Journal of Immunology Research The latest articles from Hindawi © 2018 , Hindawi Limited . All rights reserved. Preclinical and Clinical Therapeutic Strategies Affecting Tumor-Associated Macrophages in Hepatocellular Carcinoma Tue, 16 Oct 2018 00:00:00 +0000 Hepatocellular carcinoma (HCC) most often develops in patients with underlying liver disease characterized by chronic nonresolving inflammation. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations within the tumoral microenvironment. As key actors of cancer-related inflammation, they promote tumor growth by suppression of effective anticancer immunity, stimulation of angiogenesis, and tissue remodeling. Therefore, they have become an attractive and promising target for immunotherapy. The heterogeneity of TAM subtypes and their origin and dynamic phenotype during the initiation and progression of HCC has been partially unraveled and forms the base for the development of therapeutic agents. Current approaches are aimed at decreasing the population of TAMs by depleting macrophages present in the tumor, blocking the recruitment of bone marrow-derived monocytes, and/or functionally reprogramming TAMs to antitumoral behavior. In this review, the preclinical evolution and hitherto clinical trials for TAM-targeted therapy in HCC will be highlighted. H. Degroote, A. Van Dierendonck, A. Geerts, H. Van Vlierberghe, and L. Devisscher Copyright © 2018 H. Degroote et al. All rights reserved. Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models Mon, 15 Oct 2018 00:00:00 +0000 Adoptive chimeric antigen receptor-modified T or NK cells (CAR-T or CAR-NK) offer new options for cancer treatment. CAR-T therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. However, their therapeutic efficacy against solid tumors is limited. New regimens, including combinations with chemical drugs, need to be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. An epithelial cell adhesion molecule- (EpCAM-) specific second-generation CAR was constructed and transduced into NK-92 cells by lentiviral vectors. Immune effects, including cytokine release and cytotoxicity of the CAR-NK-92 cells against EpCAM-positive colon cancer cells, were evaluated in vitro. Synergistic effects of regorafenib and CAR-NK-92 cells were analyzed in a mouse model with human colorectal cancer xenografts. The CAR-NK-92 cells can specifically recognize EpCAM-positive colorectal cancer cells and release cytokines, including IFN-γ, perforin, and granzyme B, and show specific cytotoxicity in vitro. The growth suppression efficacy of combination therapy with regorafenib and CAR-NK-92 cells on established EpCAM-positive tumor xenografts was more significant than that of monotherapy with CAR-NK-92 cells or regorafenib. Our results provided a novel strategy to treat colorectal cancer and enhance the therapeutic efficacy of CAR-modified immune effector cells for solid tumors. Qing Zhang, Haixu Zhang, Jiage Ding, Hongyan Liu, Huizhong Li, Hailong Li, Mengmeng Lu, Yangna Miao, Liantao Li, and Junnian Zheng Copyright © 2018 Qing Zhang et al. All rights reserved. On the Dual Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) in Human Malignancies Sun, 14 Oct 2018 00:00:00 +0000 Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a glycoprotein belonging to the carcinoembryonic antigen (CEA) family that is expressed on a wide variety of cells and holds a complex role in inflammation through its alternate splicing and generation of various isoforms, mediating intricate mechanisms of modulation and dysregulation. Initially regarded as a tumor suppressor as its expression shows considerable downregulation within the epithelia in the early phases of many solid cancers, CEACAM1 has been linked lately to the progression of malignancy and metastatic spread as various papers point to its role in tumor progression, angiogenesis, and invasion. We reviewed the literature and discussed the various expression patterns of CEACAM1 in different types of tumors, describing its structure and general biologic functions and emphasizing the most significant findings that link this molecule to poor prognosis. The importance of understanding the role of CEACAM1 in cell transformation stands not only in this adhesion molecule’s value as a prognostic factor but also in its promising premise as a potential new molecular target that could be exploited as a specific cancer therapy. Andreea Calinescu, Gabriela Turcu, Roxana I. Nedelcu, Alice Brinzea, Anastasia Hodorogea, Mihaela Antohe, Carmen Diaconu, Coralia Bleotu, Daniel Pirici, Lucia B. Jilaveanu, Daniela A. Ion, and Ioana A. Badarau Copyright © 2018 Andreea Calinescu et al. All rights reserved. Immunoinformatics Approach for Epitope-Based Peptide Vaccine Design and Active Site Prediction against Polyprotein of Emerging Oropouche Virus Mon, 08 Oct 2018 00:00:00 +0000 Oropouche virus (OROV) is an emerging pathogen which causes Oropouche fever and meningitis in humans. Several outbreaks of OROV in South America, especially in Brazil, have changed its status as an emerging disease, but no vaccine or specific drug target is available yet. Our approach was to identify the epitope-based vaccine candidates as well as the ligand-binding pockets through the use of immunoinformatics. In this report, we identified both T-cell and B-cell epitopes of the most antigenic OROV polyprotein with the potential to induce both humoral and cell-mediated immunity. Eighteen highly antigenic and immunogenic CD8+ T-cell epitopes were identified, including three 100% conserved epitopes (TSSWGCEEY, CSMCGLIHY, and LAIDTGCLY) as the potential vaccine candidates. The selected epitopes showed 95.77% coverage for the mixed Brazilian population. The docking simulation ensured the binding interaction with high affinity. A total of five highly conserved and nontoxic linear B-cell epitopes “NQKIDLSQL,” “HPLSTSQIGDRC,” “SHCNLEFTAITADKIMSL,” “PEKIPAKEGWLTFSKEHTSSW,” and “HHYKPTKNLPHVVPRYH” were selected as potential vaccine candidates. The predicted eight conformational B-cell epitopes represent the accessibility for the entered virus. In the posttherapeutic strategy, ten ligand-binding pockets were identified for effective inhibitor design against emerging OROV infection. Collectively, this research provides novel candidates for epitope-based peptide vaccine design against OROV. Utpal Kumar Adhikari, Mourad Tayebi, and M. Mizanur Rahman Copyright © 2018 Utpal Kumar Adhikari et al. All rights reserved. Acer palmatum thumb. Ethanol Extract Alleviates Interleukin-6-Induced Barrier Dysfunction and Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation Mon, 08 Oct 2018 00:00:00 +0000 Ulcerative colitis is one inflammatory bowel disease (IBD) and is caused by diverse factors, including the extent and duration of intestinal inflammation. We investigated the effect of Acer palmatum thumb. ethanol extract (KIOM-2015E) on the expression of tight junction proteins and the levels of inflammation in the cell model induced with interleukin-6- (IL-6-) and mouse model of dextran sodium sulfate (DSS) induced with acute colitis. KIOM-2015E (100 mg/kg) was orally administered once per day to BALB/C mice with colitis induced by administration of 5% DSS in drinking water. KIOM-2015E did not affect viability in Caco-2 cells. Also, KIOM-2015E repaired the IL-6-induced intestinal barrier dysfunction in Caco-2 cells. Furthermore, KIOM-2015E recovered the loss of body weight and the abnormally short colon lengths in the DSS-induced model of acute colitis. Moreover, KIOM-2015E significantly inhibited the decrease of zonula occluden-1 and occludin in colonic tissue relative to the DSS-treated control group. KIOM-2015E also significantly inhibited the expression of IL-6 and tumor necrosis factor-α in the level of serum relative to the control group. Collectively, these data suggest that KIOM-2015E protects colitis principally by improving intestinal barrier function and promoting anti-inflammatory responses. In turn, these effects inhibit macrophage infiltration into the colon and thus may be a candidate treatment for IBD. Kwang-Youn Kim, Tae-Woo Oh, Hyun Ju Do, Ju-Hye Yang, In Jun Yang, Yong Hyun Jeon, Young-Hoon Go, Soon-Cheol Ahn, Jin-Yeul Ma, and Kwang-Il Park Copyright © 2018 Kwang-Youn Kim et al. All rights reserved. Complement System as a Target for Therapies to Control Liver Regeneration/Damage in Acute Liver Failure Induced by Viral Hepatitis Mon, 08 Oct 2018 00:00:00 +0000 The complement system plays an important role in innate immunity inducing liver diseases as well as signaling immune cell activation in local inflammation regulating immunomodulatory effects such as liver damage and/or liver regeneration. Our aim is to evaluate the role of complement components in acute liver failure (ALF) caused by viral hepatitis, involving virus-induced ALF in human subjects using peripheral blood, samples of liver tissues, and ex vivo assays. Our findings displayed low levels of C3a in plasma samples with high frequency of C3a, C5a, and C5b/9 deposition in liver parenchyma. Meanwhile, laboratory assays using HepG2 (hepatocyte cell line) showed susceptibility to plasma samples from ALF patients impairing in vitro cell proliferation and an increase in apoptotic events submitting plasma samples to heat inactivation. In summary, our data suggest that the complement system may be involved in liver dysfunction in viral-induced acute liver failure cases using ex vivo assays. In extension to our findings, we provide insights into future studies using animal models for viral-induced ALF, as well as other associated soluble components, which need further investigation. Juliana Gil Melgaço, Carlos Eduardo Veloso, Lúcio Filgueiras Pacheco-Moreira, Claudia Lamarca Vitral, and Marcelo Alves Pinto Copyright © 2018 Juliana Gil Melgaço et al. All rights reserved. Downregulation of Interleukin- (IL-) 17 through Enhanced Indoleamine 2,3-Dioxygenase (IDO) Induction by Curcumin: A Potential Mechanism of Tolerance towards Helicobacter pylori Mon, 08 Oct 2018 00:00:00 +0000 The anti-inflammatory and antimicrobial properties of curcumin suggest its use as an anti-Helicobacter pylori (H. pylori) agent, but mechanisms underlying its helpful activity are still not clear. Indoleamine 2,3-dioxygenase (IDO) promotes the effector T cell apoptosis by catalyzing the rate-limiting first step in tryptophan catabolism, and its high expression in H. pylori-infected human gastric mucosa attenuates Th1 and Th17 immune response. The aim of this study was to investigate the role of curcumin in modulating the expression of IL-17 and IDO in H. pylori-infected human gastric mucosa. In an organ culture chamber, gastric biopsies from 35 patients were treated with and without 200 μM curcumin. In H. pylori-infected patients (), IL-17 was significantly lower, both in gastric biopsies () and culture supernatant () while IDO significantly increased () in curcumin-treated sample compared with untreated samples. In a subgroup of H. pylori-infected patients (), samples treated with curcumin in addition to IDO inhibitor 1-methyl-L-tryptophan (1-MT) showed a higher expression of IL-17 compared with untreated samples and curcumin-treated alone (). Curcumin downregulates IL-17 production through the induction of IDO in H. pylori-infected human gastric mucosa, suggesting its role in dampening H. pylori-induced immune-mediated inflammatory changes. Tiziana Larussa, Serena Gervasi, Rita Liparoti, Evelina Suraci, Raffaella Marasco, Maria Imeneo, and Francesco Luzza Copyright © 2018 Tiziana Larussa et al. All rights reserved. OK-432 Acts as Adjuvant to Modulate T Helper 2 Inflammatory Responses in a Murine Model of Asthma Mon, 08 Oct 2018 00:00:00 +0000 Enhanced type 2 helper T (Th2) cell responses to inhaled harmless allergens are strongly associated with the development of allergic diseases. Antigen formulated with an appropriate adjuvant can elicit suitable systemic immunity to protect individuals from disease. Although much has been learned about Th1-favored immunomodulation of OK-432, a streptococcal preparation with antineoplastic activity, little is known about its adjuvant effect for allergic diseases. Herein, we demonstrate that OK-432 acts as an adjuvant to favor a systemic Th1 polarization with an elevation in interferon- (IFN-) γ and ovalbumin- (OVA-) immunoglobulin (Ig) G2a. Prior vaccination with OK-432 formulated against OVA attenuated lung eosinophilic inflammation and Th2 cytokine responses that were caused by challenging with OVA through the airway. This vaccination with OK-432 augmented the ratios of IFN-γ/interleukin- (IL-) 4 cytokine and IgG2a/IgG1 antibody compared to the formulation with Th2 adjuvant aluminum hydroxide (Alum) or antigen only. The results obtained in this study lead us to propose a potential novel adjuvant for clinical use such as prophylactic vaccination for pathogens and immunotherapy in atopic diseases. Cheng-Jang Wu, Pin-Hsun Tseng, Cheng-Chi Chan, Sara Quon, Li-Chen Chen, and Ming-Ling Kuo Copyright © 2018 Cheng-Jang Wu et al. All rights reserved. Autoimmunity and Otolaryngology Diseases Thu, 04 Oct 2018 00:00:00 +0000 Massimo Ralli, Arianna Di Stadio, Armando De Virgilio, Adelchi Croce, and Marco de Vincentiis Copyright © 2018 Massimo Ralli et al. All rights reserved. Reduced Activity of HDAC3 and Increased Acetylation of Histones H3 in Peripheral Blood Mononuclear Cells of Patients with Rheumatoid Arthritis Wed, 03 Oct 2018 07:58:54 +0000 Aberrant histone acetylation and deacetylation are increasingly thought to play important roles in the pathogenesis of rheumatoid arthritis (RA). However, limited data from studies about the activity of histone deacetylases (HDACs) and histone acetyltransferase (HAT) in RA are controversial. Those conflicting results may be caused by sample size, medication, and age- and sex-matched controls. The aim of this study is to investigate the expression and activity of class I HDACs (1–3.8) and their effects on histone acetylation in peripheral blood mononuclear cells (PBMCs) from RA patients. The expression of class I HDACs in PBMCs from RA patients was decreased in both mRNA and protein levels in comparison with HCs. The nuclear HAT activities were dramatically increased. Further, we found HDAC3 activity to be the most significantly reduced in overall reduction of HDACs in the RA group. The extent of total histone H3, but not H4, acetylation in PBMCs from RA patients was increased compared to that in healthy controls (HCs) (). In RA PBMCs, the activity and expression of class I HDACs are decreased, which is accompanied with enhanced HAT activity. An altered balance between HDAC and HAT activity was found in RA PBMCs. Yan Li, Mi Zhou, Xiuying Lv, Lina Song, Di Zhang, Yan He, Mian Wang, Xue Zhao, Xiaoqing Yuan, Guixiu Shi, and Dashan Wang Copyright © 2018 Yan Li et al. All rights reserved. TNIP1 in Autoimmune Diseases: Regulation of Toll-like Receptor Signaling Wed, 03 Oct 2018 05:50:44 +0000 TNIP1 protein is increasingly being recognized as a key repressor of inflammatory signaling and a potential factor in multiple autoimmune diseases. In addition to earlier foundational reports of TNIP1 SNPs in human autoimmune diseases and TNIP1 protein-protein interaction with receptor regulating proteins, more recent studies have identified new potential interaction partners and signaling pathways likely modulated by TNIP1. Subdomains within the TNIP1 protein as well as how they interact with ubiquitin have not only been mapped but inflammatory cell- and tissue-specific consequences subsequent to their defective function are being recognized and related to human disease states such as lupus, scleroderma, and psoriasis. In this review, we emphasize receptor signaling complexes and regulation of cytoplasmic signaling steps downstream of TLR given their association with some of the same autoimmune diseases where TNIP1 has been implicated. TNIP1 dysfunction or deficiency may predispose healthy cells to the inflammatory response to otherwise innocuous TLR ligand exposure. The recognition of the anti-inflammatory roles of TNIP1 and improved integrated understanding of its physical and functional association with other signaling pathway proteins may position TNIP1 as a candidate target for the design and/or testing of next-generation anti-inflammatory therapeutics. Rambon Shamilov and Brian J. Aneskievich Copyright © 2018 Rambon Shamilov and Brian J. Aneskievich. All rights reserved. Function, Structure, and Transport Aspects of ZIP and ZnT Zinc Transporters in Immune Cells Tue, 02 Oct 2018 00:00:00 +0000 Zinc is an important trace metal in immune systems, and zinc transporters are involved in many immune responses. Recent advances have revealed the structural and biochemical bases for zinc transport across the cell membrane, with clinical implications for the regulation of zinc homeostasis in immune cells like dendritic cells, T cells, B cells, and mast cells. In this review, we discuss the function, structure, and transport aspects of two major mammalian zinc transporter types, importers and exporters. First, Zrt-/Irt-like proteins (ZIPs) mediate the zinc influx from the extracellular or luminal side into the cytoplasm. There are 14 ZIP family members in humans. They form a homo- or heterodimer with 8 transmembrane domains and extra-/intracellular domains of various lengths. Several ZIP members show specific extracellular domains composed of two subdomains, a helix-rich domain and proline-alanine-leucine (PAL) motif-containing domain. Second, ZnT (zinc transporter) was initially identified in early studies of zinc biology; it mediates zinc efflux as a counterpart of ZIPs in zinc homeostasis. Ten family members have been identified. They show a unique architecture characterized by a Y-shaped conformation and a large cytoplasmic domain. A precise, comprehensive understanding of the structures and transport mechanisms of ZIP and ZnT in combination with mice experiments would provide promising drug targets as well as a basis for identifying other transporters with therapeutic potential. Bum-Ho Bin, Juyeon Seo, and Sung Tae Kim Copyright © 2018 Bum-Ho Bin et al. All rights reserved. Lipid and Bile Acid Dysmetabolism in Crohn’s Disease Mon, 01 Oct 2018 00:00:00 +0000 Crohn’s disease is one of the systemic autoimmune diseases. It commonly affects the small intestine and colon but may involve any portion of the gastrointestinal tract from the mouth to the anus. The most affected area by Crohn’s disease is the distal part of the small intestine, in which the bile acid molecules are most efficiently reabsorbed. Bile acids form mixed micelles together with fatty acids, which function as a transport vehicle to deliver fatty acids to the apical membrane of enterocytes for absorption. Therefore, if the terminal ileum is impaired, bile acid malabsorption may occur, which may cause congenital diarrhoea in Crohn’s disease. Similarly, the impairment of the terminal ileum also induces fatty acid malabsorption, which may influence the role of fatty acids in Crohn’s disease. In contrast, a recent study reported that multidrug resistance protein 1 (MDR1) regulated effector T-cell function in the ileum from bile acid-driven oxidative stress and MDR1 loss of function in a subset of patients with Crohn’s disease. However, the role of consumption of fatty acids in Crohn’s disease remains to be fully elucidated. This review is aimed at providing an overview of some recent developments in research of Crohn’s disease from comprehensive perspective with a focus on the connection between disease location and behaviour, lipid diets, and bile acid malabsorption. Koji Uchiyama, Hisashi Kishi, Wataru Komatsu, Masanori Nagao, Shuji Ohhira, and Gen Kobashi Copyright © 2018 Koji Uchiyama et al. All rights reserved. Sevoflurane Inhibits the Th2 Response and NLRP3 Expression in Murine Allergic Airway Inflammation Sun, 30 Sep 2018 06:26:26 +0000 Background. Our colleagues have demonstrated an impressive therapeutic role of sevoflurane in a murine allergic airway inflammation model, but the mechanisms underlying this effect remain undefined. In this study, we tried to investigate the effect of sevoflurane on the resolution of allergic airway inflammation and to assess whether NLRP3 or the NLRP3 inflammasome is involved in this process. Methods. Female (C57BL/6) mice were sensitized and challenged with ovalbumin (OVA). Then, some of the mice received MCC950 (10 mg/kg; i.p.) or 3% sevoflurane. Total and differential inflammatory cell numbers, proinflammatory cytokines in bronchoalveolar lavage fluid (BALF), the peribronchial inflammation density, and mucus production were evaluated. In addition, we analysed the protein levels of NLRP3, the apoptosis-associated speck-like protein containing the caspase activation and recruitment domain (ASC), pro-caspase-1, and caspase-1 in the lung tissue. Results. We found that OVA-induced inflammatory cell recruitment to peribronchial regions, goblet cell hyperplasia, the serum levels of IgE, inflammatory cells, and the Th2 cytokine secretion in BALF was potently suppressed by sevoflurane with an efficacy comparable with that suppressed by MCC950 treatment. Furthermore, sevoflurane, similar to MCC950, clearly inhibited the OVA-induced activity of NLRP3 in the lungs. In addition, we found that OVA challenge failed to increase the expression of ASC, pro-caspase-1, and caspase-1 in the lungs and the levels of IL-18 and IL-1β in BALF. Conclusion. Taken together, our data showed that sevoflurane ameliorated allergic airway inflammation by inhibiting Th2 responses and NLRP3 expression. The NLRP3 independent of inflammasomes participated in the pathogenesis of allergic asthma in this model. Lixia Wang, Binshan Zha, Qiying Shen, Hongyun Zou, Cheng Cheng, Huimei Wu, and Rongyu Liu Copyright © 2018 Lixia Wang et al. All rights reserved. Murine DX5+NKT Cells Display Their Cytotoxic and Proapoptotic Potentials against Colitis-Inducing CD4+CD62Lhigh T Cells through Fas Ligand Sun, 30 Sep 2018 00:00:00 +0000 Introduction. It has been previously shown that immunoregulatory DX5+NKT cells are able to prevent colitis induced by CD4+CD62Lhigh T lymphocytes in a SCID mouse model. The aim of this study was to further investigate the underlying mechanism in vitro. Methods. CD4+CD62Lhigh and DX5+NKT cells from the spleen of Balb/c mice were isolated first by MACS, followed by FACS sorting and cocultured for up to 96 h. After polyclonal stimulation with anti-CD3, anti-CD28, and IL-2, proliferation of CD4+CD62Lhigh cells was assessed using a CFSE assay and activity of proapoptotic caspase-3 was determined by intracellular staining and flow cytometry. Extrinsic apoptotic pathway was blocked using an unconjugated antibody against FasL, and activation of caspase-3 was measured. Results. As previously shown in vivo, DX5+NKT cells inhibit proliferation of CD4+CD62Lhigh cells in vitro after 96 h coculture compared to a CD4+CD62Lhigh monoculture (proliferation index: 1.39 ± 0.07 vs. 1.76 ± 0.12; ). The antiproliferative effect of DX5+NKT cells was likely due to an induction of apoptosis in CD4+CD62Lhigh cells as evidenced by increased activation of the proapoptotic caspase-3 after 48 h (38 ± 3% vs. 28 ± 3%; ). Furthermore, DX5+NKT cells after polyclonal stimulation showed an upregulation of FasL on their cell surface (15 ± 2% vs. 2 ± 1%; ). Finally, FasL was blocked on DX5+NKT cells, and therefore, the extrinsic apoptotic pathway abrogated the activation of caspase-3 in CD4+CD62Lhigh cells. Conclusion. Collectively, these data confirmed that DX5+NKT cells inhibit proliferation of colitis-inducing CD4+CD62Lhigh cells by induction of apoptosis. Furthermore, DX5+NKT cells likely mediate their cytotoxic and proapoptotic potentials via FasL, confirming recent reports about iNKT cells. Further studies will be necessary to evaluate the therapeutical potential of these immunoregulatory cells in patients with colitis. Jens M. Werner, Michael Damian, Stefan A. Farkas, Hans J. Schlitt, Edward K. Geissler, and Matthias Hornung Copyright © 2018 Jens M. Werner et al. All rights reserved. Activation of PAR4 Upregulates p16 through Inhibition of DNMT1 and HDAC2 Expression via MAPK Signals in Esophageal Squamous Cell Carcinoma Cells Sun, 30 Sep 2018 00:00:00 +0000 A previous study showed that a downexpression of protease-activated receptor 4 (PAR4) is associated with the development of esophageal squamous cell carcinoma (ESCC). In this study, we explored the relationship between PAR4 activation and the expression of p16, and elucidated the underlying mechanisms in PAR4 inducing the tumor suppressor role in ESCC. ESCC cell lines (EC109 and TE-1) were treated with PAR4-activating peptide (PAR4-AP). Immunohistochemistry for DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) was performed in 26 cases of ESCC tissues. We found that DNMT1 and HDAC2 immunoreactivities in ESCC were significantly higher than those in adjacent noncancerous tissues. PAR4 activation could suppress DNMT1 and HDAC2, as well as increase p16 expressions, whereas silencing PAR4 dramatically increased HDAC2 and DNMT1, as well as reduced p16 expressions. Importantly, the chromatin immunoprecipitation-PCR (ChIP-PCR) data indicated that treatment of ESCC cells with PAR4-AP remarkably suppressed DNMT1 and HDAC2 enrichments on the p16 promoter. Furthermore, we demonstrated that activation of PAR4 resulted in an increase of p38/ERK phosphorylation and activators for p38/ERK enhanced the effect of PAR4 activation on HDAC2, DNMT1, and p16 expressions, whereas p38/ERK inhibitors reversed these effects. Moreover, we found that activation of PAR4 in ESCC cells significantly inhibited cell proliferation and induced apoptosis. These findings suggest that PAR4 plays a potential tumor suppressor role in ESCC cells and represents a potential therapeutic target of this disease. Ming Wang, Shuhong An, Diyi Wang, Haizhen Ji, Xingjing Guo, and Zhaojin Wang Copyright © 2018 Ming Wang et al. All rights reserved. The Application of Nanoparticle-Based Drug Delivery Systems in Checkpoint Blockade Cancer Immunotherapy Sun, 30 Sep 2018 00:00:00 +0000 Tumor is the most serious threat to human beings. Although war against cancer has been launched over forty years, cancer treatment is still far away from being satisfactory. Immunotherapy, especially checkpoint blockade immunotherapy, is a rising star that shows a promising future. To fulfill the requirement of depleting primary tumor and inhibiting tumor metastasis and recurrence, many researchers combined checkpoint blockade immunotherapy with other treatment strategies to extend the treatment outcome. Photodynamic therapy could induce immunogenic cell death, and checkpoint blockade could further accelerate the immunity; therefore, combining these two strategies publishes many papers. Additionally, photothermal therapy and immunotherapy were also utilized for combining with checkpoint blockade, which were also reviewed in this paper. Furthermore, antibodies, siRNA, and small molecule inhibitors are developed to block the checkpoint; therefore, we categorized the papers into three sections, combination nanoparticles with checkpoint blockade antibody, combination nanoparticles with checkpoint blockade siRNA, and combination nanoparticles with small molecule checkpoint inhibitors, and related researches were summarized. In conclusion, the combination nanoparticle with checkpoint blockade cancer immunity is a promising direction that may fulfill the requirement of cancer treatment. Huan Zhao, Yuanqi Li, Dan Wei, and Hongrong Luo Copyright © 2018 Huan Zhao et al. All rights reserved. Combined Treatment with Zinc Aspartate and Intravenous Immunoglobulins (IVIGs) Ameliorates Experimental Autoimmune Encephalomyelitis (EAE) Wed, 26 Sep 2018 07:49:49 +0000 Intravenous immunoglobulins (IVIGs) are widely used in replacement therapy of primary and secondary immunodeficiency disorders and in approved autoimmune indications. In addition, IVIG application is used off-label for treatment of other autoimmune diseases, e.g., multiple sclerosis (MS), an inflammatory autoimmune disorder with a clear T cell-mediated immune pathogenesis. The trace element zinc is shown to play a regulatory role in the maintenance of immune functions. Changes of zinc homeostasis affect both the innate and the adaptive immune system. On one hand, therapeutic zinc supplementation can normalize impaired immune functions due to zinc deficiency. On the other hand, therapeutic zinc supplementation is under consideration as a possible option to treat T cell-mediated autoimmune diseases. The aim of the present study was to investigate the influence of IVIG (Octagam®), zinc aspartate (Unizink®), and the combined application of both preparations in the experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Therapeutic intraperitoneal application of zinc aspartate significantly diminished clinical signs during the relapsing-remitting phase of EAE in SJL/J mice. In contrast, IVIG given in a therapeutic manner did not influence the course of EAE. Interestingly, the combined application of both, IVIG and zinc aspartate, significantly reduced the severity of the disease during the acute and the relapsing-remitting phase of the EAE. Our data suggest that the combination of IVIG and zinc aspartate may have beneficial effects in autoimmune diseases, like MS. Further studies should verify the benefit of a controlled immunosuppressive therapy with IVIG and zinc for such diseases. Diana Straubel, Anja Thielitz, Annegret Reinhold, Kurt Grüngreiff, and Dirk Reinhold Copyright © 2018 Diana Straubel et al. All rights reserved. Update on Vertigo in Autoimmune Disorders, from Diagnosis to Treatment Wed, 26 Sep 2018 00:00:00 +0000 The prevalence of autoimmune diseases has been increasing over the last 20 years. The clinical presentation of this large and heterogeneous group of disorders depends on whether the involvement is organ-specific or non-organ-specific. Dizziness, vertigo, and disequilibrium are common symptoms reported by patients with vestibulocochlear involvement. The association of vertigo and autoimmune diseases has been largely documented, suggesting that autoimmune disorders could be overrepresented in patients with vertigo in comparison to the general population. The aim of this review is to present the recent literature findings in the field of autoimmune-mediated diseases with cochleovestibular involvement, focusing on the clinical presentation, diagnosis, and treatment of immune-mediated inner ear diseases including autoimmune inner ear disease (AIED), Meniere’s disease, and bilateral vestibulopathy, as well as of systemic autoimmune diseases with audiovestibular disorders, namely, Behçet’s disease, Cogan’s syndrome, sarcoidosis, autoimmune thyroid disease, Vogt-Koyanagi-Harada syndrome, relapsing polychondritis, systemic lupus erythematosus, antiphospholipid syndrome, IgG4-related disease, and ANCA-associated vasculitides. Laura Girasoli, Diego Cazzador, Roberto Padoan, Ennio Nardello, Mara Felicetti, Elisabetta Zanoletti, Franco Schiavon, and Roberto Bovo Copyright © 2018 Laura Girasoli et al. All rights reserved. Potential Antinociceptive Effects of Chinese Propolis and Identification on Its Active Compounds Wed, 26 Sep 2018 00:00:00 +0000 Propolis is an important bee product which has been applied to the treatment of several diseases. The aim of this study was to understand the material basis of Chinese propolis on pain relief; different Chinese propolis fractions (40W, 40E, 70E, and 95E raw propolis extracted followed by 40%, 70%, or 95% ethanol) were prepared, and their antinociceptive effects were evaluated. By analyzing using UPLC-Q-TOF-MS, we showed that 40W was rich in phenolic acids, like caffeic acid, while 40E, 70E, and 95E have relatively high levels in flavonoids, like galangin, pinocembrin, and chrysin. Notably, chrysin amounts in 70E and 95E are much higher than those in 40E fraction. Antinociceptive effects by these propolis fractions were evaluated in mice using acetic acid-induced writhing test, hot plate test, and tail immersion test, respectively. We noticed that only 40E fraction showed a significant reduction on acetic acid-induced writhing test. Importantly, in the hot plate test, all groups showed their effectiveness, except for the 70E group. We also noticed that 40W, 40E, and 95E administration caused an increase in the tail withdrawal latency of the mice. These data suggested that the different antinociceptive effects of different fractions from Chinese propolis extracts are directly link to their flavonoid composition. Liping Sun, Lei Liao, and Bei Wang Copyright © 2018 Liping Sun et al. All rights reserved. Biological Properties and the Role of IL-25 in Disease Pathogenesis Sun, 23 Sep 2018 07:25:37 +0000 The interleukin- (IL-) 17 superfamily, a T cell-derived cytokine, consists of 6 ligands (IL-17A–IL-17F) and 5 receptors (IL-17RA–IL-17RE). IL-17A, a prototype member of this family, is involved in the pathogenesis of allergies, autoimmune diseases, allograft transplantations, and malignancies. By contrast, IL-17B is reported to be closely related to certain diseases, particularly tumors such as breast cancer, gastric cancer, and pancreatic cancer. Recently, the biological function of IL-17E (also called IL-25) in disease, particularly airway diseases, has attracted the attention of researchers. However, studies on IL-25 are scant. In this review, we detail the structural characteristics, expression patterns, responder cells, biological properties, and role of IL-25 in disease pathogenesis. Yuwan Liu, Zewei Shao, Guoqiang Shangguan, Qingli Bie, and Bin Zhang Copyright © 2018 Yuwan Liu et al. All rights reserved. The Fate of Allogeneic Pancreatic Islets following Intraportal Transplantation: Challenges and Solutions Sun, 23 Sep 2018 00:00:00 +0000 Pancreatic islet transplantation as a therapeutic option for type 1 diabetes mellitus is gaining widespread attention because this approach can restore physiological insulin secretion, minimize the risk of hypoglycemic unawareness, and reduce the risk of death due to severe hypoglycemia. However, there are many obstacles contributing to the early mass loss of the islets and progressive islet loss in the late stages of clinical islet transplantation, including hypoxia injury, instant blood-mediated inflammatory reactions, inflammatory cytokines, immune rejection, metabolic exhaustion, and immunosuppression-related toxicity that is detrimental to the islet allograft. Here, we discuss the fate of intrahepatic islets infused through the portal vein and propose potential interventions to promote islet allograft survival and improve long-term graft function. Xinyu Li, Qiang Meng, and Lei Zhang Copyright © 2018 Xinyu Li et al. All rights reserved. Differentiation and Function of T Cell Subsets in Infectious Diseases Sun, 23 Sep 2018 00:00:00 +0000 Yuejin Liang, Xiaojun Chen, Jinling Chen, and Fengliang Liu Copyright © 2018 Yuejin Liang et al. All rights reserved. Silicone-Induced Granuloma of Breast Implant Capsule (SIGBIC): Histopathology and Radiological Correlation Thu, 20 Sep 2018 00:00:00 +0000 Currently, attention has been given to complications related to breast implants, especially due to the presence of anaplastic large cell lymphoma (ALCL) related to silicone implants. Many manuscripts attempt to associate silicone presence with clinical complaints reported by patients, while others try to demonstrate the mechanisms of silicone bleeding by permeability loss of breast implant surfaces. There also are reports of foreign body type reactions from implant fibrous capsule to silicone corpuscles. However, there seems to be no study that correlates the clinical, radiological, and histological correlations of these lesions. The objective of this review is to correlate radiological findings of silicone-induced granuloma of breast implant capsule (SIGBIC) from breast MRI (BMRI) scans and complementary findings of ultrasound (US) and positron emission tomography (PET) scan, and its histology originated from surgical breast implant capsulectomy. To make this correlation possible, we divided SIGBIC into three radiological findings: (1) intracapsular SIGBIC, (2) SIGBIC with extracapsular extension, and (3) mixed SIGBIC associated with seroma. Our experience demonstrates histological-radiological correlation in SIGBIC diagnosis. Knowledge of these findings may demonstrate its real importance in terms of public health and patient management. We believe that SIGBIC is currently underdiagnosed by lack of training, guidance, and management in our clinical practice. Eduardo de Faria Castro Fleury, Gabriel Salum D’Alessandro, and Sheila Cristina Lordelo Wludarski Copyright © 2018 Eduardo de Faria Castro Fleury et al. All rights reserved. Beneficial Effects of Poplar Buds on Hyperglycemia, Dyslipidemia, Oxidative Stress, and Inflammation in Streptozotocin-Induced Type-2 Diabetes Tue, 18 Sep 2018 03:40:21 +0000 The effects of propolis on blood glucose regulation and the alleviation of various complications caused by diabetes have been widely studied. The main source of propolis in the northern temperate zone is poplar buds. However, there is limited research on the antidiabetic activity of poplar buds. In order to evaluate the effect of poplar buds on type-2 diabetes, crude extract and 50% fraction of poplar buds were used to feed streptozotocin-induced type-2 diabetic mice. The results showed that 50% fraction could increase insulin sensitivity and reduce insulin resistance, as well as decrease the levels of fasting blood glucose, glycated hemoglobin, and glycosylated serum proteins in diabetic mice. Compared with the model control group, the 50% fraction-treated group showed significant decreases of malondialdehyde (MDA) and increases of superoxide dismutase (SOD) in serum and liver homogenate. Moreover, 50% fraction could significantly decrease total cholesterol (TC), alleviate abnormal lipid metabolism, and enhance antioxidant capacity in the serum. For inflammatory factors, feeding of 50% fraction could also reduce the levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), and cyclooxygenase-2 (COX-2) in liver homogenate. Taken together, our results suggest that crude extract and 50% fraction of poplar buds, particularly the latter, can decrease blood glucose levels and insulin resistance, and 50% fraction can significantly relieve dyslipidemia, oxidative stress, and inflammation caused by type-2 diabetes. Shiqin Peng, Ping Wei, Qun Lu, Rui Liu, Yue Ding, and Jiuliang Zhang Copyright © 2018 Shiqin Peng et al. All rights reserved. Viral and Nonviral Engineering of Natural Killer Cells as Emerging Adoptive Cancer Immunotherapies Mon, 17 Sep 2018 06:56:56 +0000 Natural killer (NK) cells are powerful immune effectors whose antitumor activity is regulated through a sophisticated network of activating and inhibitory receptors. As effectors of cancer immunotherapy, NK cells are attractive as they do not attack healthy self-tissues nor do they induce T cell-driven inflammatory cytokine storm, enabling their use as allogeneic adoptive cellular therapies. Clinical responses to adoptive NK-based immunotherapy have been thwarted, however, by the profound immunosuppression induced by the tumor microenvironment, particularly severe in the context of solid tumors. In addition, the short postinfusion persistence of NK cells in vivo has limited their clinical efficacy. Enhancing the antitumor immunity of NK cells through genetic engineering has been fueled by the promise that impaired cytotoxic functionality can be restored or augmented with the use of synthetic genetic approaches. Alongside expressing chimeric antigen receptors to overcome immune escape by cancer cells, enhance their recognition, and mediate their killing, NK cells have been genetically modified to enhance their persistence in vivo by the expression of cytokines such as IL-15, avoid functional and metabolic tumor microenvironment suppression, or improve their homing ability, enabling enhanced targeting of solid tumors. However, NK cells are notoriously adverse to endogenous gene uptake, resulting in low gene uptake and transgene expression with many vector systems. Though viral vectors have achieved the highest gene transfer efficiencies with NK cells, nonviral vectors and gene transfer approaches—electroporation, lipofection, nanoparticles, and trogocytosis—are emerging. And while the use of NK cell lines has achieved improved gene transfer efficiencies particularly with viral vectors, challenges with primary NK cells remain. Here, we discuss the genetic engineering of NK cells as they relate to NK immunobiology within the context of cancer immunotherapy, highlighting the most recent breakthroughs in viral vectors and nonviral approaches aimed at genetic reprogramming of NK cells for improved adoptive immunotherapy of cancer, and, finally, address their clinical status. Sandro Matosevic Copyright © 2018 Sandro Matosevic. All rights reserved. Evaluation of Soluble CD48 Levels in Patients with Allergic and Nonallergic Asthma in Relation to Markers of Type 2 and Non-Type 2 Immunity: An Observational Study Sun, 16 Sep 2018 00:00:00 +0000 CD48 is a costimulatory receptor associated with human asthma. We aimed to assess the significance of the soluble form of CD48 (sCD48) in allergic and nonallergic asthma. Volunteer patients completed an asthma and allergy questionnaire, spirometry, methacholine challenge test, a common allergen skin prick test, and a complete blood count. sCD48, IgE, IL5, IL17A, IL33, and IFNγ were quantitated in serum by ELISA. Asthma was defined as positive methacholine challenge test or a 15% increase in FEV1 post bronchodilator in symptomatic individuals. Allergy was defined as positive skin test or IgE levels > 200 IU/l in symptomatic individuals. 137 individuals participated in the study: 82 (60%) were diagnosed with asthma of which 53 (64%) was allergic asthma. sCD48 levels were significantly elevated in patients with nonallergic asthma compared to control and to the allergic asthma cohort (median (IQR) pg/ml, 1487 (1338–1758) vs. 1308 (1070–1581), , and 1336 (1129–1591), , respectively). IL17A, IL33, and IFNγ levels were significantly elevated in allergic and nonallergic asthmatics when compared to control. No correlation was found between sCD48 level and other disease markers. sCD48 is elevated in nonallergic asthma. Additional studies are required for understanding the role of sCD48 in airway disease. Oded Breuer, Roopesh Singh Gangwar, Mansour Seaf, Ahlam Barhoum, Eitan Kerem, and Francesca Levi-Schaffer Copyright © 2018 Oded Breuer et al. All rights reserved. Carbamazepine-Mediated Adverse Drug Reactions: CBZ-10,11-epoxide but Not Carbamazepine Induces the Alteration of Peptides Presented by HLA-B15:02 Thu, 13 Sep 2018 06:20:52 +0000 Among patients treated with the anticonvulsive and psychotropic drug carbamazepine (CBZ), approximately 10% develop severe and life-threatening adverse drug reactions. These immunological conditions are resolved upon withdrawal of the medicament, suggesting that the drug does not manifest in the body in long term. The HLA allele B15:02 has been described to be a genomic biomarker for CBZ-mediated immune reactions. It is not well understood if the immune reactions are triggered by the original drug or by its metabolite carbamazepine-10,11-epoxide (EPX) and how the interaction between the drug and the distinct HLA molecule occurs. Genetically engineered human B-lymphoblastoid cells expressing soluble HLA-B15:02 molecules were treated with the drug or its metabolite. Functional pHLA complexes were purified; peptides were eluted and sequenced. Applying mass spectrometric analysis, CBZ and EPX were monitored by analyzing the heavy chain and peptide fractions separately for the presence of the drug. This method enabled the detection of the drug in a biological situation post-pHLA assembly. Both drugs were bound to the HLA-B15:02 heavy chain; however, solely EPX altered the peptide-binding motif of B15:02-restricted peptides. This observation could be explained through structural insight; EPX binds to the peptide-binding region and alters the biochemical features of the F pocket and thus the peptide motif. Understanding the nature of immunogenic interactions between CBZ and EPX with the HLA immune complex will guide towards effective and safe medications. Gwendolin S. Simper, Gia-Gia T. Hò, Alexander A. Celik, Trevor Huyton, Joachim Kuhn, Heike Kunze-Schumacher, Rainer Blasczyk, and Christina Bade-Döding Copyright © 2018 Gwendolin S. Simper et al. All rights reserved. Cancer Immunotherapy: Priming the Host Immune Response with Live Attenuated Salmonella enterica Thu, 13 Sep 2018 06:14:02 +0000 In recent years, cancer immunotherapy has undergone great advances because of our understanding of the immune response and the mechanisms through which tumor cells evade it. A century after the first immunotherapy attempt based on bacterial products described by William Coley, the use of live attenuated bacterial vectors has become a promising alternative in the fight against cancer. This review describes the role of live attenuated Salmonella enterica as an oncolytic and immunotherapeutic agent, due to its high affinity for tumor tissue and its ability to activate innate and adaptive antitumor immune response. Furthermore, its potential use as delivery system of tumor antigens and immunomodulatory molecules that induce tumor regression is also reviewed. Marco Antonio Hernández-Luna and Rosendo Luria-Pérez Copyright © 2018 Marco Antonio Hernández-Luna and Rosendo Luria-Pérez. All rights reserved. Inflammatory-Driven Angiogenesis in Bone Augmentation with Bovine Hydroxyapatite, B-Tricalcium Phosphate, and Bioglasses: A Comparative Study Wed, 12 Sep 2018 06:30:44 +0000 Introduction. The clinical use of bioactive materials for bone augmentation has remained a challenge because of predictability and effectiveness concerns, as well as increased costs. The purpose of this study was to analyse the ability to integrate bone substitutes by evaluating the immunohistochemical expression of the platelet endothelial cell adhesion molecules, vascular endothelial growth factor, collagen IV, laminin, and osteonectin, in the vicinity of bone grafts, enabling tissue revascularization and appearance of bone lamellae. There is a lack of in vivo studies of inflammatory-driven angiogenesis in bone engineering using various grafts. Methods. The study was performed in animal experimental model on the standardized monocortical defects in the tibia of 20 New Zealand rabbits. The defects were augmented with three types of bone substituents. The used bone substituents were beta-tricalcium phosphate, bovine hydroxyapatite, and bioactive glasses. After a period of 6 months, bone fragments were harvested for histopathologic examination. Endothelial cell analysis was done by analysing vascularization with PECAM/CD31 and VEGF and fibrosis with collagen IV, laminin, and osteonectin stains. Statistical analysis was realized by descriptive analysis which was completed with the kurtosis and skewness as well as the Kruskal-Wallis and Mann-Whitney statistical tests. Results. The discoveries show that the amount of bone that is formed around beta-tricalcium phosphate and bovine hydroxyapatite is clearly superior to the bioactive glasses. Both the lumen diameter and the number of vessels were slightly increased in favor of beta-tricalcium phosphate. Conclusion. We can conclude that bone substitutes as bovine bone and beta-tricalcium phosphate have significant increased angiogenesis (and subsequent improved osteogenesis) compared to the bioactive glass. In our study, significant angiogenesis is linked with a greater tissue formation, indicating that in bone engineering with the allografts we used, inflammation has more benefic effects, the catabolic action being exceeded by the tissue formation. Vlad M. Anghelescu, Ioana Neculae, Octavian Dincă, Cristian Vlădan, Claudiu Socoliuc, Mirela Cioplea, Luciana Nichita, Cristiana Popp, Sabina Zurac, and Alexandru Bucur Copyright © 2018 Vlad M. Anghelescu et al. All rights reserved.