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PubMed | McGill University, R&D Laboratory, St Jude Childrens Research Hospital, Radboud University Nijmegen and 2 more.
Type: Journal Article | Journal: Immunity | Year: 2015

Plasmacytoid dendritic cells (pDCs) are primary producers of type I interferon (IFN) in response to viruses. The IFN-producing capacity of pDCs is regulated by specific inhibitory receptors, yet none of the known receptors are conserved in evolution. We report that within the human immune system, receptor protein tyrosine phosphatase sigma (PTPRS) is expressed specifically on pDCs. Surface PTPRS was rapidly downregulated after pDC activation, and only PTPRS(-) pDCs produced IFN-. Antibody-mediated PTPRS crosslinking inhibited pDC activation, whereas PTPRS knockdown enhanced IFN response in a pDC cell line. Similarly, murine Ptprs and the homologous receptor phosphatase Ptprf were specifically co-expressed in murine pDCs. Haplodeficiency or DC-specific deletion of Ptprs on Ptprf-deficient background were associated with enhanced IFN response of pDCs, leukocyte infiltration in the intestine and mild colitis. Thus, PTPRS represents an evolutionarily conserved pDC-specific inhibitory receptor, and is required to prevent spontaneous IFN production and immune-mediated intestinal inflammation.


Seo J.H.,R&D Laboratory | VanTyne C.J.,Colorado School of Mines | Moon Y.H.,Pusan National University
International Journal of Material Forming | Year: 2015

Turn down warping is a shape defect observed at the front end of a plate during hot rolling. To produce a flat plate without warping, a precise prediction of turn down warping is essential to achieve optimal control. Therefore, we propose a model based on a Gaussian function to predict turn down warping. The model uses the results from numerical analyses of hot plate rolling. The finite element code MARC was used for the numerical analysis. Hot plate rolling processing parameters, such as roll diameter, plate dimension, rolling speed, and pass line were all considered in the model. To verify the accuracy of the prediction model, the numerical results obtained by FEM were confirmed with data measured during industrial hot plate rolling. For the actual measurements of turn down warping, image processed high speed camera data from the exit side of the rolling were used. The results show that the proposed Gaussian function model can successfully predict turn down warping of a plate’s front end under various hot plate rolling conditions. © 2015 Springer-Verlag France


Tomasiello S.,University of Basilicata | Tomasiello S.,RD Laboratory
International Journal of Computer Mathematics | Year: 2010

In this paper, the Burgers-Huxley equation has been solved by a generalized version of the Iterative Differential Quadrature (IDQ) method for the first time. The IDQ method is a method based on the quadrature rules. It has been proposed by the author applying to a certain class of non-linear problems. Stability and error analysis are performed, showing the efficiency of the method. Besides, an error bound is tried. In the discussion about the numerical examples, the generalized Burgers-Huxley equation is involved too.


Mukherjee F.,R&D Laboratory | Bahekar V.S.,R&D Laboratory | Bahekar V.S.,Jawaharlal Nehru Technological University | Prasad A.,R&D Laboratory | And 4 more authors.
European Journal of Wildlife Research | Year: 2015

Tuberculosis (TB) in domestic and wild ruminants is mostly caused by Mycobacterium bovis (MB). However, the present paper describes the first report of TB of antelopes (Antelope cervicapra) and chinkara (Gazella bennettii) due to Mycobacterium tuberculosis (MT) in India. These wild hosts may represent a vehicle for the dissemination of MT infection to domestic livestock or human. MT was isolated by culture employing the MGITTM BACTECTM 960 (Becton Dickinson, BD) system and Middlebrook 7H10 Agar enriched with oleic albumin dextrose catalase (OADC) and Lowenstein-Jensen (LJ) medium supplemented with glycerol, but not sodium pyruvate. The isolates were confirmed as a member of the Mycobacterium tuberculosis complex (MTC) by using a commercial nested PCR that targeted the IS6110 sequence. Further confirmation of the isolates as MT strains was achieved by employing commercial line probe assay genotyping kits (Hain Lifescience, Germany) that specifically identifies MT within the MTC group. © 2015, Springer-Verlag Berlin Heidelberg.


PubMed | R&D Laboratory, Japan National Institute of Materials Science and University of Toyama
Type: | Journal: Colloids and surfaces. B, Biointerfaces | Year: 2013

A copolymer film composed of zwitterionic carboxymethylbetaine (CMB) and n-butyl methacrylate (BMA), Poly(CMB-r-BMA), was cast on a flat plane of an octadecyltrichlorosilane (ODS)-modified fused quartz prism with a semi-cylindrical shape. CH stretching of the polymer film and O-H stretching of water at the surface of the film were examined using the sum frequency generation (SFG) technique. The C-H stretching band of the cast film, indicating a gauche defect of the film, was affected by the contact medium including dry nitrogen, water vapor-saturated nitrogen and liquid water. In contrast, the C-H stretching of an octadecyl group introduced onto the quartz prism for stable attachment of the cast film was not significantly changed by the contact medium. The O-H stretching band indicated that water molecules at the surface of the Poly(CMB-r-BMA) film in contact with liquid water were not greatly oriented in comparison with those at the surfaces of a bare prism, an ODS SAM-modified prism, and a prism covered with a PolyBMA film or a copolymer film of BMA and methacrylic acid or 2-(dimethylamino)ethyl methacrylate. A similar small perturbation of the structure of water was previously observed in the vicinity of water-soluble zwitterionic polymers and zwitterionic copolymer films using Raman and attenuated total reflection infrared spectroscopies, respectively. A distinct effect of charge neutralization to diminish the perturbation of the structure of interfacial water around polymer materials was suggested.


PubMed | R&D Laboratory
Type: Journal Article | Journal: The Journal of investigative dermatology | Year: 2012

Several sources of evidence suggest that tumor-specific T cells have the potential to control melanoma tumors. Current active and adoptive therapeutic approaches to elicit such T cells are either not sufficiently clinically efficient or require fastidious processes that impede their extensive clinical use. As plasmacytoid dendritic cells (pDCs) have a crucial role in triggering antitumor immunity especially in melanoma, we explored their potential as a cell-based approach for melanoma immunotherapy. An irradiated human HLA-A(*)0201(+) pDC line loaded with peptides derived from the major melanoma tumor antigens, MelA/MART-1, gp100/pmel17, tyrosinase, and MAGE-A3, was used to trigger functional multi-specific T cells ex vivo from peripheral blood mononuclear cells and tumor-infiltrating lymphocytes from stage I-IV HLA-A(*)0201(+) melanoma patients. pDCs loaded with melanoma-derived peptides promptly induced high levels of melanoma tumor-specific T cells from both sources. pDC-primed central/effector memory antitumor T cells were highly functional as indicated by the specific IFN secretion and membrane CD107 expression upon stimulation. Cells also exhibited strong cytotoxicity toward semi-allogeneic melanoma cells and patient-derived tumor cells. The simple design and potent efficacy of this promising approach provides a preclinical basis for the development of a pDC-based vaccine and an alternative means to produce tumor-specific T cells for adoptive cellular immunotherapy in melanoma patients.


PubMed | R&D Laboratory
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2012

The immune control of hepatitis B virus (HBV) infection is essential for viral clearance. Therefore, restoring functional anti-HBV immunity is a promising immunotherapeutic approach to treatment of chronic infection. Plasmacytoid dendritic cells (pDCs) play a crucial role in triggering antiviral immunity through their ability to capture and process viral antigens and subsequently induce adaptive immune responses. We investigated the potential of pDCs to trigger antiviral cellular immunity against HBV. We used a human leukocyte antigen A (HLA-A)*0201(+) pDC line loaded with HLA-A*0201-restricted peptides derived from hepatitis B core/hepatitis B surface (HBc/HBs) antigens to amplify specific CD8 T cells ex vivo from chronic HBV patients and established a Hepato-HuPBL mouse model to address the therapeutic potential of the strategy in vivo. Stimulation of PBMCs or liver-infiltrating lymphocytes from HLA-A*0201(+) chronic HBV patients by HBc peptide-loaded pDCs elicited up to 23.1% and 76.1% HBV-specific CD8 T cells in 45.8% of cases. The specific T cells from the responder group secreted interferon-, expressed CD107 upon restimulation, and efficiently lysed HBV antigen-expressing hepatocytes. Circulating hepatitis B e antigen (HBeAg) was found to distinguish the group of patients not responding to the pDC stimulation. The therapeutic efficacy of the pDC vaccine was evaluated in immunodeficient NOD-SCID (2) m(-/-) mice reconstituted with HBV patients PBMCs and xenotransplanted with human HBV-transfected hepatocytes. Vaccination of Hepato-HuPBL mice with the HBc/HBs peptide-loaded pDCs elicited HBV-specific T cells able to specifically lyse the transfected hepatocytes and reduce the systemic viral load.pDCs loaded with HBV-derived peptides can elicit functional virus-specific T cells. HBeAg appears to be critical in determining the outcome of immunotherapies in chronic HBV patients. A pDC-based immunotherapeutic approach could be of interest in attempts to restore functional antiviral immunity, which is critical for the control of the virus in chronic HBV patients.


PubMed | R&D Laboratory
Type: Journal Article | Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | Year: 2011

Virus-associated hematologic malignancies (EBV lymphoproliferative disease) and opportunistic infections (CMV) represent a major cause of hematopoietic stem cell and solid organ transplantation failure. Adoptive transfer of antigen-specific T lymphocytes appears to be a major and successful immunotherapeutic strategy, but improvements are needed to reliably produce high numbers of virus-specific T cells with appropriate requirements for adoptive immunotherapy that would allow extensive clinical use. Since plasmacytoid dendritic cells (pDCs) are crucial in launching antiviral responses, we investigated their capacity to elicit functional antiviral T-cell responses for adoptive cellular immunotherapy using a unique pDC line and antigens derived from Influenza, CMV and EBV viruses. Stimulation of peripheral blood mononuclear cells from HLA-A*0201(+) donors by HLA-A0201 matched pDCs pulsed with viral-derived peptides triggered high levels of multi-specific and functional cytotoxic T-cell responses (up to 99% tetramer(+) CD8 T cells) in vitro. Furthermore, the central/effector memory cytotoxic T cells elicited by the pDCs strongly display antiviral activity upon adoptive transfer into a humanized mouse model that mimics a virus-induced malignancy. We provide a simple and potent method to generate virus-specific CTL with the required properties for adoptive cellular immunotherapy of post-transplant diseases.


PubMed | R&D Laboratory
Type: Journal Article | Journal: Nanoscale | Year: 2013

This study aims to investigate gadolinium-based nanoparticles (Gd-HNP) for in vitro labeling of human plasmacytoid dendritic cells (HuPDC) to allow for in vivo tracking and HuPDC quantifying using magnetic resonance imaging (MRI) following parenteral injection. Human plasmacytoid DC were labeled (LabHuPDC) with fluorescent Gd-HNP (Gd-FITC-HNP) and injected via intraperitoneal and intravenous routes in 4-5 NOD-SCID 2m(-/-)mice (treated mice = TM). Control mice (CM) were similarly injected with unlabeled HuPDC. In vivo 7 T MRI was performed 24 h later and all spleens were removed in order to measure Gd and fluorescence contents and identify HuPDC. Gd-FITC-HNP efficiently labeled HuPDC (0.05 to 0.1 pg per cell), without altering viability and activation properties. The magnetic resonance (MR) signal was exclusively due to HuPDC. The normalized MR splenic intensity for TM was significantly higher than for CM (p < 0.024), and highly correlated with the spleen Gd content (r = 0.97), and the number of HuPDC found in the spleen (r = 0.94). Gd-FITC-HNP allowed for in vivo tracking and HuPDC quantifying by means of MRI following parenteral injection, with very high sensitivity (<3000 cells per mm(3)). The safety of these new nanoparticle types must be confirmed via extensive toxicology tests including in vivo stability and biodistribution studies.


Hepatitis B virus (HBV) modulates the immune system to escape clearance. Plasmacytoid dendritic cells (pDCs) initiate antiviral immunity and might determine outcomes of HBV infections. Functional defects in pDCs and natural killer (NK) cells have been reported in patients with chronic HBV infection. However, the mechanisms of these immune dysfunctions and the interactions between pDCs and NK cells have not been determined. We investigated features of pDCs from patients with chronic HBV infection and their interactions with NK cells.We used flow cytometry and cytokine assays to analyze pDCs from patients with chronic HBV infection (118 aviremic and 67 viremic) and compared them with pDCs from uninfected individuals (controls). We performed coculture assays to analyze the ability of pDCs to activate heterologous NK cells.Circulating and hepatic pDCs from patients with chronic HBV infection had higher levels of activation than pDCs from controls and defective responses to stimulation with Toll-like receptor 9 ligand (TLR9-L), regardless of the patients viral load. TLR9-L-activated pDCs from viremic patients with HBV did not induce cytolytic activity of NK cells. This altered function of pDCs was associated with reduced expression of OX40L and could be reproduced by incubating control pDCs with plasma from viremic patients with HBV. A high level of interferon-induced protein 10 (IP-10 or CXCL10) and hepatitis B surface and e antigens might induce these defective pDC functions.HBV escapes antiviral immunity by altering pDC functions, to disrupt interactions between pDC and NK cells. This could reduce immune control of HBV and lead to chronic infection.

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