Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Recent Advances in Assessing Immunogenicity of Therapeutic Proteins: Impact on Biotherapeutic Development Tue, 23 Aug 2016 09:07:27 +0000 Yanmei Lu, Leslie A. Khawli, Shobha Purushothama, Frank-Peter Theil, and Michael A. Partridge Copyright © 2016 Yanmei Lu et al. All rights reserved. Follicular Helper T Cells in Systemic Lupus Erythematosus: Why Should They Be Considered as Interesting Therapeutic Targets? Mon, 22 Aug 2016 13:23:59 +0000 Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by B cell hyperactivity leading to the production of autoantibodies, some of which having a deleterious effect. Reducing autoantibody production thus represents a way of controlling lupus pathogenesis, and a better understanding of the molecular and cellular factors involved in the differentiation of B cells into plasma cells could allow identifying new therapeutic targets. Follicular helper T cells () represent a distinct subset of CD4+ T cells specialized in providing help to B cells. They are required for the formation of germinal centers and the generation of long-lived serological memory and, as such, are suspected to play a central role in SLE. Recent advances in the field of biology have allowed the identification of important molecular factors involved in differentiation, regulation, and function. Interestingly, some of these -related molecules have been described to be dysregulated in lupus patients. In the present review, we give an overview of the aberrant expression and/or function of such key players in lupus, and we highlight their potential as therapeutic targets. Matthieu Sawaf, Hélène Dumortier, and Fanny Monneaux Copyright © 2016 Matthieu Sawaf et al. All rights reserved. Schistosome-Derived Molecules as Modulating Actors of the Immune System and Promising Candidates to Treat Autoimmune and Inflammatory Diseases Sun, 21 Aug 2016 08:52:52 +0000 It is long known that some parasite infections are able to modulate specific pathways of host’s metabolism and immune responses. This modulation is not only important in order to understand the host-pathogen interactions and to develop treatments against the parasites themselves but also important in the development of treatments against autoimmune and inflammatory diseases. Throughout the life cycle of schistosomes the mammalian hosts are exposed to several biomolecules that are excreted/secreted from the parasite infective stage, named cercariae, from their tegument, present in adult and larval stages, and finally from their eggs. These molecules can induce the activation and modulation of innate and adaptive responses as well as enabling the evasion of the parasite from host defense mechanisms. Immunomodulatory effects of helminth infections and egg molecules are clear, as well as their ability to downregulate proinflammatory cytokines, upregulate anti-inflammatory cytokines, and drive a Th2 type of immune response. We believe that schistosomes can be used as a model to understand the potential applications of helminths and helminth-derived molecules against autoimmune and inflammatory diseases. Luis Janssen, Gisele Lorranna Silva Santos, Herick Sampaio Muller, Anderson Rodrigues Araújo Vieira, Tatiana Amabile de Campos, and Vicente de Paulo Martins Copyright © 2016 Luis Janssen et al. All rights reserved. Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model Thu, 18 Aug 2016 16:31:45 +0000 Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p.) for 14 days before common carotid artery occlusion (CCAO) in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and a 2.5-fold increase in zinc levels was detected after 7 days. Although CXCL12 and FGF2 protein levels were significantly increased, the long-term memory was impaired 12 days after reperfusion in the Zn+CCAO group. Our data suggest that the chronic administration of zinc at tolerable doses causes nitrosative stress, toxic zinc accumulation, and neuroinflammation, which might account for the neuronal death and cerebral dysfunction after CCAO. Constantino Tomas-Sanchez, Victor Manuel Blanco-Alvarez, Juan Antonio Gonzalez-Barrios, Daniel Martinez-Fong, Guadalupe Garcia-Robles, Guadalupe Soto-Rodriguez, Eduardo Brambila, Maricela Torres-Soto, Alejandro Gonzalez-Vazquez, Ana Karina Aguilar-Peralta, José-Luis Garate-Morales, Luis-Angel Aguilar-Carrasco, Daniel I. Limón, Jorge Cebada, and Bertha Alicia Leon-Chavez Copyright © 2016 Constantino Tomas-Sanchez et al. All rights reserved. Nerve Growth Factor Regulation by TNF-α and IL-1β in Synovial Macrophages and Fibroblasts in Osteoarthritic Mice Thu, 18 Aug 2016 07:01:09 +0000 To investigate the role of macrophages as a regulator and producer of nerve growth factor (NGF) in the synovial tissue (ST) of osteoarthritis (OA) joints, the gene expression profiles of several inflammatory cytokines in the ST, including synovial macrophages and fibroblasts, of OA mice (STR/Ort) were characterized. Specifically, real-time polymerase chain reaction analysis was used to evaluate the expression of tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and NGF in CD11b+ and CD11b– cells isolated from the ST of a murine OA model. The effects of TNF-α, IL-1β, and IL-6 on the expression of NGF in cultured synovial cells were also examined. The expression of TNF-α, IL-1β, IL-6, and NGF in the ST of STR/Ort was higher than that in C57/BL6J mice. Compared to the CD11b– cell fraction, higher expression levels of TNF-α, IL-1β, and IL-6 were detected in the CD11b+ cell fraction, whereas no differences in the expression of NGF were detected between the two cell fractions. Notably, TNF-α upregulated NGF expression in synovial fibroblasts and macrophages and IL-1β upregulated NGF expression in synovial fibroblasts. IL-1β and TNF-α may regulate NGF signaling in OA joints and be suitable therapeutic targets for treating OA pain. Shotaro Takano, Kentaro Uchida, Masayuki Miyagi, Gen Inoue, Hisako Fujimaki, Jun Aikawa, Dai Iwase, Atsushi Minatani, Kazuya Iwabuchi, and Masashi Takaso Copyright © 2016 Shotaro Takano et al. All rights reserved. Effect of HSV-IL12 Loaded Tumor Cell-Based Vaccination in a Mouse Model of High-Grade Neuroblastoma Wed, 17 Aug 2016 12:55:37 +0000 We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor. The syngeneic but unrelated H6 hepatocellular tumor cell line grew unrestricted in vaccinated mice, indicative of vaccine-mediated specific immunity to Neuro 2a tumors. Longitudinal analyses of tumor-infiltrating lymphocytes revealed a primary adaptive T cell response involving both CD4+ and CD8+ T cell subsets. Spleen cell mononuclear preparations from vaccinated mice were significantly more cytotoxic to Neuro 2a tumor cells than spleen cells from control mice as demonstrated in a four-hour in vitro cytotoxicity assay. These results strongly suggest that an irradiated whole cell tumor vaccine incorporating IL-12-expressing M002 HSV can produce a durable, specific immunization in a murine model of intracranial tumor. David F. Bauer, Larisa Pereboeva, G. Yancey Gillespie, Gretchen A. Cloud, Osama Elzafarany, Catherine Langford, James M. Markert, and Lawrence S. Lamb Jr. Copyright © 2016 David F. Bauer et al. All rights reserved. Soluble HLA-G and HLA-E Levels in Bone Marrow Plasma Samples Are Related to Disease Stage in Neuroblastoma Patients Tue, 16 Aug 2016 16:13:21 +0000 The role of nonclassical HLA-class Ib molecules HLA-G and HLA-E in the progression of Neuroblastoma (NB), the most common pediatric extracranial solid tumor, has been characterized in the last years. Since BM infiltration by NB cells is an adverse prognostic factor, we have here analyzed for the first time the concentration of soluble (s)HLA-G and HLA-E in bone marrow (BM) plasma samples from NB patients at diagnosis and healthy donors. sHLA-G and sHLA-E are present in BM plasma samples, and their levels were similar between NB patients and controls, thus suggesting that these molecules are physiologically released by resident or stromal BM cell populations. This hypothesis was supported by the finding that sHLA-G and sHLA-E levels did not correlate with BM infiltration and other adverse prognostic factors (MYCN amplification and age at diagnosis). In contrast, BM plasma levels of both molecules were higher in patients with metastatic disease than in patients with localized NB, thus suggesting that concentration of these molecules might be correlated with disease progression. The prognostic role of sHLA-G and sHLA-E concentration in the BM plasma for NB patients will be evaluated in future studies, by analyzing the clinical outcome of the same NB patients at follow-up. Fabio Morandi, Sarah Pozzi, Barbara Carlini, Loredana Amoroso, Vito Pistoia, and Maria Valeria Corrias Copyright © 2016 Fabio Morandi et al. All rights reserved. Delta Procalcitonin Is a Better Indicator of Infection Than Absolute Procalcitonin Values in Critically Ill Patients: A Prospective Observational Study Mon, 15 Aug 2016 15:53:09 +0000 Purpose. To investigate whether absolute value of procalcitonin (PCT) or the change (delta-PCT) is better indicator of infection in intensive care patients. Materials and Methods. Post hoc analysis of a prospective observational study. Patients with suspected new-onset infection were included in whom PCT, C-reactive protein (CRP), temperature, and leukocyte (WBC) values were measured on inclusion () and data were also available from the previous day (). Based on clinical and microbiological data, patients were grouped post hoc into infection- (I-) and noninfection- (NI-) groups. Results. Of the 114 patients, 85 (75%) had proven infection. PCT levels were similar at : I-group (median [interquartile range]): 1.04 [0.40–3.57] versus NI-group: 0.53 [0.16–1.68], . By PCT levels were significantly higher in the I-group: 4.62 [1.91–12.62] versus 1.12 [0.30–1.66], . The area under the curve to predict infection for absolute values of PCT was 0.64 [95% CI = 0.52–0.76], ; for percentage change: 0.77 [0.66–0.87], ; and for delta-PCT: 0.85 [0.78–0.92], . The optimal cut-off value for delta-PCT to indicate infection was 0.76 ng/mL (sensitivity 80 [70–88]%, specificity 86 [68-96]%). Neither absolute values nor changes in CRP, temperature, or WBC could predict infection. Conclusions. Our results suggest that delta-PCT values are superior to absolute values in indicating infection in intensive care patients. This trial is registered with identifier: NCT02311816. Domonkos Trásy, Krisztián Tánczos, Márton Németh, Péter Hankovszky, András Lovas, András Mikor, Edit Hajdú, Angelika Osztroluczki, János Fazakas, and Zsolt Molnár Copyright © 2016 Domonkos Trásy et al. All rights reserved. In Vitro Effects of Some Botanicals with Anti-Inflammatory and Antitoxic Activity Mon, 15 Aug 2016 09:38:58 +0000 Several extrinsic factors, like drugs and chemicals, can foster autoimmunity. Tetracyclines, in particular oxytetracycline (OTC), appear to correlate with the emergence of immune-mediated diseases. Accumulation of OTC, the elective drug for gastrointestinal and respiratory infectious disease treatment in broiler chickens, was reported in chicken edible tissues and could represent a potential risk for pets and humans that could assume this antibiotic as residue in meat or in meat-derived byproducts. We investigated the in vitro anti-inflammatory properties of a pool of thirteen botanicals as a part of a nutraceutical diet, with proven immunomodulatory activity. In addition, we evaluated the effect of such botanicals in contrasting the in vitro proinflammatory toxicity of OTC. Our results showed a significant reduction in interferon- (INF-) γ production by human and canine lymphocytes in presence of botanicals (). Increased INF-γ production, dependent on 24-hour OTC-incubation of T lymphocytes, was significantly reduced by the coincubation with Haematococcus pluvialis, with Glycine max, and with the mix of all botanicals (). In conclusion, the use of these botanicals was shown to be able to contrast OTC-toxicity and could represent a new approach for the development of functional foods useful to enhance the standard pharmacological treatment in infections as well as in preventing or reducing the emergence of inflammatory diseases. Gianandrea Guidetti, Alessandro Di Cerbo, Angela Giovazzino, Valentina Rubino, Anna Teresa Palatucci, Sara Centenaro, Elena Fraccaroli, Laura Cortese, Maria Grazia Bonomo, Giuseppina Ruggiero, Sergio Canello, and Giuseppe Terrazzano Copyright © 2016 Gianandrea Guidetti et al. All rights reserved. T Helper Cell Subsets in Clinical Manifestations of Psoriasis Wed, 10 Aug 2016 14:26:26 +0000 Psoriasis is a chronic inflammatory skin disease, which is associated with systemic inflammation and comorbidities, such as psoriatic arthritis and cardiovascular diseases. The autoimmune nature of psoriasis has been established only recently, conferring a central role to epidermal CD8 T cells recognizing self-epitopes in the initial phase of the disease. Different subsets of helper cells have also been reported as key players in the psoriasis pathogenesis. Here, we reviewed the knowledge on the role of each subset in the psoriatic cascade and in the different clinical manifestations of the disease. We will discuss the role of Th1 and Th17 cells in the initiation and in the amplification phase of cutaneous inflammation. Moreover, we will discuss the recently proposed role of tissue resident Th22 cells in disease memory in sites of recurrent psoriasis and the possible involvement of Th9 cells. Finally, we will discuss the hypothesis of a link between T helper cell subsets recirculating from the skin and the systemic manifestations of psoriasis. Marco Diani, Gianfranco Altomare, and Eva Reali Copyright © 2016 Marco Diani et al. All rights reserved. Downregulation of p70S6K Enhances Cell Sensitivity to Rapamycin in Esophageal Squamous Cell Carcinoma Tue, 09 Aug 2016 12:24:26 +0000 It has been demonstrated that mTOR/p70S6K pathway was abnormally activated in many cancers and rapamycin and its analogs can restrain tumor growth through inhibiting this pathway, but some tumors including esophageal squamous cell carcinoma (ESCC) appear to be insensitive to rapamycin in recent studies. In the present study, we explored the measures to improve the sensitivity of ESCC cells to rapamycin and identified the clinical significance of the expression of phosphorylated p70S6K (p-p70S6K). The results showed that, after downregulating the expression of p70S6K and p-p70S6K by p70S6K siRNA, the inhibitory effects of rapamycin on cell proliferation, cell cycle, and tumor growth were significantly enhanced in vitro and in vivo. Furthermore, p-p70S6K had strong positive expression in ESCC tissues and its expression was closely related to lymph node metastasis and the TNM staging. These results indicated that p-p70S6K may participate in the invasion and metastasis in the development of ESCC and downregulation of the expression of p-p70S6K could improve the sensitivity of cells to rapamycin in ESCC. Zhaoming Lu, Kezheng Peng, Ning Wang, Hong-Min Liu, and Guiqin Hou Copyright © 2016 Zhaoming Lu et al. All rights reserved. Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins Mon, 08 Aug 2016 12:24:08 +0000 Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes. Additionally, their potential for immunogenicity has proven to be a challenge to developing safe and reliably efficacious drugs. Our discussion will emphasize immunogenicity in the context of therapeutic proteins, a well-known class of biologics. We set out to describe what is known and unknown about the mechanisms underlying the interplay between antigenicity and immune response and their effect on the safety, efficacy, pharmacokinetics, and pharmacodynamics of these therapeutic agents. Alison Smith, Hugh Manoli, Stacey Jaw, Kimberley Frutoz, Alan L. Epstein, Leslie A. Khawli, and Frank-Peter Theil Copyright © 2016 Alison Smith et al. All rights reserved. Plasma IL-6/IL-10 Ratio and IL-8, LDH, and HBDH Level Predict the Severity and the Risk of Death in AIDS Patients with Pneumocystis Pneumonia Sun, 07 Aug 2016 06:27:00 +0000 Objective. To identify blood biomarkers to predict severity and mortality in AIDS PCP patients. Methods. Biomarkers including clinical parameters and plasma inflammatory cytokines were assessed in 32 HIV-infected patients with Pneumocystis pneumonia (PCP) at time of admission. Predictive value of the biomarkers for clinical severity and in-hospital mortality was evaluated by corresponding ROC curve. Results. Levels of CRP, WBC, LDH, HBDH, and Ferritin were significantly higher in the severe and nonsurvivor AIDS PCP patients. These important biochemical indicators have inverse correlation with oxygenation index, especially levels of LDH (, ), HBDH (, ), and Ferritin (, ). Plasma IL-8 and IL-6 levels were significantly higher in patients with PaO2/FiO2 ≤ 200 mmHg and nonsurvivors than in those with PaO2/FiO2 > 200 mmHg and survivors. Severe and nonsurvival groups showed higher ratio of mean IL-6/IL-10 level (1.78 ± 1.56, ; 1.11 ± 0.72, ), larger AUC (95% CI 0.781–1.000, ; 95% CI 0.592–0.917, ), and more significantly inverse correlation with the oxygenation index. Conclusion. Plasma IL-8, LDH, and HBDH levels and IL-6/IL-10 ratio could be helpful for early evaluation of the severity and predicting fatal outcomes in AIDS PCP patients. Jia Sun, Junwei Su, Yirui Xie, Michael T. Yin, Ying Huang, Lijun Xu, Qihui Zhou, and Biao Zhu Copyright © 2016 Jia Sun et al. All rights reserved. Association of Immunosuppression with DR6 Expression during the Development and Progression of Spontaneous Ovarian Cancer in Laying Hen Model Thu, 04 Aug 2016 12:45:20 +0000 Ovarian cancer (OVCA) mainly disseminates in the peritoneal cavity. Immune functions are important to prevent OVCA progression and recurrence. The mechanism of immunosuppression, a hallmark of tumor progression, is not well understood. The goal of this study was to determine the immune system’s responses and its suppression during OVCA development and progression in hens. Frequencies of CD8+ T cells and IgY-containing cells and expression of immunosuppressors including IRG1 and DR6 in OVCA at early and late stages in hens were examined. Frequencies of stromal but not the intratumoral CD+8 T cells and IgY-containing cells increased significantly () during OVCA development and progression. Tumor progression was associated with increased expression of IRG1 and DR6 and decreased infiltration of immune cells into the tumor. Frequency of stromal but not intratumoral immune cells increases during OVCA development and progression. Tumor-induced IRG1 and DR6 may prevent immune cells from invading the tumor. Sa’Rah McNeal, Pincas Bitterman, Janice M. Bahr, Seby L. Edassery, Jacques S. Abramowicz, Sanjib Basu, and Animesh Barua Copyright © 2016 Sa’Rah McNeal et al. All rights reserved. The Relationship of Cytokines IL-13 and IL-17 with Autoantibodies Profile in Early Rheumatoid Arthritis Thu, 04 Aug 2016 06:43:22 +0000 Aims. In the present study, we aimed to assess the concentrations of IL-13 and IL-17 in serum of patients with early rheumatoid arthritis (eRA), the investigation of correlation between the concentrations of these cytokines and disease activity score, and the concentration of some autoantibodies and the evaluation of the utility of IL-13 and -17 concentration measurements as markers of disease activity. Materials and Methods. Serum samples were collected from 30 patients and from 28 controls and analysed parameters. Results. The serum concentrations of IL-13, IL-17, anti-CCP, and IgM-RF were statistically significantly higher in patients with eRA, compared to the controls. IL-13 concentrations in the severe and moderate groups with eRA were statistically higher than in the mild and control groups. Also, in the case of IL-17, serum concentrations increased proportionally with the disease activity of eRA. We observe that concentrations of IL-13 and -17 did not correlate with autoantibodies. IL-17 concentration significantly positively correlated with CRP, while IL-13 concentration significantly negatively correlated with CRP. Disease activity score, DAS28, was strongly positively correlated with levels of ESR and weakly positively correlated with concentrations of anti-RA33 autoantibodies. IL-13 has a higher diagnostic utility than IL-17, CRP, ESR, IgM-RF, and anti-CCP as markers of disease activity. Conclusions. The presence of higher IL-13 and IL-17 serum levels in patients, compared with those of controls, confirms that these markers, found with high specificity, might be involved in the pathogenesis of eRA. IL-13 and IL-17 might be of better usefulness in the prediction of eRA activity status than IgM-RF and anti-CCP. Isabela Siloşi, Mihail Virgil Boldeanu, Manole Cojocaru, Viorel Biciuşcă, Vlad Pădureanu, Maria Bogdan, Ramona Georgiana Badea, Carmen Avramescu, Ileana Octavia Petrescu, Florin Petrescu, and Cristian A. Siloşi Copyright © 2016 Isabela Siloşi et al. All rights reserved. Effects of Invariant NKT Cells on Parasite Infections and Hygiene Hypothesis Wed, 03 Aug 2016 06:47:03 +0000 Invariant natural killer T (iNKT) cells are unique subset of innate-like T cells recognizing glycolipids. iNKT cells can rapidly produce copious amounts of cytokines upon antigen stimulation and exert potent immunomodulatory activities for a wide variety of immune responses and diseases. We have revealed the regulatory effect of iNKT cells on autoimmunity with a serial of publications. On the other hand, the role of iNKT cells in parasitic infections, especially in recently attractive topic “hygiene hypothesis,” has not been clearly defined yet. Bacterial and parasitic cell wall is a cellular structure highly enriched in a variety of glycolipids and lipoproteins, some of which may serve as natural ligands of iNKT cells. In this review, we mainly summarized the recent findings on the roles and underlying mechanisms of iNKT cells in parasite infections and their cross-talk with Th1, Th2, Th17, Treg, and innate lymphoid cells. In most cases, iNKT cells exert regulatory or direct cytotoxic roles to protect hosts against parasite infections. We put particular emphasis as well on the identification of the natural ligands from parasites and the involvement of iNKT cells in the hygiene hypothesis. Jun-Qi Yang, Yonghua Zhou, and Ram Raj Singh Copyright © 2016 Jun-Qi Yang et al. All rights reserved. SEC Based Method for Size Determination of Immune Complexes of Therapeutic Antibodies in Animal Matrix Sun, 31 Jul 2016 17:07:47 +0000 Therapeutic monoclonal antibodies (mAbs) represent a milestone in pharmacological development. Their superiority is based on the combination of high specificity, low toxicity, and long half-life that characterizes biologics. If biologics have Achilles’ heel, it is their potential immunogenicity. To better understand the impact of the size of immune complexes of mAbs on anti-drug antibody (ADA) dependent adverse reactions in Macaca fascicularis, we developed an efficient high-throughput size exclusion chromatography- (SEC-) based methodology that enables analysis of the size, size distribution, and ratio of free and ADA-complexed mAb in serum allowing for assessment of formation and clearance of circulating ADA-mAb immune complexes (CIC). Marta Boysen, Laura Schlicksupp, Ingeborg Dreher, Ralf Loebbert, and Mario Richter Copyright © 2016 Marta Boysen et al. All rights reserved. PD-1/PD-L1 Interaction Maintains Allogeneic Immune Tolerance Induced by Administration of Ultraviolet B-Irradiated Immature Dendritic Cells Sun, 31 Jul 2016 14:06:23 +0000 Our previous study demonstrated that transfusion of ultraviolet B-irradiated immature dendritic cells (UVB-iDCs) induced alloantigen-specific tolerance between two different strains of mice. Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been suggested to play an important role in maintaining immune tolerance. In the present study, we seek to address whether PD-1/PD-L1 plays a role in the maintenance of UVB-iDC-induced tolerance. We first observe that the UVB-iDC-induced alloantigen-specific tolerance can be maintained for over 6 weeks. Supporting this, at 6 weeks after tolerance induction completion, alloantigen-specific tolerance is still able to be transferred to syngeneic naïve mice through adoptive transfer of CD4+ T cells. Furthermore, skin transplantation study shows that the survival of allogeneic grafts is prolonged in those tolerant recipients. Further studies show that PD-1/PD-L1 interaction is essential for maintaining the induced tolerance as blockade of PD-1/PD-L1 by anti-PD-L1 antibodies largely breaks the tolerance at both cellular and humoral immunological levels. Importantly, we show that PD-1/PD-L1 interaction in tolerant mice is also essential for controlling alloantigen-responding T cells, which have never experienced alloantigens. The above findings suggest that PD-1/PD-L1 plays a crucial role in maintaining immune tolerance induced by UVB-iDCs, as well as in actively controlling effector T cells specific to alloantigens. Lanfang Zhang and Chang-Qing Xia Copyright © 2016 Lanfang Zhang and Chang-Qing Xia. All rights reserved. Emerging Technologies and Generic Assays for the Detection of Anti-Drug Antibodies Sun, 31 Jul 2016 11:29:39 +0000 Anti-drug antibodies induced by biologic therapeutics often impact drug pharmacokinetics, pharmacodynamics response, clinical efficacy, and patient safety. It is critical to assess the immunogenicity risk of potential biotherapeutics in producing neutralizing and nonneutralizing anti-drug antibodies, especially in clinical phases of drug development. Different assay methodologies have been used to detect all anti-drug antibodies, including ELISA, radioimmunoassay, surface plasmon resonance, and electrochemiluminescence-based technologies. The most commonly used method is a bridging assay, performed in an ELISA or on the Meso Scale Discovery platform. In this report, we aim to review the emerging new assay technologies that can complement or address challenges associated with the bridging assay format in screening and confirmation of ADAs. We also summarize generic anti-drug antibody assays that do not require drug-specific reagents for nonclinical studies. These generic assays significantly reduce assay development efforts and, therefore, shorten the assay readiness timeline. Michael A. Partridge, Shobha Purushothama, Chinnasamy Elango, and Yanmei Lu Copyright © 2016 Michael A. Partridge et al. All rights reserved. Effect of N-Feruloylserotonin and Methotrexate on Severity of Experimental Arthritis and on Messenger RNA Expression of Key Proinflammatory Markers in Liver Sun, 31 Jul 2016 07:28:46 +0000 Rheumatoid arthritis (RA) is a chronic inflammatory disease, leading to progressive destruction of joints and extra-articular tissues, including organs such as liver and spleen. The purpose of this study was to compare the effects of a potential immunomodulator, natural polyphenol N-feruloylserotonin (N-f-5HT), with methotrexate (MTX), the standard in RA therapy, in the chronic phase of adjuvant-induced arthritis (AA) in male Lewis rats. The experiment included healthy controls (CO), arthritic animals (AA), AA given N-f-5HT (AA-N-f-5HT), and AA given MTX (AA-MTX). N-f-5HT did not affect the body weight change and clinical parameters until the 14th experimental day. Its positive effect was rising during the 28-day experiment, indicating a delayed onset of N-f-5HT action. Administration of either N-f-5HT or MTX caused reduction of inflammation measured as the level of CRP in plasma and the activity of LOX in the liver. mRNA transcription of TNF-α and iNOS in the liver was significantly attenuated in both MTX and N-f-5HT treated groups of arthritic rats. Interestingly, in contrast to MTX, N-f-5HT significantly lowered the level of IL-1β in plasma and IL-1β mRNA expression in the liver and spleen of arthritic rats. This speaks for future investigations of N-f-5HT as an agent in the treatment of RA in combination therapy with MTX. Ľudmila Pašková, Viera Kuncírová, Silvester Poništ, Danica Mihálová, Radomír Nosáľ, Juraj Harmatha, Iveta Hrádková, Tomáš Čavojský, František Bilka, Katarína Šišková, Ingrid Paulíková, Lýdia Bezáková, and Katarína Bauerová Copyright © 2016 Ľudmila Pašková et al. All rights reserved. Effects of Adoptive Transfer of Tolerogenic Dendritic Cells on Allograft Survival in Organ Transplantation Models: An Overview of Systematic Reviews Thu, 28 Jul 2016 16:16:12 +0000 Objective. To dissect the efficacy of Tol-DC therapy with or without IS in multiple animal models of transplantation. Methods and Results. PubMed, Medline, Embase, and the Cochrane Library were searched for reviews published up to April 2015. Six systematic reviews and a total of 61 articles were finally included. Data were grouped by organ transplantation models and applied to meta-analysis. Our meta-analysis shows that Tol-DC therapy successfully prolonged allograft survival to varying extents in all except the islet transplantation models and with IS drugs further prolonged the survival of heart, skin, and islet allografts in mice, but not of heart allografts in rats. Compared with IS drugs alone, Tol-DC therapy with IS extended islet allograft survival in rats but failed to influence the survival of skin, small intestine, and heart allografts in rats or of heart and skin allografts in mice. Conclusion. Tol-DC therapy significantly prolonged multiple allograft survival and further prolonged survival with IS. However, standardized protocols for modification of Tol-DC should be established before its application in clinic. Yanni Zhou, Juan Shan, Yingjia Guo, Shengfu Li, Dan Long, Youping Li, and Li Feng Copyright © 2016 Yanni Zhou et al. All rights reserved. Mesenchymal Stem Cells and Myeloid Derived Suppressor Cells: Common Traits in Immune Regulation Wed, 27 Jul 2016 11:20:15 +0000 To protect host against immune-mediated damage, immune responses are tightly regulated. The regulation of immune responses is mediated by various populations of mature immune cells, such as T regulatory cells and B regulatory cells, but also by immature cells of different origins. In this review, we discuss regulatory properties and mechanisms whereby two distinct populations of immature cells, mesenchymal stem cells, and myeloid derived suppressor cells mediate immune regulation, focusing on their similarities, discrepancies, and potential clinical applications. Irina Lyadova Vladimirovna, Ekaterina Sosunova, Alexander Nikolaev, and Tatiana Nenasheva Copyright © 2016 Irina Lyadova Vladimirovna et al. All rights reserved. Lactobacillus rhamnosus GG Activation of Dendritic Cells and Neutrophils Depends on the Dose and Time of Exposure Wed, 20 Jul 2016 12:15:45 +0000 This study evaluates the ability of Lactobacillus rhamnosus GG (LGG) to activate DC and neutrophils and modulate T cell activation and the impact of bacterial dose on these responses. Murine bone marrow derived DC or neutrophils were stimulated with LGG at ratios of 5 : 1, 10 : 1, and 100 : 1 (LGG : cells) and DC maturation (CD40, CD80, CD86, CD83, and MHC class II) and cytokine production (IL-10, TNF-α, and IL-12p70) were examined after 2 h and 18 h coculture and compared to the ability of BCG (the present immunotherapeutic agent for bladder cancer) to stimulate these cells. A 2 h exposure to 100 : 1 (high dose) or an 18 h exposure to 5 : 1 or 10 : 1 (low dose), LGG : cells, induced the highest production of IL-12 and upregulation of CD40, CD80, CD86, and MHC II on DC. In DCs stimulated with LGG activated neutrophils IL-12 production decreased with increasing dose. LGG induced 10-fold greater IL-12 production than BCG. T cell IFNγ and IL-2 production was significantly greater when stimulated with DC activated with low dose LGG. In conclusion, DC or DC activated with neutrophils exposed to low dose LGG induced greater Th1 polarization in T cells and this could potentially exert stronger antitumor effects. Thus the dose of LGG used for immunotherapy could determine treatment efficacy. Shirong Cai, Matheswaran Kandasamy, Juwita N. Rahmat, Sin Mun Tham, Boon Huat Bay, Yuan Kun Lee, and Ratha Mahendran Copyright © 2016 Shirong Cai et al. All rights reserved. Dengue Fever: Causes, Complications, and Vaccine Strategies Wed, 20 Jul 2016 06:09:30 +0000 Dengue is a highly endemic infectious disease of the tropical countries and is rapidly becoming a global burden. It is caused by any of the 4 serotypes of dengue virus and is transmitted within humans through female Aedes mosquitoes. Dengue disease varies from mild fever to severe conditions of dengue hemorrhagic fever and shock syndrome. Globalization, increased air travel, and unplanned urbanization have led to increase in the rate of infection and helped dengue to expand its geographic and demographic distribution. Dengue vaccine development has been a challenging task due to the existence of four antigenically distinct dengue virus serotypes, each capable of eliciting cross-reactive and disease-enhancing antibody response against the remaining three serotypes. Recently, Sanofi Pasteur’s chimeric live-attenuated dengue vaccine candidate has been approved in Mexico, Brazil, and Philippines for usage in adults between 9 and 45 years of age. The impact of its limited application to the public health system needs to be evaluated. Simultaneously, the restricted application of this vaccine candidate warrants continued efforts in developing a dengue vaccine candidate which is additionally efficacious for infants and naïve individuals. In this context, alternative strategies of developing a designed vaccine candidate which does not allow production of enhancing antibodies should be explored, as it may expand the umbrella of efficacy to include infants and naïve individuals. Niyati Khetarpal and Ira Khanna Copyright © 2016 Niyati Khetarpal and Ira Khanna. All rights reserved. Soluble Urokinase Receptors in Focal Segmental Glomerulosclerosis: A Review on the Scientific Point of View Mon, 18 Jul 2016 15:57:47 +0000 Focal segmental glomerulosclerosis (FSGS) is one of the primary glomerular disorders in both children and adults which can progress to end-stage renal failure. Although there are genetic and secondary causes, circulating factors have also been regarded as an important factor in the pathogenesis of FSGS, because about 40% of the patients with FSGS have recurrence after renal transplantation. Soluble urokinase-type plasminogen activator receptor (suPAR) is a soluble form of uPAR, which is a membrane-bound protein linked to GPI in various immunologically active cells, including podocytes. It has recently been suggested as a potential circulating factor in FSGS by in vitro podocyte experiments, in vivo mice models, and human studies. However, there have also been controversies on this issue, because subsequent studies showed conflicting results. suPAR levels were also increased in patients with other glomerular diseases and were inversely correlated with estimated glomerular filtration rate. Nevertheless, there has been no balanced review on this issue. In this review, we compare the conflicting data on the involvement of suPAR in the pathogenesis of FSGS and shed light on interpretation by taking into account many points and the potential variables and confounders influencing serum suPAR levels. Andreas Kronbichler, Moin A. Saleem, Björn Meijers, and Jae Il Shin Copyright © 2016 Andreas Kronbichler et al. All rights reserved. Eradication and Current Status of Poliomyelitis in Pakistan: Ground Realities Mon, 18 Jul 2016 13:33:12 +0000 Pakistan is among the last three countries along with Afghanistan and Nigeria, where polio virus is still endemic. More or less, with some fluctuations, numbers of reported cases in the past few years have shown a rising trend. Year 2014 pushed the country into the deep sea of difficulties, as number of cases rose to red alert level of 328. Security situation has adversely affected the whole immunization coverage campaign. In a country where 40 polio vaccinators have been killed since 2012, such a big number of cases is not a surprising outcome. Worse perception of parents about polio vaccine as in Karachi and FATA, the high risk zones, makes 100% coverage a dream. Minor and perhaps delayed payments to polio workers make them frustrated, resulting in decline of trained manpower for vaccination. Strong implementation of policies is required and those found guilty of attack on polio workers need to be punished. Targeted community awareness programme, strong surveillance network, and involvement of influential religious entities can help to root out polio disease from country. Present review is aimed at analyzing all barriers on the road to success in eradication of polio from Pakistan. Shazia Ghafoor and Nadeem Sheikh Copyright © 2016 Shazia Ghafoor and Nadeem Sheikh. All rights reserved. Actions of Thyroid Hormone Analogues on Chemokines Sun, 17 Jul 2016 13:39:22 +0000 The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. Paul J. Davis, Gennadi V. Glinsky, Hung-Yun Lin, and Shaker A. Mousa Copyright © 2016 Paul J. Davis et al. All rights reserved. HLA-01:03 Allele in Lung Transplant Recipients Correlates with Higher Chronic Lung Allograft Dysfunction Occurrence Sun, 17 Jul 2016 06:38:56 +0000 Lung transplantation (LTx) is a valid therapeutic option for selected patients with end-stage lung disease. HLA-E seems to play a major role in the immune response to different viral infections and to affect transplantation outcome, in Hematopoietic Stem Cell Transplantation, for example. Two nonsynonymous alleles, HLA-01:01 and HLA-01:03, have functional differences, involving relative peptide affinity, cell surface expression, and potential lytic activity of NK cells. The aim of this retrospective study was to determine the impact of these two alleles for LTx recipients on anti-HLA alloimmunization risk, overall survival, and chronic rejection (CLAD). HLA-E was genotyped in 119 recipients who underwent LTx from 1998 to 2010 in a single transplantation center. In univariate analysis, both HLA-E homozygous states were associated with impaired overall survival compared to heterozygous HLA-E alleles (). In multivariate analysis, HLA-01:03 allele showed increased CLAD occurrence when compared to homozygous HLA-01:01 status (HR: 3.563 (CI 95%, 1.016–12), ). HLA-E allele did not affect pathogen infection or the production of de novo DSA. This retrospective study shows an uninvestigated, deleterious association of HLA-E alleles with LTx and requires verification using a larger cohort. Julie Di Cristofaro, Mathieu Pelardy, Anderson Loundou, Agnès Basire, Carine Gomez, Jacques Chiaroni, Pascal Thomas, Martine Reynaud-Gaubert, and Christophe Picard Copyright © 2016 Julie Di Cristofaro et al. All rights reserved. Circulating Regulatory T-Cells in Monoclonal Gammopathies of Uncertain Significance and Multiple Myeloma: In Search of a Role Thu, 14 Jul 2016 14:14:11 +0000 The frequency and function of regulatory T-cells (Tregs) in multiple myeloma (MM) are still matter of debate. The percentage and absolute number of circulating Tregs (CD4+) from 39 patients with untreated MM and 44 patients with monoclonal gammopathies of uncertain significance (MGUS) were tested and compared with 20 healthy subjects as controls. The mean percentage number of circulating Tregs was 2.1%  ± 1.0 (range 0.75–6.1%) in MM patients; 2.1%  ± 0.9 (range 0.3–4.4%) in MGUS; and 1.5%  ± 0.4 (range 0.9–2.1%) in controls ( ns). Mean absolute number of Tregs was 36.3/μL ± 23.7 (range 6.7–149/μL) in MM; 38.8/μL ± 19.1 (range 4.3–87/μL) in MGUS; and 39.4/μL ± 12.5 (range 18–63/μL) in controls ( ns). After a median follow-up of 38 months, 5 MGUS and 2 smoldering MM (SMM) transformed into overt MM; however Tregs number did not predict this evolution. With respect to MM patients and after a median follow-up of 33 months, Tregs did not show any significant correlation with main clinical and laboratory characteristics. Finally, from a functional point of view, Tregs displayed an effective suppressor function, irrespective of disease status. This study indicates that the number of circulating Tregs does not differ in different monoclonal gammopathies and normal subjects and do not correlate with clinical features of MM. Giovanni D’Arena, Giovanni Rossi, Luca Laurenti, Teodora Statuto, Fiorella D’Auria, Luciana Valvano, Vittorio Simeon, Aldo Giudice, Idanna Innocenti, Vincenzo De Feo, Rosanna Filosa, and Pellegrino Musto Copyright © 2016 Giovanni D’Arena et al. All rights reserved. An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment Thu, 14 Jul 2016 11:51:05 +0000 Inflamm-aging is a challenging and promising new branch of aging-related research fields that includes areas such as immunosenescence. Increasing evidence indicates that inflamm-aging is intensively associated with many aging diseases, such as Alzheimer’s disease, atherosclerosis, heart disease, type II diabetes, and cancer. Mounting studies have focused on the role of inflamm-aging in disease progression and many advances have been made in the last decade. However, the underlying mechanisms by which inflamm-aging affects pathological changes and disease development are still unclear. Here, we review studies of inflamm-aging that explore the concept, pathological features, mechanisms, intervention, and the therapeutic strategies of inflamm-aging in disease progression. Shijin Xia, Xinyan Zhang, Songbai Zheng, Ramin Khanabdali, Bill Kalionis, Junzhen Wu, Wenbin Wan, and Xiantao Tai Copyright © 2016 Shijin Xia et al. All rights reserved.