bluuebunny/crossref_metadata_2025 huggingface dataset:
Activated Vγ9Vδ2 T Cells Trigger Granulocyte Functions via MCP-2 Release
Authors: Agrati Chiara , Cimini Eleonora , Sacchi Alessandra , Bordoni Veronica , Gioia Cristiana , Casetti Rita , Turchi Federica , Tripodi Marco , Martini Federico
Published: April 2014

Vγ9Vδ2 T cells display a broad antimicrobial activity by directly killing infected cells and by inducing an effective adaptive immune response. The activation of Vγ9Vδ2 T cells by aminobisphosphonate drugs such as zoledronic acid (ZOL) results in a massive release of cytokines and chemokines that may induce a bystander activation of other immune cells. The aim of this work was to evaluate the ability of soluble factors released by ZOL-activated Vγ9Vδ2 T cells to induce granulocyte activation. We showed that soluble factors released by ZOL-stimulated Vγ9Vδ2 T cells activate granulocytes by inducing their chemotaxis, phagocytosis, and α-defensins release. Proteomic analysis allowed us to identify a number of cytokines and chemokines specifically released by activated Vγ9Vδ2 T cells. Moreover, MCP-2 depletion by neutralizing Ab revealed a critical role of this chemokine in induction of granulocyte α-defensins release. Altogether, these data show a Vγ9Vδ2-mediated activation of granulocytes through a bystander mechanism, and confirm the wide ability of Vγ9Vδ2 T-lymphocytes in orchestrating the immune response. In conclusion, an immune modulating strategy targeting Vγ9Vδ2 T cells may represent a key switch to induce an effective and well-coordinated immune response, and can be proposed as a way to strengthen the immune competence during infectious diseases.
Crosstalk between Prostaglandin E2 and Leukotriene B4 Regulates Phagocytosis in Alveolar Macrophages via Combinatorial Effects on Cyclic AMP
Authors: Lee Sang Pyo , Serezani Carlos H. , Medeiros Alexandra I. , Ballinger Megan N. , Peters-Golden Marc
Published: April 2014

Eicosanoid lipid mediators, including prostaglandin E2 (PGE2) and leukotrienes (LTs) B4 and D4, are produced in abundance in the infected lung. We have previously demonstrated that individually, PGE2 suppresses while both classes of LTs augment alveolar macrophage (AM) innate immune functions. In this study, we sought to more appropriately model the milieu at a site of infection by studying the in vitro effects of these lipid mediators on FcγR-mediated phagocytosis when they are present in combination. Consistent with their individual actions, both LTB4 and LTD4 opposed the suppressive effect of PGE2 on phagocytosis, but only LTB4 did so by mitigating the stimulatory effect of PGE2 on intracellular cAMP production. Unexpectedly, we observed that IgG-opsonized targets themselves elicited a dose-dependent reduction in intracellular cAMP in AMs, but this was not observed in peritoneal macrophages or elicited peritoneal neutrophils; this effect in AMs was completely abolished by treatment with the LT synthesis inhibitor AA861, the BLT receptor 1 antagonist CP 105,696, and the Gαi inhibitor pertussis toxin. Of two downstream cAMP effectors, protein kinase A and exchange protein activated by cAMP, the ability of PGE2 to activate the latter but not the former was abrogated by both LTs B4 and D4. Taken together, our results indicate that both classes of LTs oppose the immune suppressive actions of PGE2, with the stimulatory actions of LTB4 reflecting combinatorial modulation of intracellular cAMP and those of LTD4 being cAMP independent.
Interacting Neuroendocrine and Innate and Acquired Immune Pathways Regulate Neutrophil Mobilization from Bone Marrow following Hemorrhagic Shock
Authors: Liu Yujian , Yuan Youzhong , Li Yuehua , Zhang Jian , Xiao Guozhi , Vodovotz Yoram , Billiar Timothy R. , Wilson Mark A. , Fan Jie
Published: April 2014

Polymorphonuclear neutrophils (PMN) are critical innate immune effector cells that either protect the host or exacerbate organ dysfunction by migrating to injured or inflamed tissues. Resuscitated hemorrhagic shock following major trauma promotes the development of organ inflammation by priming PMN migration and activation in response to a second, often trivial, stimulus (a so-called “two hit” phenomenon). PMN mobilization from bone marrow supports a sustained, hemorrhagic shock/resuscitation (HS/R)-primed migration of PMN. We addressed the role and mechanism of HS/R in regulating PMN egress from bone marrow. We demonstrate that HS/R through the alarmin HMGB1 induces IL-23 secretion from macrophages in an autocrine and TLR4 signaling-dependent manner. In turn IL-23, through an IL-17 G-CSF-mediated mechanism, induces PMN egress from bone marrow. We also show that β-adrenergic receptor activation by catecholamine of macrophages mediates the HS/R-induced release of HMGB1. These data indicate that HS/R, a global ischemia/reperfusion stimulus, regulates PMN mobilization through a series of interacting pathways that include neuroendocrine and innate and acquired immune systems. Blocking this novel signaling axis may present a novel therapeutic target for posttrauma inflammation.
Adiponectin and Functional Adiponectin Receptor 1 Are Expressed by Airway Epithelial Cells in Chronic Obstructive Pulmonary Disease
Authors: Miller Marina , Cho Jae Youn , Pham Alexa , Ramsdell Joe , Broide David H.
Published: April 2014

We screened bronchoalveolar lavage (BAL) fluids from COPD-E (chronic obstructive pulmonary disease-Emphysema) and control subjects using a 120 Ab cytokine array and demonstrated that adiponectin was highly expressed in BAL in COPD-E. An adiponectin ELISA confirmed that adiponectin was highly expressed in BAL in COPD-E compared with smokers and healthy control subjects. Immunohistochemistry studies of lung sections from subjects with COPD-E demonstrated that airway epithelial cells expressed significant levels of adiponectin and adiponectin receptor (AdipoR) 1 but not AdipoR2. In vitro studies with purified populations of human lung A549 epithelial cells demonstrated that they expressed both adiponectin and AdipoR1 (but not AdipoR2) as assessed by RT-PCR, Western blot, and immunohistochemistry. Lung A549 epithelial AdipoR1were functional as incubation with adiponectin induced release of IL-8, which was inhibited by small interfering RNA to AdipoR1. Using a mouse model of COPD, tobacco smoke exposure induced both evidence of COPD as well as increased levels of adiponectin in BAL fluid and increased adiponectin expression by airway epithelial cells. As adiponectin expression in adipocytes is dependent upon NF-κB we determined levels of adiponectin in tobacco smoke exposed CC10-Cretg/IkkβΔ/Δ mice (deficient in the ability to activate NF-κB in airway epithelium). These studies demonstrated that CC10-Cretg/IkkβΔ/Δ and wild-type mice had similar levels of BAL adiponectin and airway epithelial adiponectin immunostaining. Overall, these studies demonstrate the novel observation that adiponectin and functional AdipoR1are expressed by lung epithelial cells, suggesting a potential autocrine and/or paracrine pathway for adiponectin to activate epithelial cells in COPD-E.
Fulminant Lymphocytic Choriomeningitis Virus-Induced Inflammation of the CNS Involves a Cytokine-Chemokine-Cytokine-Chemokine Cascade
Authors: Christensen Jeanette E. , Simonsen Stine , Fenger Christina , Sørensen Maria R. , Moos Torben , Christensen Jan P. , Finsen Bente , Thomsen Allan R.
Published: April 2014

Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30–50% of the mice succumb to the infection. Similar results are obtained in mice deficient in the matching chemokine receptor, CXCR3. Together, these findings point to a key role for CXCL10 in regulating the severity of the LCMV-induced inflammatory process. For this reason, we now address the mechanisms regulating the expression of CXCL10 in the CNS of LCMV-infected mice. Using mice deficient in type I IFN receptor, type II IFN receptor, or type II IFN, as well as bone marrow chimeras expressing CXCL10 only in resident cells or only in bone marrow-derived cells, we analyzed the up-stream regulation as well as the cellular source of CXCL10. We found that expression of CXCL10 initially depends on signaling through the type I IFN receptor, while late expression and up-regulation requires type II IFN produced by the recruited CD8+ T cells. Throughout the infection, the producers of CXCL10 are exclusively resident cells of the CNS, and astrocytes are the dominant expressors in the neural parenchyma, not microglial cells or recruited bone marrow-derived cell types. These results are consistent with a model suggesting a bidirectional interplay between resident cells of the CNS and the recruited virus-specific T cells with astrocytes as active participants in the local antiviral host response.
IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection
Authors: Guilliams Martin , Movahedi Kiavash , Bosschaerts Tom , VandenDriessche Thierry , Chuah Marinee Khim , Hérin Michel , Acosta-Sanchez Abel , Ma Ling , Moser Muriel , Van Ginderachter Jo A. , Brys Lea , De Baetselier Patrick , Beschin Alain
Published: April 2014

Antiparasite responses are associated with the recruitment of monocytes that differentiate to macrophages and dendritic cells at the site of infection. Although classically activated monocytic cells are assumed to be the major source of TNF and NO during Trypanosoma brucei brucei infection, their cellular origin remains unclear. In this study, we show that bone marrow-derived monocytes accumulate and differentiate to TNF/inducible NO synthase-producing dendritic cells (TIP-DCs) in the spleen, liver, and lymph nodes of T. brucei brucei-infected mice. Although TIP-DCs have been shown to play a beneficial role in the elimination of several intracellular pathogens, we report that TIP-DCs, as a major source of TNF and NO in inflamed organs, could contribute actively to tissue damage during the chronic stage of T. brucei brucei infection. In addition, the absence of IL-10 leads to enhanced differentiation of monocytes to TIP-DCs, resulting in exacerbated pathogenicity and early death of the host. Finally, we demonstrate that sustained production of IL-10 following IL-10 gene delivery treatment with an adeno-associated viral vector to chronically infected mice limits the differentiation of monocytes to TIP-DCs and protects the host from tissue damage.
IL-12-Dependent Inducible Expression of the CD94/NKG2A Inhibitory Receptor Regulates CD94/NKG2C+ NK Cell Function
Authors: Sáez-Borderías Andrea , Romo Neus , Magri Giuliana , Gumá Mónica , Angulo Ana , López-Botet Miguel
Published: April 2014

The inhibitory CD94/NKG2A and activating CD94/NKG2C killer lectin-like receptors specific for HLA-E have been reported to be selectively expressed by discrete NK and T cell subsets. In the present study, minor proportions of NK and T cells coexpressing both CD94/NKG2A and CD94/NKG2C were found in fresh peripheral blood from adult blood donors. Moreover, CD94/NKG2A surface expression was transiently detected upon in vitro stimulation of CD94/NKG2C+ NK cells in the presence of irradiated allogeneic PBMC or rIL-12. A similar effect was observed upon coculture of NKG2C+ NK clones with human CMV-infected autologous dendritic cell cultures, and it was prevented by an anti-IL-12 mAb. NKG2A inhibited the cytolytic activity of NKG2C+ NK clones upon engagement either by a specific mAb or upon interaction with a transfectant of the HLA class I-deficient 721.221 cell line expressing HLA-E. These data indicate that beyond its constitutive expression by an NK cell subset, NKG2A may be also transiently displayed by CD94/NKG2C+ NK cells under the influence of IL-12, providing a potential negative regulatory feedback mechanism.
Epicutaneous Immunization with Protein Antigen in the Presence of TLR4 Ligand Induces TCRαβ+CD4+ T Contrasuppressor Cells That Reverse Skin-Induced Suppression of Th1-Mediated Contact Sensitivity
Authors: Ptak Włodzimierz , Majewska Monika , Bryniarski Krzysztof , Ptak Maria , Lobo Francis M. , Zając Katarzyna , Askenase Philip W. , Szczepanik Marian
Published: April 2014

Our previous work showed that epicutaneous (EC) immunization of mice with different protein Ags applied on the skin in the form of a patch induces a state of subsequent Ag-nonspecific unresponsiveness due to suppressor CD4+8+ T cells (Ts) that inhibit Th1-mediated contact sensitivity (CS) reactions via released TGF-β. In the present work we show that EC immunization with Ag together with the TLR4 ligand LPS induced cells that could prevent suppression by the Ag-nonspecific Ts. These up-regulatory cells, called contrasuppressor T cells (Tcs), belong to a population of Ag-specific TCRαβ CD4+ lymphocytes and are different from Th1 CD4+ cells that mediate the CS reaction. Experiments using knockout mice showed that EC induced contrasuppression is MyD88, INF-γ, and IL-12 dependent, whereas IL-6 is not involved in this phenomenon. Additional experiments with anti-IFN-γ mAb showed that IFN-γ is required for induction of Tcs cells but does not play a crucial role in the effector phase of contrasuppression. Additionally, treatment of CS effector cells with rIL-12 makes them resistant to EC induced suppression without affecting Ts cells, whereas IL-12 neutralization in vitro abrogates contrasuppression. These data show that IL-12 is indeed involved in the effector phase of EC induced contrasuppression and that this cytokine does not act directly on Ts cells. The mechanism of action of Tcs protects Th1 effector cells mediating CS from the nonspecific Ts, leaving suppression to other Ags intact. Ts and Tcs cells do not influence each other and can be induced simultaneously in the same animal.
Generation of a Novel System for Studying Spleen Tyrosine Kinase Function in Macrophages and B Cells
Authors: Miller Allison L. , Zhang Chao , Shokat Kevan M. , Lowell Clifford A.
Published: April 2014

Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is expressed primarily in hematopoietic cells. Because this protein has been implicated in processes such as Fc-mediated phagocytosis, BCR signaling, oxidative burst, degranulation, cytokine secretion, and integrin-mediated outside-in signaling, it is hypothesized that Syk may be a viable target in the treatment of a variety of autoimmune and inflammatory diseases. Because efforts to design a small-molecule therapeutic that specifically inhibits Syk have been largely unsuccessful, and genetic studies of Syk have been hampered by the fact that syk−/− mice die in utero, we have taken a chemical genetic approach to study the function of Syk. Specifically, we have created a mutant form of Syk that retains its wild-type function, but is susceptible to inhibition by enlarged derivatives of the tyrosine kinase inhibitor, PP1. We report in this study that Syk M442A S505A reconstituted wild-type function when introduced into murine syk−/− bone marrow-derived macrophages and syk−/− DT40 chicken B cells, as determined by functional and biochemical assays. Furthermore, after screening a series of PP1 derivatives, we identified one compound, namely 2,3-DMB-PP1, that specifically inhibited Syk M442A S505A, but not wild-type Syk. This system provides us with the power to characterize immune functions that are Syk specific, and furthermore, it provides us with a tool to assess how inhibition of Syk may alter an immune response and influence disease pathogenesis and/or progression.
Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance
Authors: Burns Audrea M. , Ma Lianli , Li Yijin , Yin Dengping , Shen JiKun , Xu Jing , Chong Anita S.
Published: April 2014

The impact of memory B cells and alloantibodies on the ability to induce transplantation tolerance has not been elucidated. We have developed a murine heart transplant model that isolates the contributions of functional memory B cells from memory T cells in allograft rejection. Memory 3-83 B cells with dual specificity for H-2Kk and H-2Kb were generated in 3-83 Igi BCR knockin (BALB/c background) mice by the transplantation of C3H (H-2Kk) hearts in the absence of immunosuppression. To test the effect of functional memory 3-83 B cells, C3H-primed 3-83 Igi recipients were challenged with C57BL/6 hearts (H-2Kb) at 60–90 days post-C3H heart transplant and treated with anti-CD154 mAbs. Despite immunosuppression, the C57BL/6 hearts were acutely rejected within 10–13 days and graft rejection was associated with increased frequencies of C57BL/6-specific IFN-γ-producing T cells. Histology revealed significant numbers of infiltrating T cells, consistent with acute T cell-mediated rejection. The resistance to tolerance induction was dependent on the synergistic effects of memory 3-83 B cells and alloantibodies, whereas memory T cells are not necessary. We conclude that the combined effects of functional memory B cells and alloantibodies prevent anti-CD154-mediated graft acceptance by facilitating the CD40-CD154-independent activation of alloreactive T cells. This study provides insight into the potential ability of memory B cells and alloantibodies to prevent anti-CD154-mediated graft acceptance.
The Adaptor Molecule Signaling Lymphocytic Activation Molecule-Associated Protein (SAP) Regulates IFN-γ and IL-4 Production in Vα14 Transgenic NKT Cells via Effects on GATA-3 and T-bet Expression
Authors: Cen Osman , Ueda Aki , Guzman Laura , Jain Jimmy , Bassiri Hamid , Nichols Kim E. , Stein Paul L.
Published: April 2014

NKT cells comprise a rare regulatory T cell population of limited TCR diversity, with most cells using a Vα14Jα18 TCR. These cells exhibit a critical dependence on the signaling adapter molecule, signaling lymphocytic activation molecule-associated protein (SAP), for their ontogeny, an aspect not seen in conventional αβ T cells. Prior studies demonstrate that SAP enhances TCR-induced activation of NF-κB in CD4+ T cells. Because NF-κB is required for NKT cell development, SAP might promote the ontogeny of this lineage by signaling to NF-κB. In this study, we demonstrate that forced expression of the NF-κB target gene, Bcl-xL, or inhibitory NF-κB kinase β, a catalytic subunit of the IκB kinase complex essential for NF-κB activation, fails to restore NKT cell development in sap−/− mice, suggesting that SAP mediates NKT cell development independently of NF-κB. To examine the role of SAP in NKT cell function, we generated NKT cells in sap−/− mice by expressing a transgene encoding the Vα14Jα18 component of the invariant TCR. These cells bound α-galactosylceramide-loaded CD1d tetramers, but exhibited a very immature CD24+NK1.1− phenotype. Although sap−/− tetramer-reactive cells proliferated in response to TCR activation, they did not produce appreciable levels of IL-4 or IFN-γ. The reduction in cytokine production correlated with the near absence of GATA-3 and T-bet, key transcription factors regulating cytokine expression and maturation of NKT cells. Ectopic expression of GATA-3 partially restored IL-4 production by the NKT cells. Collectively, these data suggest that by promoting GATA-3 and T-bet expression, SAP exerts control over NKT cell development and mature NKT cell cytokine production.
TLR9-Dependent Activation of Dendritic Cells by DNA from Leishmania major Favors Th1 Cell Development and the Resolution of Lesions
Authors: Hkima Abou Fakher Faihaa , Rachinel Nicolas , Klimczak Martine , Louis Jacques , Doyen Noëlle
Published: April 2014

In its vertebrate host, Leishmania encounters cells that express TLRs. Using genetically resistant C57BL/6 mice deficient in either TLR2, 4, or 9, we show in this study that only TLR9-deficient mice are more susceptible to infection with Leishmania major. TLR9-deficient mice resolved their lesions and controlled parasites growth with much lower efficiency than wild-type C57BL/6 mice. The absence of TLR9 also transiently inhibited the development of curative Th1 response. In an attempt to analyze the possible basis for such aberrant response in TLR9−/− mice, we have studied the importance of TLR9 for the activation of dendritic cells (DCs) by L. major. Results show that DCs in the draining lymph nodes are activated following infection with L. major. Furthermore, bone marrow-derived DCs as well as DCs freshly isolated from the spleen of C57BL/6 mice can be activated by either heat-killed or live L. major in vitro. In sharp contrast, L. major failed to activate DCs from TLR9−/− mice. Noteworthily, activation of DCs was abolished either following treatment of the parasites with DNase or after acidification of the endosomal compartment of DCs by chloroquine, pinpointing the DNA of L. major as the possible ligand of TLR9 leading to the activation of DCs. Results showed that DNA purified from L. major was indeed capable of activating DCs in a strictly TLR9-dependent manner. Moreover we showed that the L. major DNA-induced TLR9 signaling in DCs condition these cells to promote IFN-γ production by CD4+ T cells.
Increased IL-15 Production Is Associated with Higher Susceptibility of Memory CD4 T Cells to Simian Immunodeficiency Virus during Acute Infection
Authors: Eberly Matthew D. , Kader Muhamuda , Hassan Wail , Rogers Kenneth A. , Zhou Jianzhong , Mueller Yvonne M. , Mattapallil Mary J. , Piatak Michael , Lifson Jeffrey D. , Katsikis Peter D. , Roederer Mario , Villinger Francois , Mattapallil Joseph J.
Published: April 2014

Acute SIV infection is characterized by explosive infection of memory CD4 T cells in peripheral and mucosal tissues. Interestingly, relatively few memory CD4 T cells are infected until as late as days 7–8 after challenge. However, by day 10 postinfection, most of the memory CD4 T cells are infected and carry viral DNA. The rapidity with which infection expands within 2–3 days to encompass virtually the entire memory CD4 T cell compartment suggests significant alterations in the susceptibility of memory CD4 T cells to infection during this period. The mechanism(s) underlying this increased permissiveness to infection is not known. In this study, we show that IL-15 secretion significantly correlates with the up-regulated expression of CD4 on memory CD4 T cells that is associated with increased permissiveness to SIV infection. Activation and proliferation of memory CD8, but not memory CD4 T cells, preceded the amplification of viral infection. Although memory CD4 T cells did not express normal activation markers, they displayed a significant up-regulation in the density of CD4 but not CCR5 expression between days 7 and 10 postinfection that correlated with increased plasma IL-15 levels and infection in these cells. Culture of purified CD4 T cells with IL-15 and/or SIV was associated with a significant increase in the expression of CD4 and infection of these sorted cells. Our results demonstrate that IL-15 contributes to the increased susceptibility of memory CD4 T cells to SIV during the early phase of acute SIV infection.
Human Circulating CD4+CD25highFoxp3+ Regulatory T Cells Kill Autologous CD8+ but Not CD4+ Responder Cells by Fas-Mediated Apoptosis
Authors: Strauss Laura , Bergmann Christoph , Whiteside Theresa L.
Published: April 2014

Mechanisms utilized by human regulatory T cells (Treg) for elimination of effector cells may vary. We investigated the possibility that the mechanism of Treg suppression depends on Fas/FasL-mediated apoptosis of responder cells (RC). CD4+CD25highFoxp3+ Treg and autologous CD4+CD25− and CD8+CD25− subsets of RC were isolated from blood of 25 cancer patients and 15 normal controls and cocultured in the presence of OKT3 and IL-2 (150 or 1000 IU/ml). Suppression of RC proliferation was measured in CFSE assays. RC and Treg apoptosis was monitored by 7-aminoactinomycin D staining in flow-based cytotoxicity assays. Treg from all subjects expressed CD95+, but only Treg from cancer patients expressed CD95L. These Treg, when activated via TCR plus IL-2, up-regulated CD95 and CD95L expression (p < 0.001) and suppressed CD8+ RC proliferation (p < 0.001) by inducing Fas-mediated apoptosis. However, Treg cocultured with CD4+ RC suppressed proliferation independently of Fas/FasL. In cocultures, Treg were found to be resistant to apoptosis in the presence of 1000 IU/ml IL-2, but at lower IL-2 concentrations (150 IU/ml) they became susceptible to RC-induced death. Thus, Treg and RC can reciprocally regulate Treg survival, depending on IL-2 concentrations present in cocultures. This divergent IL-2-dependent resistance or sensitivity of Treg and RC to apoptosis is amplified in patients with cancer.
A Signaling Polypeptide Derived from an Innate Immune Adaptor Molecule Can Be Harnessed as a New Class of Vaccine Adjuvant
Authors: Kobiyama Kouji , Takeshita Fumihiko , Ishii Ken J. , Koyama Shohei , Aoshi Taiki , Akira Shizuo , Sakaue-Sawano Asako , Miyawaki Atsushi , Yamanaka Yuko , Hirano Hisashi , Suzuki Koichi , Okuda Kenji
Published: April 2014

Modulation of intracellular signaling using cell-permeable polypeptides is a promising technology for future clinical applications. To develop a novel approach to activate innate immune signaling by synthetic polypeptides, we characterized several different polypeptides derived from the caspase recruitment domain (CARD) of IFN-β promoter stimulator 1, each of which localizes to a different subcellular compartment. Of particular interest was, N′-CARD, which consisted of the nuclear localization signal of histone H2B and the IFN-β promoter stimulator 1CARD and which localized to the nucleus. This polypeptide led to a strong production of type I IFNs and molecular and genetic analyses showed that nuclear DNA helicase II is critically involved in this response. N′-CARD polypeptide fused to a protein transduction domain (N′-CARD-PTD) readily transmigrated from the outside to the inside of the cell and triggered innate immune signaling. Administration of N′-CARD-PTD polypeptide elicited production of type I IFNs, maturation of bone marrow-derived dendritic cells, and promotion of vaccine immunogenicity by enhancing Ag-specific Th1-type immune responses, thereby protecting mice from lethal influenza infection and from outgrowth of transplanted tumors in vivo. Thus, our results indicate that the N′-CARD-PTD polypeptide belongs to a new class of vaccine adjuvant that directly triggers intracellular signal transduction by a distinct mechanism from those engaged by conventional vaccine adjuvants, such as TLR ligands.
β-Defensin-2 Promotes Resistance against Infection with P. aeruginosa
Authors: Wu Minhao , McClellan Sharon A. , Barrett Ronald P. , Hazlett Linda D.
Published: April 2014

Corneal infection with Pseudomonas aeruginosa results in corneal perforation in susceptible C57BL/6 (B6) mice, but not in resistant BALB/c mice. To explore the role of two important defensins, murine β-defensin-1 (mBD1) and mBD2, in the ocular immune defense system, their mRNA and protein expression levels were tested by real-time RT-PCR and Western blot, respectively. mRNA, protein, and immunostaining data demonstrated that both mBD1 and mBD2 were constitutively expressed in normal BALB/c and B6 corneas, and they were disparately up-regulated in BALB/c (more) vs B6 (less) corneas after infection. To determine whether either defensin played a role in host resistance, BALB/c mice were treated with either mBD1 or mBD2 small interfering RNA by subconjunctival injection together with topical application. Increased corneal opacity and worsened disease were displayed after knockdown of mBD2 but not of mBD1. mBD2 silencing also increased bacterial counts and polymorphonuclear neutrophil infiltration in BALB/c corneas. Real-time RT-PCR data further demonstrated that mBD2, not mBD1, differentially modulated mRNA expression of proinflammatory cytokines/molecules such as IFN-γ, MIP-2, IL-1β, TNF-α, IL-6, and inducible NO synthase; TLR signaling molecules, including TLR2, TLR4, TLR9, and MyD88; and the transcription factor NF-κB. Additionally, in vivo studies indicated that mBD2 silencing enhanced corneal nitrite levels and NF-κB activation. Collectively, the data provide evidence that mBD2, but not mBD1, is required for host resistance against P. aeruginosa-induced corneal infection.
Dendritic Cell-Based Therapeutic Vaccination against Myeloma: Vaccine Formulation Determines Efficacy against Light Chain Myeloma
Authors: Cohen Sharon , Haimovich Joseph , Hollander Nurit
Published: April 2014

Multiple myeloma is an incurable plasma cell malignancy. Immunotherapy in myeloma patients had limited success to date. We have previously demonstrated that dendritic cells (DCs) pulsed with autologous Ig Id induced Id-reactive CD8+ T cells and protection against a myeloma tumor challenge. In this work, we studied the therapeutic efficacy of chemotherapy combined with different formulations of DC-based vaccines in mice bearing large plasma cell tumors. The comparative study demonstrated that s.c. injection of DCs loaded with Id coupled to keyhole limpet hemocyanin, s.c. injection of DCs loaded with irradiated tumor cells, and intratumoral injection of naive DCs were similarly effective in mediating tumor regression and long-term survival. However, whereas the Id-keyhole limpet hemocyanin-DC vaccine was inefficient against myeloma cells that lost expression of the Ig H chain, intratumoral injection of naive DCs and s.c. injection of DCs loaded with irradiated tumor cells were highly effective against cells producing L chains only. This may be of particular importance for patients with L chain myeloma. Given that T cells respond primarily to peptides derived from H chain CDRs, attempts to treat L chain disease with myeloma protein-pulsed DCs may be futile. Vaccination with tumor cell-loaded DCs may, however, induce an effective antitumor response.
Disruption of CCR5-Dependent Homing of Regulatory T Cells Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer
Authors: Tan Marcus C. B. , Goedegebuure Peter S. , Belt Brian A. , Flaherty Brian , Sankpal Narendra , Gillanders William E. , Eberlein Timothy J. , Hsieh Chyi-Song , Linehan David C.
Published: April 2014

Tumors evade immune destruction by actively inducing immune tolerance through the recruitment of CD4+CD25+Foxp3+ regulatory T cells (Treg). We have previously described increased prevalence of these cells in pancreatic adenocarcinoma, but it remains unclear what mechanisms are involved in recruiting Tregs into the tumor microenvironment. Here, we postulated that chemokines might direct Treg homing to tumor. We show, in both human pancreatic adenocarcinoma and a murine pancreatic tumor model (Pan02), that tumor cells produce increased levels of ligands for the CCR5 chemokine receptor and, reciprocally, that CD4+ Foxp3+ Tregs, compared with CD4+ Foxp3− effector T cells, preferentially express CCR5. When CCR5/CCL5 signaling is disrupted, either by reducing CCL5 production by tumor cells or by systemic administration of a CCR5 inhibitor (N,N-dimethyl-N-{{4-{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl}amino}}benzyl]-N,N-dimethyl-N- {{{4-{{{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptan-8-yl]carbonyl}amino}}benzyl}}}tetrahydro-2H-pyran-4-aminiumchloride; TAK-779), Treg migration to tumors is reduced and tumors are smaller than in control mice. Thus, this study demonstrates the importance of Tregs in immune evasion by tumors, how blockade of Treg migration might inhibit tumor growth, and, specifically in pancreatic adenocarcinoma, the role of CCR5 in the homing of tumor-associated Tregs. Selective targeting of CCR5/CCL5 signaling may represent a novel immunomodulatory strategy for the treatment of cancer.
A Novel Antiangiogenic Effect for Telomerase-Specific Virotherapy through Host Immune System
Authors: Ikeda Yoshihiro , Kojima Toru , Kuroda Shinji , Endo Yoshikatsu , Sakai Ryo , Hioki Masayoshi , Kishimoto Hiroyuki , Uno Futoshi , Kagawa Shunsuke , Watanabe Yuichi , Hashimoto Yuuri , Urata Yasuo , Tanaka Noriaki , Fujiwara Toshiyoshi
Published: April 2014

Soluble factors in the tumor microenvironment may influence the process of angiogenesis; a process essential for the growth and progression of malignant tumors. In this study, we describe a novel antiangiogenic effect of conditional replication-selective adenovirus through the stimulation of host immune reaction. An attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1 genes, could replicate in and cause selective lysis of cancer cells. Mixed lymphocyte-tumor cell culture demonstrated that OBP-301-infected cancer cells stimulated PBMC to produce IFN-γ into the supernatants. When the supernatants were subjected to the assay of in vitro angiogenesis, the tube formation of HUVECs was inhibited more efficiently than recombinant IFN-γ. Moreover, in vivo angiogenic assay using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice showed that tumor cell-induced neovascularization was markedly reduced when the chambers contained the mixed lymphocyte-tumor cell culture supernatants. The growth of s.c. murine colon tumors in syngenic mice was significantly inhibited due to the reduced vascularity by intratumoral injection of OBP-301. The antitumor as well as antiangiogenic effects, however, were less apparent in SCID mice due to the lack of host immune responses. Our data suggest that OBP-301 seems to have antiangiogenic properties through the stimulation of host immune cells to produce endogenous antiangiogenic factors such as IFN-γ.
Metabolic syndrome and cognitive decline: the role of physical activity
Authors: Rinaldi M. , Graffi G. , Rabino Massa E.
Published: April 2014

Metabolic Syndrome (MetS) is a cluster of conditions, each of which represents a risk factor for cardiovascular disease: central obesity, hyperglycemia, dyslipidemia and hypertension. Any of these conditions and MetS itself have been associated to Alzheimer's Disease and Vascular Dementia. In recent years there is a growing evidence for the role of physical activity in preventing metabolic diseases and cognitive decline. In our research we assessed the prevalence of MetS in a sample of 154 elderly people. Furthermore, we evaluated cognition (with Mini Mental State Examination, MMSE)  and the physical activity level in every patient. We found a significant association between MetS, borderline cognitive impairment and sedentary lifestyle.
Methodology for rapid assessment of seismic damage to buildings in Canadian settings
Authors: Abo-El-Ezz A , Nollet M J , Nastev M
Published: April 2014

A framework for rapid risk assessment is proposed considering local inventory of the building stock, definition of the seismic hazard and evaluation of the respective structural vulnerabilities. Structural vulnerability represents the central component of the
framework and is based on the concept of fragility functions which combine the intensity of the seismic motion to the expected damage for a given structural type. This report documents the development of a rapid procedure for the seismic risk assessment of buildings. The procedure was first
developed using the structural characteristics of the existing buildings in Old Quebec City with an emphasis to historic stone masonry buildings. Still it can be applied to existing or planned buildings of any structural type incorporating respective: (1) capacity curves which characterize the
nonlinear behaviour of a building (exposure); (2) displacement fragility curves which represent the probability of exceedance of specified damage state under various levels of structural response (vulnerability); and (3) site specific response spectra used to estimate the structural demand for a
series of earthquake magnitude-distance combinations (hazard). A modified approach to the capacity spectrum method is proposed for evaluation of the expected damage as opposed to the usual iterative procedure for the displacement response, e.g., the one implemented in the well known U.S. Federal
Emergency Management Agency - FEMA's Hazus software. The developed methodology revealed to be a powerful tool for rapid assessment of seismic risk of a single building type or a regional risk assessment as it significantly reduces the computation time. It was validated through seismic damage
assessment of 1220 buildings in Old Quebec City for a scenario event of M6.2 and distance 15km. The results were compared to those obtained by applying the Hazus software for the same input parameters (capacity curves and displacement based fragility functions) and showed negligible
differences.
Rural prevalence of type 2 diabetes mellitus: A cross sectional study
Authors: Rathod Hetal , Darade Sanjay , Chitnis Uday , Bhawalkar Jitendra , Jadhav Sudhir , Banerjee Amitav
Published: April 2014

Background: Recent studies in India indicate rising trends of diabetes even in rural areas. Continuous monitoring of the diabetes situation is required by repeated cross sectional studies in different parts of the country both urban rural to plan control measures. Aim: To estimate the prevalence of Type 2 diabetes in a sample of rural population and explore associations between diabetes and known risk factors. Materials and Methods: A cross sectional study was carried out in 3 villages in the rural field practice area of a medical college in Pune, India. All eligible adults of both genders were included and screened for diabetes by house to house survey. A total of 1000 subjects were examined. Physical examination included measuring height, weight, and waist hip ratio. Blood glucose was estimated using glucometer. Family history of diabetes was also elicited. Data was analysed by descriptive statistics using proportions with 95% confidence intervals. Various associations were explored using using Odds Ratio with 95% confidence intervals as applicable. Results: The prevalence of diabetes mellitus was 9.1% (91/1000; 95% CI 7.4, 11). Most cases of newly detected diabetics were in the age group 36 - 40 years. There was no association between gender and diabetes (OR = 1.38, 95% CI 0.88, 2.17). Overweight status was associated with diabetes: 38.5% (35/91) of diabetics were overweight compared to 18.6% (169/909) of non-diabetics (OR = 2.74, 95% CI 1.69, 4.41). Similarly abnormal waist hip ratio was associated with diabetes: 47.25% (43/91) of diabetics had high waist hip ratio compared with 29.59% (269/909) of non-diabetics (OR = 2.13, 95% CI 1.35, 3.37). Also family history was strongly associated with diabetes: 27.5% (25/91) of diabetics gave positive family history compared with 9.4% (85/909) of non-diabetics (OR = 3.67, 95% CI = 2.13, 6.30). Conclusion: The burden of diabetes was present in the rural population studied. The associated known risk factors were also prevalent and showed strong relationship with diabetes. Diabetes mellitus erstwhile thought to be a disease of urban life appears to be equally prevalent in the rural setting.
Analysis on the Unequal Welfare Service Distribution among Local Governments in Korea
Authors: Koo Chan Dong , Kim Heung Ju , Kim Pan Suk
Published: April 2014

This study analyzes the inequality of service distribution of Korea's local welfare services including basic living security, childcare, and senior care services in terms of territorial justice. Using Korea's welfare finance database, the units and resources of local governments, annual tendencies and factors of inequality are investigated by employing the welfare expenditure per service consumer as a measurement index. The results show that inequality is high in the expenditures of Si (city), Gun (county), and Gu (district) governments per service consumer, with grants from upper governments excluded. It is lessened when the budget includes the aid of the central government, which implies that the assistance of the central government plays a role in resolving the unequal expenditure distribution per service consumer. High inequality in the self-funded expenditure of Si, Gun, and Gu governments hints to wide regional gaps caused by differences in financial independence of local governments which will affect social welfare services provided by local governments. Therefore, welfare programs need to be fully financed by the central government in light of territorial justice.
State and future of the ‘citadel’ and of the heterodoxies in economics: challenges and dangers, convergences and cooperation
Authors: Elsner Wolfram
Published: April 2014

This keynote reflects on the phased-out original neoclassical research program and the dominance of originally heterodox issues and questions, all beyond the ‘optimality and equilibrium of the market economy’, in modern cutting-edge economic research. This provides opportunities for heterodoxies and a number of severe internal consistency problems in the current mainstream – between their serious research in terms of complexity, dynamics, evolution, institutions and political economy, which they share with the different heterodoxies, and the ideological mantras they keep sticking to in mass teaching, textbooks, commercial research, policy advice and media statements. The severe financial and comprehensive crises have not only left the mainstream largely unswayed, but have rendered economics an even more contested area. The ideological function of the mainstream for the existing economic system seems to have become even more pronounced. On top of that, there is a comprehensive and fatal counterattack against a potential pluralism of ideas and theories and paradigmatic competition, put forward against the heterodoxies and for ideological cleansing of the discipline, spurred on in the disguise of ranking games. The conception and methodologies of the evaluation and ranking procedures have been proved to be fundamentally mistaken and flawed, but are nevertheless implemented against heterodox thinking worldwide. Examples are given throughout the note. Against this background, this keynote reflects about the status of the heterodoxies and current opportunities and ways to establish a relevant, real-world and useful economic discipline through cooperation and proactive pluralism.
Modale partikels en vertaling
Authors: Vandeweghe Willy
Published: April 2014

Dutch, like German, is characterized by its prolific use of modal particles, a category which is much less present in languages like English and French. This paper reports on the results of an investigation into the differences between original Dutch and Dutch translated from English of French, for which data from two parallel corpora were used. The hypothesis, that translated Dutch has a lower density of modal particles, due to a lack of stimulus from the source text, was not unequivocally borne out.
De Nederlandse Reynaert-traditie in prenationaal, nationaal en transnationaal perspectief
Authors: Wackers Paul
Published: April 2014

In the recent past, two medieval Dutch Reynaert-stories have been published in separate editions, each with a modern translation: Van den vos Reynaerde with an English translation, Reynaerts historie with a German translation. In this article these two editions are presented as the outcome of a transnational approach. Following a sketch of the medieval tradition of stories about the famous fox, it is substantiated that both Dutch Reynaert stories form an integral part of this European tradition. It is also shown that Reynaerts historie is a key text in this tradition. Furthermore it is described how these stories were rediscovered in the nineteenth century, the period in which the modern nations of Belgium and The Netherlands came into existence, and how during that time Van den vos Reynaerde became gradually seen as a unique masterpiece and a perfect expression of (aspects of) national identity. Against this background, it is shown how the recent bilingual editions reveal a new awareness of the needs of an international public – without completely breaking with the scholarly tradition – and thus transcend the boundaries of a nationalistic approach.
Werken aan de toekomst - De historische roman van onze tijd
Authors: Vervaeck Bart
Published: April 2014

This article deals with the recent surge of encyclopaedic historical novels in Dutch literature. A first characteristic of these novels is that they install an identification between the I-narrator and the history he or she narrates. This identification does not take on the traditional form of the typical character embodying the historical average, nor that of the hopeful Michelet-like historian who acts as a prophet for his people. Rather, the I-figure is linked with history because they both follow the same exceptional, a-typical and apocalyptic logic, exemplified in viruses or nuclear fission. A second characteristic of these novels concerns the alterity and multiplicity of the I-character and history. Identity is revealed as a set of historical stories that penetrate one another. History turns out to be a multilayered image of various periods interpenetrating each other. On this basis, the article proposes a typology of historical novels based on the amount of historical layers: the one-dimensional novel corresponds with Ankersmit’s objective historical experience (the past is experienced as past); the two-dimensional novel corresponds with his subjective historical experience (the past is experienced from the viewpoint of the present); and the three-dimensional novels discussed in the article correspond with Ankersmit’s sublime historical experience (the distinction between the past and the present is erased). This leads to a short discussion of the ‘historicity regime’ (François Hartog) involved in the sublime historical novel.
‘De heiligst denkbare levenswijze’ - De vrijheid, dan wel gebondenheid van menselijk handelen in A.F.Th. van der Heijdens Mim of de doorstoken globe (2007)
Authors: Konst J.W.H.
Published: April 2014

The novel Mim (2007) by A.F.Th. van der Heijden is closely connected with S-ophocles’ Oedipus Rex. This article examines the relationship between the Dutch novel and the Greek drama. It demonstrates that a ‘diegetic transposition’ is involved: Van der H-eijden has transposed the Oedipus theme more or less literally into a late twentieth-century context. His main character Movo / Tibbolt Satink is a latter-day Oedipus who not only kills his father but has three children with his mother into the bargain. The analysis of Mim is brought to a point by asking to what extent voluntary action is involved. Would Movo / Tibbolt Satink have been able to avoid his crimes or was he at the mercy of higher powers? In this connection one could for example think of an unchangeable destiny or of the god Apollo, who plays a key role in the Homo duplex cycle of which Mim is a part. The question elaborated here, i.e. as to whether human actions are free or predetermined, will prove to provide a promising introduction to the work of Van der Heijden.
Geen prooi voor de sfinx - De lezer en het achttiende-eeuwse embleem
Authors: Stronks Els
Published: April 2014

In this article, I examine the changing emblematic genre of the eighteenth century. Once functioning as complex riddles for a learned audience, emblems came to be direct moralisations for a large audience during the Enlightenment. The textual and visual allegories which, in combination with the iconological tradition, once served as vehicle for the transfer of knowledge were replaced by different structures of meaning. This process is being studied in the Dutch emblematics of the eighteenth century, revealing various strategies used by poets to apply the literary allegory in a changing context.
De uitgever als poortwachter?
Authors: Nico Laan
Published: April 2014

Publishers are often compared to gatekeepers both on account of the role they play in the selection process as on account of their vital contribution to the social recognition of authorship. The comparison signals an important phenomenon but has its limitations. The first is of a historical nature. For centuries the printing culture coexisted with the much older manuscript culture. Publishers only started to play a key role between authors and the market at the moment when in the 18th and 19th century a print society originated. The second limitation concerns the distinction between literary genres. Those who call publishers gatekeepers suggest that they do so all across the board. That this is incorrect appears from an investigation into the publication of poetry and plays.