bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Adenovirus Expressing Flt3 Ligand Enhances Mucosal Immunity by Inducing Mature Nasopharyngeal-Associated Lymphoreticular Tissue Dendritic Cell Migration
Authors: Sekine Shinichi , Kataoka Kosuke , Fukuyama Yoshiko , Adachi Yasuo , Davydova Julia , Yamamoto Masato , Kobayashi Ryoki , Fujihashi Keiko , Suzuki Hideaki , Curiel David T. , Shizukuishi Satoshi , McGhee Jerry R. , Fujihashi Kohtaro 
Published: April 2014

AbstractPreviously, we showed that nasal administration of a naked cDNA plasmid expressing Flt3 ligand (FL) cDNA (pFL) enhanced CD4+ Th2-type, cytokine-mediated mucosal immunity and increased lymphoid-type dendritic cell (DC) numbers. In this study, we investigated whether targeting nasopharyngeal-associated lymphoreticular tissue (NALT) DCs by a different delivery mode of FL, i.e., an adenovirus (Ad) serotype 5 vector expressing FL (Ad-FL), would provide Ag-specific humoral and cell-mediated mucosal immunity. Nasal immunization of mice with OVA plus Ad-FL as mucosal adjuvant elicited high levels of OVA-specific Ab responses in external secretions and plasma as well as significant levels of OVA-specific CD4+ T cell proliferative responses and OVA-induced IFN-γ and IL-4 production in NALT, cervical lymph nodes, and spleen. We also observed higher levels of OVA-specific CTL responses in the spleen and cervical lymph nodes of mice given nasal OVA plus Ad-FL than in mice receiving OVA plus control Ad. Notably, the number of CD11b+CD11c+ DCs expressing high levels of costimulatory molecules was preferentially increased. These DCs migrated from the NALT to mucosal effector lymphoid tissues. Taken together, these results suggest that the use of Ad-FL as a nasal adjuvant preferentially induces mature-type NALT CD11b+CD11c+ DCs that migrate to effector sites for subsequent CD4+ Th1- and Th2-type cytokine-mediated, Ag-specific Ab and CTL responses.
CTLs Directed against HER2 Specifically Cross-React with HER3 and HER4
Authors: Conrad Heinke , Gebhard Kerstin , Krönig Holger , Neudorfer Julia , Busch Dirk H. , Peschel Christian , Bernhard Helga 
Published: April 2014

AbstractThe human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated Ag by T cell-based immunotherapeutical strategies such as cancer vaccines and adoptive T cell transfer. The prerequisite for a successful T cell-based therapy is the induction of T cells capable of recognizing the HER2-expressing tumor cells. In this study, we generated human cytotoxic T cell clones directed against the HER2369–377 epitope known to be naturally presented with HLA-A*0201. Those HER2-reactive CTLs, which were also tumor lytic, exhibited a similar lysis pattern dividing the targets in lysable and nonlysable tumor cells. Several HER2-expressing tumor cells became susceptible to CTL-mediated lysis after IFN-γ treatment and, in parallel, up-regulated molecules of the Ag-presenting machinery, indicating that the tumor itself also contributes to the success of CTL-mediated killing. Some of the HER2369–377-reactive T cells specifically cross-reacted with the corresponding peptides derived from the family members HER3 and/or HER4 due to a high sequence homology. The epitopes HER3356–364 and HER4361–369 were endogenously processed and contributed to the susceptibility of cell lysis by HER cross-reacting CTLs. The principle of “double” or “triple targeting” the HER Ags by cross-reacting T cells will impact the further development of T cell-based therapies.
Single-Chain TNF, a TNF Derivative with Enhanced Stability and Antitumoral Activity
Authors: Krippner-Heidenreich Anja , Grunwald Ingo , Zimmermann Gudrun , Kühnle Marie , Gerspach Jeannette , Sterns Theobald , Shnyder Steve D. , Gill Jason H. , Männel Daniela N. , Pfizenmaier Klaus , Scheurich Peter 
Published: April 2014

Abstract
The inflammatory and proapoptotic cytokine TNF possesses a compelling potential as an antitumoral therapeutic agent. Possible target cells include the malignant cells themselves, the tumor vasculature, or the immune system. As the clinical use of TNF is limited by systemic toxicity, targeting strategies using TNF-based fusion proteins are currently used. A major obstacle, however, is that homotrimeric TNF ligands are prone to activity loss due to dissociation into their monomers. In this study, we report the construction of single-chain TNF molecule, a TNF mutant consisting of three TNF monomers fused by short peptide linkers. In comparison to wild-type TNF, single-chain TNF was found to possess increased stability in vitro and in vivo, displayed reduced systemic toxicity yet slightly enhanced antitumoral activity in mouse models. Creation of single-chain variants is a new approach for improvement of functional activity of therapeutics based on TNF family ligands.
The T Cell Receptor’s α-Chain Connecting Peptide Motif Promotes Close Approximation of the CD8 Coreceptor Allowing Efficient Signal Initiation
Authors: Mallaun Michel , Naeher Dieter , Daniels Mark A. , Yachi Pia P. , Hausmann Barbara , Luescher Immanuel F. , Gascoigne Nicholas R. J. , Palmer Ed 
Published: April 2014

Abstract
The CD8 coreceptor contributes to the recognition of peptide-MHC (pMHC) ligands by stabilizing the TCR-pMHC interaction and enabling efficient signaling initiation. It is unclear though, which structural elements of the TCR ensure a productive association of the coreceptor. The α-chain connecting peptide motif (α-CPM) is a highly conserved sequence of eight amino acids in the membrane proximal region of the TCR α-chain. TCRs lacking the α-CPM respond poorly to low-affinity pMHC ligands and are unable to induce positive thymic selection. In this study we show that CD8 participation in ligand binding is compromised in T lineage cells expressing mutant α-CPM TCRs, leading to a slight reduction in apparent affinity; however, this by itself does not explain the thymic selection defect. By fluorescence resonance energy transfer microscopy, we found that TCR-CD8 association was compromised for TCRs lacking the α-CPM. Although high-affinity (negative-selecting) pMHC ligands showed reduced TCR-CD8 interaction, low-affinity (positive-selecting) ligands completely failed to induce molecular approximation of the TCR and its coreceptor. Therefore, the α-CPM of a TCR is an important element in mediating CD8 approximation and signal initiation.
Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii
Authors: Aronoff David M. , Hao Yibai , Chung Jooho , Coleman Nicole , Lewis Casey , Peres Camila M. , Serezani Carlos H. , Chen Gwo-Hsiao , Flamand Nicolas , Brock Thomas G. , Peters-Golden Marc 
Published: April 2014

Abstract
Fatal cases of acute shock complicating Clostridium sordellii endometritis following medical abortion with mifepristone (also known as RU-486) used with misoprostol were reported. The pathogenesis of this unexpected complication remains enigmatic. Misoprostol is a pharmacomimetic of PGE2, an endogenous suppressor of innate immunity. Clinical C. sordellii infections were associated with intravaginal misoprostol administration, suggesting that high misoprostol concentrations within the uterus impair immune responses against C. sordellii. We modeled C. sordellii endometritis in rats to test this hypothesis. The intrauterine but not the intragastric delivery of misoprostol significantly worsened mortality from C. sordellii uterine infection, and impaired bacterial clearance in vivo. Misoprostol also reduced TNF-α production within the uterus during infection. The intrauterine injection of misoprostol did not enhance mortality from infection by the vaginal commensal bacterium Lactobacillus crispatus. In vitro, misoprostol suppressed macrophage TNF-α and chemokine generation following C. sordellii or peptidoglycan challenge, impaired leukocyte phagocytosis of C. sordellii, and inhibited uterine epithelial cell human β-defensin expression. These immunosuppressive effects of misoprostol, which were not shared by mifepristone, correlated with the activation of the Gs protein-coupled E prostanoid (EP) receptors EP2 and EP4 (macrophages) or EP4 alone (uterine epithelial cells). Our data provide a novel explanation for postabortion sepsis leading to death and also suggest that PGE2, in which production is exaggerated within the reproductive tract during pregnancy, might be an important causal determinant in the pathogenesis of more common infections of the gravid uterus.
Transient Local Depletion of Foxp3+ Regulatory T Cells during Recovery from Colitis via Fas/Fas Ligand-Induced Death
Authors: Reardon Colin , Wang Arthur , McKay Derek M. 
Published: April 2014

AbstractRegulatory T cells (Tregs) play a fundamental role in regulating the immune system in health and disease. Considerable evidence exists demonstrating that transfer of Tregs can cure colitis and a variety of other inflammatory disorders. However, little is known about the effects of inflammation on resident Tregs. Mice (BALB/c or C57BL/6) treated with an intrarectal instillation of the haptenizing agent 2,4-dinitrobenzene sulfonic acid (DNBS) develop an acute inflammatory disease, the histopathology of which peaks at 3 days posttreatment and resolves spontaneously thereafter. In this study we demonstrate that DNBS (or oxazolone)-induced colitis causes a depletion of colonic Foxp3+ Tregs 8 days posttreatment, while the proportion of Foxp3+ cells in the ileum, mesenteric lymph nodes, and spleen remains unchanged. Replenishment of the colonic Treg population was associated with the reappearance of mucosal homing (α4β7+) CD4+Foxp3+ Tregs. Assessing the mechanism of local Treg depletion, we found no evidence to implicate cytokine-induced phenotypic switching in the Foxp3+ population or increased SMAD7 expression despite the essential role that TGF-β has in Foxp3+ Treg biology. Increased Fas ligand (FasL) expression was observed in the colon of colitic mice and in vitro stimulation with a Fas cross-linking Ab resulted in apoptosis of CD4+Foxp3+ but not CD4+Foxp3− cells. Furthermore, DNBS-induced colitis in Fas/FasL-deficient mice did not result in depletion of colonic Tregs. Finally, adoptively transferred synergic Fas−/− but not Fas+/+ Tregs were protected from depletion in the colon 8 days post-DNBS treatment, thus substantiating the hypothesis that inflammation-induced local depletion of Foxp3+ Tregs in the colon of mice occurs via Fas/FasL-mediated death.
The Neuropeptide Substance P Is a Critical Mediator of Burn-Induced Acute Lung Injury
Authors: Sio Selena Wei Shan , Puthia Manoj Kumar , Lu Jia , Moochhala Shabbir , Bhatia Madhav 
Published: April 2014

Abstract
The classical tachykinin substance P (SP) has numerous potent neuroimmunomodulatory effects on all kinds of airway functions. Belonging to a class of neuromediators targeting not only residential cells but also inflammatory cells, studying SP provides important information on the bidirectional linkage between how neural function affects inflammatory events and, in turn, how inflammatory responses alter neural activity. Therefore, this study aimed to investigate the effect of local burn injury on inducing distant organ pulmonary SP release and its relevance to lung injury. Our results show that burn injury in male BALB/c mice subjected to 30% total body surface area full thickness burn augments significant production of SP, preprotachykinin-A gene expression, which encodes for SP, and biological activity of SP-neurokinin-1 receptor (NK1R) signaling. Furthermore, the enhanced SP-NK1R response correlates with exacerbated lung damage after burn as evidenced by increased microvascular permeability, edema, and neutrophil accumulation. The development of heightened inflammation and lung damage was observed along with increased proinflammatory IL-1β, TNF-α, and IL-6 mRNA and protein production after injury in lung. Chemokines MIP-2 and MIP-1α were markedly increased, suggesting the active role of SP-induced chemoattractants production in trafficking inflammatory cells. More importantly, administration of L703606, a specific NK1R antagonist, 1 h before burn injury significantly disrupted the SP-NK1R signaling and reversed pulmonary inflammation and injury. The present findings show for the first time the role of SP in contributing to exaggerated pulmonary inflammatory damage after burn injury via activation of NK1R signaling.
Molecular Mimicry between Neurons and an Intracerebral Pathogen Induces a CD8 T Cell-Mediated Autoimmune Disease
Authors: Sanchez-Ruiz Monica , Wilden Laura , Müller Werner , Stenzel Werner , Brunn Anna , Miletic Hrvoje , Schlüter Dirk , Deckert Martina 
Published: April 2014

Abstract
To identify basic mechanisms of how infections may induce a neuron-specific autoimmune response, we generated mice expressing OVA as neuronal autoantigen under control of the neuron-specific enolase promoter (NSE-OVA mice). Intracerebral, but not systemic, infection with attenuated Listeria monocytogenes-secreting OVA induced an atactic-paretic neurological syndrome in NSE-OVA mice after bacterial clearance from the brain, whereas wild-type mice remained healthy. Immunization with attenuated Listeria monocytogenes-secreting OVA before intracerebral infection strongly increased the number of intracerebral OVA-specific CD8 T cells aggravating neurological disease. T cell depletion and adoptive transfer experiments identified CD8 T cells as decisive mediators of the autoimmune disease. Importantly, NSE-OVA mice having received OVA-specific TCR transgenic CD8 T cells developed an accelerated, more severe, and extended neurological disease. Adoptively transferred pathogenic CD8 T cells specifically homed to OVA-expressing MHC class I+ neurons and, corresponding to the clinical symptoms, ∼30% of neurons in the anterior horn of the spinal cord became apoptotic. Thus, molecular mimicry between a pathogen and neurons can induce a CD8 T cell-mediated neurological disease, with its severity being influenced by the frequency of specific CD8 T cells, and its induction, but not its symptomatic phase, requiring the intracerebral presence of the pathogen.
TNF-α Antagonism Generates a Population of Antigen-Specific CD4+CD25+ T Cells That Inhibit Protective Immunity in Murine Histoplasmosis
Authors: Deepe George S. , Gibbons Reta S. 
Published: April 2014

AbstractIn both humans and mice, treatment with TNF-α antagonists is associated with serious infectious complications including disseminated histoplasmosis. The mechanisms by which inhibition of endogenous TNF-α alter protective immunity remain obscure. Herein, we tested the possibility that neutralization of this cytokine triggered the emergence of T cells that dampen immunity. The lungs of mice given mAb to TNF-α contained a higher proportion and number of CD4+CD25+ cells than controls. This elevation was not observed in IFN-γ- or GM-CSF-deficient mice or in those given a high inoculum. Phenotypic analysis revealed that these cells lacked many of the characteristics of natural regulatory T cells, including Foxp3. CD4+CD25+ cells from TNF-α-neutralized mice suppressed Ag-specific, but not nonspecific, responses in vitro. Elimination of CD25+ cells in vivo restored protective immunity in mice given mAb to TNF-α and adoptive transfer of CD4+CD25+ cells inhibited immunity. In vitro and in vivo, the suppressive effect was reversed by mAb to IL-10. Thus, neutralization of TNF-α is associated with the induction of a population of regulatory T cells that alter protective immunity in an Ag-specific manner to Histoplasma capsulatum.
The Proinflammatory Cytokine Response toChlamydia trachomatisElementary Bodies in Human Macrophages Is Partly Mediated by a Lipoprotein, the Macrophage Infectivity Potentiator, through TLR2/TLR1/TLR6 and CD14
Authors: Bas Sylvette , Neff Laurence , Vuillet Madeleine , Spenato Ursula , Seya Tsukasa , Matsumoto Misako , Gabay Cem 
Published: April 2014

AbstractChlamydiae components and signaling pathway(s) responsible for the production of proinflammatory cytokines by human monocytes/macrophages are not clearly identified. To this aim, Chlamydia trachomatis-inactivated elementary bodies (EB) as well as the following seven individual Ags were tested for their ability to induce the production of proinflammatory cytokines by human monocytes/macrophages and THP-1 cells: purified LPS, recombinant heat shock protein (rhsp)70, rhsp60, rhsp10, recombinant polypeptide encoded by open reading frame 3 of the plasmid (rpgp3), recombinant macrophage infectivity potentiator (rMip), and recombinant outer membrane protein 2 (rOmp2). Aside from EB, rMip displayed the highest ability to induce release of IL-1β, TNF-α, IL-6, and IL-8. rMip proinflammatory activity could not be attributed to Escherichia coli LPS contamination as determined by the Limulus Amoebocyte lysate assay, insensitivity to polymyxin B (50 μg/ml), and different serum requirement. We have recently demonstrated that Mip is a “classical” bacterial lipoprotein, exposed at the surface of EB. The proinflammatory activity of EB was significantly attenuated in the presence of polyclonal Ab to rMip. Native Mip was able to induce TNF-α and IL-8 secretion, whereas a nonlipidated C20A rMip variant was not. Proinflammatory activity of rMip was unaffected by heat or proteinase K treatments but was greatly reduced by treatment with lipases, supporting a role of lipid modification in this process. Stimulating pathways appeared to involve TLR2/TLR1/TLR6 with the help of CD14 but not TLR4. These data support a role of Mip lipoprotein in pathogenesis of C. trachomatis-induced inflammatory responses.
Urokinase-Type Plasminogen Activator Plays Essential Roles in Macrophage Chemotaxis and Skeletal Muscle Regeneration
Authors: Bryer Scott C. , Fantuzzi Giamila , Van Rooijen Nico , Koh Timothy J. 
Published: April 2014

Abstract
Although macrophages are thought to play important roles in tissue repair, the molecular mechanisms involved remain to be elucidated. Mice deficient in urokinase-type plasminogen activator (uPA−/−) exhibit decreased accumulation of macrophages following muscle injury and severely impaired muscle regeneration. We tested whether macrophage-derived uPA plays essential roles in macrophage chemotaxis and skeletal muscle regeneration. Macrophage uPA was required for chemotaxis, even when invasion through matrix was not necessary. The mechanism by which macrophage uPA promoted chemotaxis was independent of receptor binding but appeared to depend on proteolytic activity. Exogenous uPA restored chemotaxis to uPA−/− macrophages and rescued muscle regeneration in uPA−/− mice. Macrophage depletion in wild-type (WT) mice using clodronate liposomes resulted in impaired muscle regeneration, confirming that macrophages are required for efficient healing. Furthermore, transfer of WT bone marrow cells to uPA−/− mice restored macrophage accumulation and muscle regeneration. In this rescue, transferred WT cells appeared to contribute to IGF-1 expression but did not fuse to regenerating fibers. These data indicate that WT leukocytes, including macrophages, that express uPA were sufficient to rescue muscle regeneration in uPA−/− mice. Overall, the results indicate that uPA plays a fundamental role in macrophage chemotaxis and that macrophage-derived uPA promotes efficient muscle regeneration.
Cutting Edge: Cooperation of IPS-1- and TRIF-Dependent Pathways in Poly IC-Enhanced Antibody Production and Cytotoxic T Cell Responses
Authors: Kumar Himanshu , Koyama Shohei , Ishii Ken J. , Kawai Taro , Akira Shizuo 
Published: April 2014

Abstract
Double-stranded RNA, polyriboinosinic-polyribocytidylic acid (poly IC), acts as an adjuvant that enhances adaptive immune responses. The recognition of poly IC is mediated by endosomal TLR3 and cytoplasmic RNA helicase melanoma differentiation-associated gene 5 (Mda5), which signal through the adaptors Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) and IFN-β promoter stimulator-1 (IPS-1), respectively. However, the contribution of these pathways to the adjuvant effects of poly IC remains unclear. In this study, we found that poly IC-enhanced, Ag-specific Ab production was severely decreased in IPS-1-deficient mice but not in TRIF-deficient mice. However, the double deficiency resulted in a complete loss of Ab production. Furthermore, Ag-specific CD8+ T cell expansion was reduced in both IPS-1-deficient and TRIF-deficient mice and entirely abrogated in the doubly deficient mice. Taken together, these results demonstrate that the adjuvant effects of poly IC require a cooperative activation of TLR and cytoplasmic RNA helicase pathways.
Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks
Authors: Anolik Jennifer H. , Ravikumar Rajan , Barnard Jennifer , Owen Teresa , Almudevar Anthony , Milner Eric C. B. , Miller Chase H. , Dutcher Paul O. , Hadley James A. , Sanz Iñaki 
Published: April 2014

Abstract
Rheumatoid arthritis (RA) is mediated by a proinflammatory cytokine network with TNF at its apex. Accordingly, drugs that block TNF have demonstrated significant efficacy in the treatment of RA. A great deal of experimental evidence also strongly implicates B cells in the pathogenesis of RA. Yet, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In this study we demonstrate that RA patients on anti-TNF (etanercept) display a paucity of follicular dendritic cell networks and germinal center (GC) structures accompanied by a reduction in CD38+ GC B cells and peripheral blood memory B cell lymphopenia compared with healthy controls and RA patients on methotrexate. This study provides initial evidence in humans to support the notion that anti-TNF treatment disrupts GC reactions at least in part via effects on follicular dendritic cells.
Plasmodium Infection and Endotoxic Shock Induce the Expansion of Regulatory Dendritic Cells
Authors: Wong Kurt A. , Rodriguez Ana 
Published: April 2014

Abstract
During an acute Plasmodium infection, uncontrolled proinflammatory responses can cause morbidity and mortality. Regulation of this response is required to prevent immunopathology. We therefore decided to investigate a recently characterized subset of regulatory dendritic cells (DCs) that expresses low levels of CD11c and high levels of CD45RB. During a Plasmodium yoelii infection, these regulatory CD11clowCD45RBhigh DCs become the prevalent CD11c-expressing cells in the spleen, overtaking the conventional CD11chigh DCs. Furthermore, the regulatory CD11clowCD45RBhigh DCs induce IL-10-expressing CD4 T cells. A similar change in splenic DC subsets is seen when mice are injected with sublethal doses of LPS, suggesting that shifting the splenic DC subsets in favor of regulatory CD11clowCD45RBhigh DCs can be triggered solely by a high inflammatory stimulus. This is the first time regulatory DCs have been observed in a natural immune response to an infectious disease or endotoxic shock.