bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenoviral Delivery of Human and Viral IL-10 in Murine Sepsis
Authors: Minter Rebecca M. , Ferry Maria A. , Murday Michelle E. , Tannahill Cynthia L. , Bahjat Frances R. , Oberholzer Caroline , Oberholzer Andreas , LaFace Drake , Hutchins Beth , Wen Shufen , Shinoda Jeremy , Copeland Edward M. , Moldawer Lyle L. 
Published: April 2014

AbstractAdenovirus (Ad) gene therapy has been proposed as a drug-delivery system for the targeted administration of protein-based therapies, including growth factors and biological response modifiers. However, inflammation associated with Ad transduction has raised concern about its safety and efficacy in acute inflammatory diseases. In the present report, intratracheal and i.v. administration of a first-generation adenoviral recombinant (E1,E3 deleted) either containing an empty cassette or expressing the anti-inflammatory cytokines viral or human IL-10 (IL-10) was administered to mice subjected to zymosan-induced multisystem organ failure or to acute necrotizing pancreatitis. Pretreatment of mice with the intratracheal instillation of Ad expressing human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflammatory cytokine response, and reduced mortality in the zymosan-induced model, whereas pretreatment with a control adenoviral recombinant did not significantly exacerbate the response. Pretreatment of mice with pancreatitis using adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered systemically, but not intratracheally. We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and expression of the anti-inflammatory protein IL-10 can be used to suppress the underlying inflammatory process.
Respiratory Syncytial Virus Predisposes Mice to Augmented Allergic Airway Responses Via IL-13-Mediated Mechanisms
Authors: Lukacs Nicholas W. , Tekkanat Kim K. , Berlin Aaron , Hogaboam Cory M. , Miller Allison , Evanoff Holly , Lincoln Pam , Maassab Hussien 
Published: April 2014

AbstractThe development of severe childhood asthma may be influenced by several factors including environmental and infectious stimuli. The causal relationship between infectious viral responses, such as respiratory syncytial virus (RSV), and severe asthma during early childhood is unclear. In these studies, the ability for an initial RSV infection to exacerbate and promote a more severe asthmatic-type response was investigated by combining established murine models of disease. We examined the ability of RSV to induce exacerbation of allergic disease over a relatively long period, leading to development of severe airway responses including airway inflammation and hyperreactivity. The preferential production of IL-13 during a primary RSV infection appears to play a critical role for the exacerbation of cockroach allergen-induced disease. The depletion of IL-13 during RSV infections inhibited the exacerbation and acceleration of severe allergen-induced airway hyperreactivity. This was indicated by decreases in airway hyperreactivity and changes in lung chemokine production. These data suggest that the airway responses during asthma can be greatly affected by a previous RSV infection, even when infection occurs before allergen sensitization. Overall, infection of the airways with RSV can induce an IL-13-dependent change in airway function and promotes an environment that contributes to the development of severe allergic asthmatic responses.
Lymphoid Neogenesis in Rheumatoid Synovitis
Authors: Takemura Seisuke , Braun Andrea , Crowson Cynthia , Kurtin Paul J. , Cofield Robert H. , O’Fallon William M. , Goronzy Jörg J. , Weyand Cornelia M. 
Published: April 2014

AbstractIn rheumatoid arthritis (RA), tissue-infiltrating lymphocytes can be arranged in sophisticated organizations that resemble microstructures usually formed in secondary lymphoid organs. Molecular pathways and host risk factors involved in this process of lymphoid neogenesis remain to be defined. In a series of 64 synovial tissue biopsies, lymphoid follicles with germinal centers (GCs) were found in 23.4% of the patients. Follicular dendritic cells (FDCs) were exclusively present in tissues with GCs, suggesting that the recruitment or in situ maturation of FDCs is a critical factor for GC formation in the synovial membrane. Primary follicles were absent, emphasizing the role of Ag recognition in the generation of inflammation-associated lymphoid organogenesis. Multivariate logistic regression analysis of tissue cytokines and chemokines identified two parameters, in situ transcription of lymphotoxin (LT)-β and of B lymphocyte chemoattractant (BLC; BLC/CXCL13), that were predictors for FDC recruitment and synovial GC formation. LT-β and BLC/CXCL13 were found to be independent variables that could, in part, compensate for each other to facilitate GC formation. Prediction models incorporating in situ transcription of LT-β and BLC/CXCL13 had high negative yet moderate positive predictive values, suggesting that LT-β and BLC/CXCL13 are necessary but not sufficient. LT-β protein was detected on a subset of mantle zone and GC B cells, but also on T cells in follicular structures. BLC/CXCL13 was produced by FDCs in follicular centers, but was predominantly found in endothelial cells and synovial fibroblasts, suggesting heterotypic signaling between cells of the synovial membrane and infiltrating lymphocytes in regulating extranodal lymphoid neogenesis.
Immunofluorescence Detection of δ Opioid Receptors (DOR) on Human Peripheral Blood CD4+ T Cells and DOR-Dependent Suppression of HIV-1 Expression
Authors: Sharp Burt M. , McAllen Kathy , Gekker Genya , Shahabi Nahid A. , Peterson Phillip K. 
Published: April 2014

AbstractThe δ opioid receptors (DORs) modulate T cell proliferation, IL-2 production, chemotaxis, and intracellular signaling. Moreover, in DOR-transfected Jurkat cells, δ opioids have been shown to suppress HIV-1 p24 Ag expression. These observations led us to characterize the expression of DORs by human peripheral blood T cells and to determine whether a specific DOR agonist, benzamide,4-{[2,5-dimethyl-4-(2-propenyl)-1-piperazinyl](3-methoxyphenyl)methyl]-N,−,{2S[1(S*),2α,5β]}-(9Cl) (SNC-80), can suppress p24 Ag expression by HIV-1-infected CD4+ T cells obtained from normal donors. By immunofluorescence flow cytometry, PHA stimulated the expression of DOR from 1.94 ± 0.70 (mean ± SEM) to 20.70 ± 1.88% of the PBMC population by 48 h (p &lt; 0.0001). DOR expression was ∼40% of both the PHA-stimulated CD4+ and CD8+ T cell subsets, and virtually all DORs were found on these subsets. To determine whether activated DORs suppress HIV-1 expression, PBMC were prestimulated with PHA, and then CD4+ T cells were purified, pretreated with SNC-80, and infected with HIV-1. In a concentration-dependent manner, SNC-80 inhibited production of p24 Ag. SNC-80 10−10 M maximally suppressed (∼50%) both lymphocytotropic (HIV-1 MN) and monocytotropic (SF162) strains; higher concentrations were less effective. Naltrindole, a selective DOR antagonist, abolished the inhibitory effects of SNC-80. Kinetic studies indicated that 24-h pre- or postincubation with SNC-80, relative to infection with HIV-1, eliminated its suppressive effects. Thus, stimulating the DORs expressed by activated CD4+ T cells significantly suppressed the expression of HIV-1. These findings suggest that opioid immunomodulation directed at host T cells may be adjunctive to standard antiviral approaches to HIV-1 infection.
Acetylcholine Receptor Peptide Recognition in HLA DR3-Transgenic Mice: In Vivo Responses Correlate with MHC-Peptide Binding
Authors: Raju Raghavanpillai , Spack Edward G. , David Chella S. 
Published: April 2014

AbstractHLA DR3 is an MHC molecule that reportedly predisposes humans to myasthenia gravis (MG). Though MG is an Ab-mediated autoimmune disease, CD4+ T cells are essential for the generation of high-affinity Abs; hence the specificities of autoreactive CD4+ T cells are important. In this study we report the HLA DR3-restricted T cell determinants on the extracellular region sequence of human acetylcholine receptor α subunit. We find two promiscuous determinants on this region 141–160 and 171–190 as defined by their immunogenicity in HLA DR3-, HLA DQ8-, and HLA DQ6-transgenic mice in the absence of endogenous mouse class II molecules. We also studied the minimal determinants of these two regions by truncation analysis, and the MHC binding affinity of a set of overlapping peptides spanning the complete sequence region of human acetylcholine receptor α subunit. One of the peptide sequences strongly immunogenic in HLA DR3-transgenic mice also had the highest binding affinity to HLA DR3. Identification of T cell determinants restricted to an MHC molecule known to predispose to MG may be an important step toward the development of peptide-based immunomodulation strategies for this autoimmune disease.
Failure to Induce Neonatal Tolerance in Mice That Lack Both IL-4 and IL-13 but Not in Those That Lack IL-4 Alone
Authors: Inoue Yoshihiko , Konieczny Bogumila T. , Wagener Maylene E. , McKenzie Andrew N. J. , Lakkis Fadi G. 
Published: April 2014

AbstractCurrent evidence suggests that neonatal tolerance to a foreign Ag is the consequence of IL-4-mediated Th2 immunity rather than the thymic deletion of Ag-specific T cells. Here, we addressed the role of IL-4 in neonatal tolerance by testing whether tolerance to a minor histocompatibility Ag can be induced in newborn mice that lack IL-4 (IL-4−/−). We found that IL-4 does not play a dominant role in the induction of neonatal tolerance as newborn female IL-4−/− mice could be readily tolerized to the H-Y male Ag. In contrast, mice that lack both IL-4 and IL-13 (IL-4−/−/IL-13−/−) were resistant to the induction of neonatal tolerance, and their splenocytes produced exaggerated amounts of IFN-γ on rechallenge with the same Ag encountered during the neonatal period. These findings argue against the view that IL-4 alone is critical for the induction of neonatal tolerance and suggest that the combined actions of both IL-4 and IL-13 are essential for this process.
Cutting Edge: Editing of Recycling Class II:Peptide Complexes by HLA-DM
Authors: Pathak Sulabha S. , Lich John D. , Blum Janice S. 
Published: April 2014

AbstractHLA-DM catalyzes the exchange and selection of ligands for MHC class II molecules within mature endosomal/lysosomal compartments. Here, evidence is provided that DM edits peptides in early endosomes, thus influencing presentation via recycling class II molecules. Maximal class II-restricted presentation of an albumin-derived peptide, dependent on endocytosis and recycling class II molecules, was observed in cells lacking HLA-DM. DM editing of this epitope was observed in early endocytic compartments as shown using inhibitors of early to late endosomal transport. Editing was tempered by coexpression of HLA-DO, suggesting that DM:DO ratio may be important in guiding epitope editing in early endosomal compartments. Thus, HLA-DM appears to interact with, and edit epitopes displayed by, recycling class II molecules.
Chromatin-Independent Binding of Serum Amyloid P Component to Apoptotic Cells
Authors: Familian Atoosa , Zwart Bas , Huisman Han G. , Rensink Irma , Roem Dorina , Hordijk Peter L. , Aarden Lucien A. , Hack C. Erik 
Published: April 2014

AbstractHuman serum amyloid P component (SAP) is a glycoprotein structurally belonging to the pentraxin family of proteins, which has a characteristic pentameric organization. Mice with a targeted deletion of the SAP gene develop antinuclear Abs, which was interpreted as evidence for a role of SAP in controlling the degradation of chromatin. However, in vitro SAP also can bind to phosphatidylethanolamine, a phospholipid which in normal cells is located mainly in the inner leaflet of the cell membrane, to be translocated to the outer leaflet of the cell membrane during a membrane flip-flop. We hypothesized that SAP, because of its specificity for phosphatidylethanolamine, may bind to apoptotic cells independent of its nuclear binding. Calcium-dependent binding of SAP to early, nonpermeable apoptotic Jurkat, SKW, and Raji cells was indeed observed. Experiments with flip-flopped erythrocytes confirmed that SAP bound to early apoptotic cells via exposed phosphatidylethanolamine. Binding of SAP was stronger to late, permeable apoptotic cells. Experiments with enucleated neutrophils, with DNase/RNase treatment of late apoptotic Jurkat cells, and competition experiments with histones suggested that binding of SAP to late apoptotic cells was largely independent of chromatin. Confocal laser microscopic studies indeed suggested that SAP bound to these apoptotic cells mainly via the blebs. Thus, this study shows that SAP binds to apoptotic cells already at an early stage, which raises the possibility that SAP is involved in dealing with apoptotic cells in vivo.
Expansion of the Antigenic Repertoire of a Single T Cell Receptor upon T Cell Activation
Authors: Amrani Abdelaziz , Serra Pau , Yamanouchi Jun , Trudeau Jacqueline D. , Tan Rusung , Elliott John F. , Santamaria Pere 
Published: April 2014

AbstractActivated T cells and their naive precursors display different functional avidities for peptide/MHC, but are thought to have identical antigenic repertoires. We show that, following activation with a cognate mimotope (NRP), diabetogenic CD8+ T cells expressing a single TCR (8.3) respond vigorously to numerous peptide analogs of NRP that were unable to elicit any responses from naive 8.3-CD8+ T cells, even at high concentrations. The NRP-reactive, in vivo activated CD8+ cells arising in pancreatic islets of nonobese diabetic mice are similarly promiscuous for peptide/MHC, and paradoxically this promiscuity expands as the aviditiy of the T cell population for NRP/MHC increases with age. Thus, activation and avidity maturation of T lymphocyte populations can lead to dramatic expansions in the range of peptides that elicit functional T cell responses.
Fas Ligand (CD95L) Protects Neurons Against Perforin- Mediated T Lymphocyte Cytotoxicity
Authors: Medana Isabelle , Li Zhaoxia , Flügel Alexander , Tschopp Jürg , Wekerle Hartmut , Neumann Harald 
Published: April 2014

Abstract
Previous work showed that neurons of the CNS are protected against perforin-mediated T cell cytotoxicity, but are susceptible to Fas-mediated apoptosis. In this study, we report that Fas ligand (FasL) expression by neurons is involved in protection against perforin-mediated T cell cytotoxicity. Gene transcripts for FasL were identified in single murine hippocampal neurons by RT-PCR combined with patch clamp electrophysiology, and constitutive expression of FasL protein was confirmed in neurons by immunohistochemistry. Neurons derived from wild-type C57BL/6 (BL6) mice and mutant BL6.gld mice lacking functional FasL were confronted with allogeneic CTLs and continuously monitored in real time for changes in levels of intracellular calcium ([Ca2+]i), an indicator of cytotoxic damage. Perforin-mediated plasma membrane lysis, characterized by rapid, massive [Ca2+]i influx into the target cells within 0.5 h, was not detected in wild-type neurons. In striking contrast, FasL-deficient neurons showed rapid increase in [Ca2+]i within 0.5 h, reflecting perforin-dependent cell lysis. FasL seems to protect neurons by blocking degranulation of CTLs, since CD3-induced release of cytotoxic granules was reduced by coapplication of Fas-specific Abs or rFasL.
IL-6 Inhibits the Tolerogenic Function of CD8α+ Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase
Authors: Grohmann Ursula , Fallarino Francesca , Bianchi Roberta , Belladonna Maria Laura , Vacca Carmine , Orabona Ciriana , Uyttenhove Catherine , Fioretti Maria Cristina , Puccetti Paolo 
Published: April 2014

Abstract
The outcome of dendritic cell (DC) presentation of tumor and/or self peptides, including P815AB (a tumor peptide of murine mastocytoma cells) and NRP-A7 (a synthetic peptide mimotope recognized by diabetogenic T cells), may depend on a balance between the activities of immunogenic (CD8α−) and tolerogenic (CD8α+) DC. By virtue of their respective actions on CD8− and CD8+ DC, IL-12 and IFN-γ have functionally opposing effects on peptide presentation by the CD8− DC subset, and IFN-γ-activated CD8+ DC mediate tolerogenic effects that prevail over the adjuvant activity of IL-12 on CD8− DC. We have previously shown that CD40 ligation abrogates the tolerogenic potential of CD8+ DC, an effect associated with an impaired capacity of the CD40-modulated and IFN-γ-treated DC to degrade tryptophan and initiate T cell apoptosis in vitro. We report here that IL-6 may both replace (upon administration of the recombinant cytokine) and mediate (as assessed by the use of neutralizing Abs) the effect of CD40 ligation in ablating the tolerogenic activity of CD8+ DC. The activity of IL-6 includes down-regulation of IFN-γR expression in the CD8+ DC subset and correlates to a reduced ability of these cells to metabolize tryptophan and initiate T cell apoptosis in vitro.
Enforced Expression of GATA-3 During T Cell Development Inhibits Maturation of CD8 Single-Positive Cells and Induces Thymic Lymphoma in Transgenic Mice
Authors: Nawijn Martijn C. , Ferreira Rita , Dingjan Gemma M. , Kahre Olev , Drabek Dubravka , Karis Alar , Grosveld Frank , Hendriks Rudolf W. 
Published: April 2014

Abstract
The zinc finger transcription factor GATA-3 is of critical importance for early T cell development and commitment of Th2 cells. To study the role of GATA-3 in early T cell development, we analyzed and modified GATA-3 expression in vivo. In mice carrying a targeted insertion of a lacZ reporter on one allele, we found that GATA-3 transcription in CD4+CD8+ double-positive thymocytes correlated with the onset of positive selection events, i.e., TCRαβ up-regulation and CD69 expression. LacZ expression remained high (∼80% of cells) during maturation of CD4 single-positive (SP) cells in the thymus, but in developing CD8 SP cells the fraction of lacZ-expressing cells decreased to &lt;20%. We modified this pattern by enforced GATA-3 expression driven by the CD2 locus control region, which provides transcription of GATA-3 throughout T cell development. In two independent CD2-GATA3-transgenic lines, ∼50% of the mice developed thymic lymphoblastoid tumors that were CD4+CD8+/low and mostly CD3+. In tumor-free CD2-GATA3-transgenic mice, the total numbers of CD8 SP cells in the thymus were within normal ranges, but their maturation was hampered, as indicated by increased apoptosis of CD8 SP cells and a selective deficiency of mature CD69lowHSAlow CD8 SP cells. In the spleen and lymph nodes, the numbers of CD8+ T cells were significantly reduced. These findings indicate that GATA-3 supports development of the CD4 lineage and inhibits maturation of CD8 SP cells in the thymus.
A Pivotal Role for DNase I-Sensitive Regions 3b and/or 4 in the Induction of Somatic Hypermutation of IgH Genes
Authors: Terauchi Akiko , Hayashi Katsuhiko , Kitamura Daisuke , Kozono Yuko , Motoyama Noboru , Azuma Takachika 
Published: April 2014

AbstractChimeric mice were prepared from embryonic stem cells transfected with IgH genes as transgenes and RAG-2-deficient blastocysts for the purpose of identifying the cis-acting elements responsible for the induction of somatic hypermutation. Among the three transgene constructs used, the VH promoter, the rearranged VH-D-JH, an intron enhancer/matrix attachment region, and human Cμ were common to all, but the 3′-untranslated region in each construct was different. After immunization of mice with a T cell-dependent Ag, the distribution and frequency of hypermutation in transgenes were analyzed. The transgene lacking the 3′ untranslated region showed a marginal degree of hypermutation. Addition of the 3′ enhancer resulted in a slight increase in the number of mutations. However, the transgene containing DNase I-sensitive regions 3b and 4 in addition to the 3′ enhancer showed more than a 10-fold increase in hypermutation, reaching levels comparable to those observed in endogenous VH186.2 genes of C57BL/6 mice.
IFN-γ Overproduction and High Level Apoptosis Are Associated with High but Not Low VirulenceToxoplasma gondiiInfection
Authors: Gavrilescu L. Cristina , Denkers Eric Y. 
Published: April 2014

AbstractToxoplasma gondii is an opportunistic intracellular parasite which induces a highly strong type 1 cytokine response. The present study focuses on defining the factors influencing the outcome of infection with tachyzoites of the type I, highly lethal RH strain, relative to the type II, low virulence strain ME49. Infection with the RH strain led to widespread parasite dissemination and rapid death of mice; in contrast, mice survived low virulence strain ME49 infection, and tachyzoite dissemination was much less extensive. Furthermore, massive apoptosis and disintegration of the splenic architecture was characteristic of RH, but not ME49, infection. In addition, hyperinduction of IFN-γ and lack of NO production were found during RH, in contrast to ME49 infection. These data demonstrate that Toxoplasma strain characteristics exert a profound effect on the host immune response and that the latter itself is a crucial determinant in parasite virulence.
Overexpression of IL-15 In Vivo Enhances Protection AgainstMycobacterium bovisBacillus Calmette-Guérin Infection Via Augmentation of NK and T Cytotoxic 1 Responses
Authors: Umemura Masayuki , Nishimura Hitoshi , Hirose Kenji , Matsuguchi Tetsuya , Yoshikai Yasunobu 
Published: April 2014

AbstractTo investigate the immunomodulating effects of IL-15 in vivo on mycobacterial infection, we used IL-15-transgenic (Tg) mice, which were recently constructed with cDNA-encoding secretable isoform of IL-15 precursor protein under the control of a MHC class I promoter. The IL-15-Tg mice exhibited resistance against infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG), as assessed by bacteria growth. IFN-γ level in serum was significantly higher in IL-15-Tg mice than in non-Tg mice after BCG infection. NK cells were remarkably increased, and Ag-specific T cytotoxic 1 response mediated by CD8+ T cells producing IFN-γ was significantly augmented in the IL-15-Tg mice following BCG infection. Neutralization of endogenous IFN-γ by in vivo administration of anti-IFN-γ mAb deteriorated the clearance of the bacteria. Depletion of of NK cells or CD8+ T cells by invivo administration of anti-asialo-GM1 Ab or anti-CD8 mAb hampered the exclusion of bacteria. Thus, overexpression of IL-15 in vivo enhanced protection against BCG infection via augmentation of NK and T cytotoxic 1 responses.