robert A Kirken
Regulation of intracellular signaling pathways in lymphocytes is critical for cell homeostasis and immune response. Interleukin 2 (IL-2), a key regulator of lymphocytes, signals following receptor-ligand engagement and subsequent recruitment and activation of effector proteins including JAKs and STATs. Lymphocytes can also be regulated by the central nervous system through the β2 adrenergic receptor (β2AR) pathway which can affect cell trafficking, proliferation, differentiation, and cytokine production. The crosstalk between these two signaling pathways represents an important mechanism that has yet to be fully elucidated...
August 17, 2018: Biochemical Journal
Marie Cantier, Adeline Morisot, Emmanuel Guérot, Bruno Megarbane, Keyvan Razazi, Damien Contou, Eric Mariotte, Emmanuel Canet, Etienne De Montmollin, Vincent Dubée, Eric Boulet, Stéphane Gaudry, Guillaume Voiriot, Julien Mayaux, Frédéric Pène, Mathilde Neuville, Bruno Mourvillier, Stéphane Ruckly, Lila Bouadma, Michel Wolff, Jean-François Timsit, Romain Sonneville
BACKGROUND: Tuberculous meningitis (TBM) is a devastating infection in tuberculosis endemic areas with limited access to intensive care. Functional outcomes of severe adult TBM patients admitted to the ICU in nonendemic areas are not known. METHODS: We conducted a retrospective multicenter cohort study (2004-2016) of consecutive TBM patients admitted to 12 ICUs in the Paris area, France. Clinical, biological, and brain magnetic resonance imaging (MRI) findings at admission associated with a poor functional outcome (i...
August 17, 2018: Critical Care: the Official Journal of the Critical Care Forum
Priyesh Jain, Hsiang-Chieh Hung, Bowen Li, Jinrong Ma, Dianyu Dong, Xiaojie Lin, Andrew Sinclair, Peng Zhang, Mary Beth O'Kelly, Liqian Niu, Shaoyi Jiang
We report the synthesis of a zwitterionic carboxybetaine disulfide crosslinker (CBX-SS), and biodegradable poly(carboxybetaine) (PCB) hydrogels and nanocages (NCs) made using this crosslinker. The structure of CBX-SS combines zwitterionic carboxybetaine to confer nonfouling properties and a disulfide linkage to facilitate degradation. The physical, mechanical and fouling characteristics of PCB hydrogels crosslinked with CBX-SS were investigated. Then, the degradation characteristics of CBX-SS-crosslinked hydrogels were evaluated through their weight loss and release of an encapsulated protein in a reducing environment...
August 17, 2018: Langmuir: the ACS Journal of Surfaces and Colloids
Fei He, Jun Wang, Yao Liu, Xiaojing Wang, Nan Cai, Chao Wu, Qingling Gao
BACKGROUND: The mechanism in lung injury caused by acute organophosphate pesticide poisoning (AOPP) and an effective treatment remains unclear. We aim to clarify how the inflammatory lung injury caused by AOPP might be modulated by Xuebijing (XBJ) injection. METHODS: AOPP-induced lung injury model was induced by dichlorvos (DDVP) subcutaneous administration in rats and XBJ injection was administered by intraperitoneal injection after DDVP challenge. The effects of XBJ injection were assessed by lung histopathological analysis and lung injury scores, lung wet-to-dry weight ratios (WDR) and oxygenation, differential immune cell count in bronchoalveolar lavage fluid (BALF), IL-6 and TNF-α levels in blood, the levels of TLR4 and NF-κB proteins in lung tissue and blood acetylcholinesterase (AChE) activity...
July 23, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Yu Xia, Bo Yu, Chaozhi Ma, Yijun Tu, Ling Zhai, Yanfang Yang, Dan Liu, Yanwen Liu, Hezhen Wu, Hanxiong Dan, Pengtao You
Yu Gan Long (YGL) is a Chinese traditional herbal medicine that has been used in the treatment of liver fibrosis for many years in clinical practice. However, its anti-hepatofibrotic mechanism has not been studied yet. In this study, the effect and mechanism of YGL in reducing liver fibrosis was demonstrated in vivo. Our results showed that liver fibrosis biomarkers collagen IV (Col IV), type III precollagen (PCIII), hyaluronuc acid (HA) and laminin (LN), were increased after CCl4 treatment and decreased by YGL...
July 21, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Daniel S Chen, Herbert Hurwitz
Cancer immunotherapy (CIT) has transformed cancer treatment. In particular, immunotherapies targeting the programmed death ligand 1 (PD-L1)/programmed death 1 pathway have demonstrated durable clinical benefit in some patients. However, CIT combinations may create a more favorable environment in which to maximize the potential of the immune system to eliminate cancer. Here we describe 3 key mechanisms related to vascular endothelial growth factor (VEGF)-mediated immunosuppression: inhibition of dendritic cell maturation, reduction of T-cell tumor infiltration, and promotion of inhibitory cells in the tumor microenvironment; supporting data are also described...
July 2018: Cancer Journal
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