bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peroxisome Proliferator Activator Receptor-γ Ligands, 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone, Reduce Systemic Inflammation in Polymicrobial Sepsis by Modulation of Signal Transduction Pathways
Authors: Zingarelli Basilia , Sheehan Maeve , Hake Paul W. , O’Connor Michael , Denenberg Alvin , Cook James A. 
Published: April 2014

Abstract
Peroxisome proliferator activator receptor-γ (PPARγ) is a nuclear receptor that controls the expression of several genes involved in metabolic homeostasis. We investigated the role of PPARγ during the inflammatory response in sepsis by the use of the PPARγ ligands, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) and ciglitazone. Polymicrobial sepsis was induced by cecal ligation and puncture in rats and was associated with hypotension, multiple organ failure, and 50% mortality. PPARγ expression was markedly reduced in lung and thoracic aorta after sepsis. Immunohistochemistry showed positive staining for nitrotyrosine and poly(ADP-ribose) synthetase in thoracic aortas. Plasma levels of TNF-α, IL-6, and IL-10 were increased. Elevated activity of myeloperoxidase was found in lung, colon, and liver, indicating a massive infiltration of neutrophils. These events were preceded by degradation of inhibitor κBα (IκBα), activation of IκB kinase complex, and c-Jun NH2-terminal kinase and, subsequently, activation of NF-κB and AP-1 in the lung. In vivo treatment with ciglitazone or 15d-PGJ2 ameliorated hypotension and survival, blunted cytokine production, and reduced neutrophil infiltration in lung, colon, and liver. These beneficial effects of the PPARγ ligands were associated with the reduction of IκB kinase complex and c-Jun NH2-terminal kinase activation and the reduction of NF-κB and AP-1 DNA binding in the lung. Furthermore, treatment with ciglitazone or 15d-PGJ2 up-regulated the expression of PPARγ in lung and thoracic aorta and abolished nitrotyrosine formation and poly(ADP-ribose) expression in aorta. Our data suggest that PPARγ ligands attenuate the inflammatory response in sepsis through regulation of the NF-κB and AP-1 pathways.
Trachea Allograft Class I Molecules Directly Activate and Retain CD8+ T Cells That Cause Obliterative Airways Disease
Authors: Richards David M. , Dalheimer Stacy L. , Hertz Marshall I. , Mueller Daniel L. 
Published: April 2014

AbstractHuman T cells responding against transplanted allogeneic lung tissue have been implicated in late graft failure secondary to obliterative bronchiolitis. This obliterative airways disease (OAD) also develops in heterotopic murine tracheal allografts in association with graft infiltration by both CD8+ and CD4+ T cells. To date, there has been little evidence to suggest that directly alloreactive CD8+ T cells either promote chronic rejection or lead to the development of OAD following airway allotransplantation. Using Ld-specific TCR-Tg 2C CD8+ T cells adoptively transferred into wild-type B6 (H-2b) mice and the transplantation of BALB/c (H-2d) tracheal allografts, we now show that the direct recognition of donor-specific class I MHC molecules by host CD8+ T cells leads to their activation, clonal expansion within the graft, and differentiation to an effector phenotype with the capacity to induce airway fibrosis. In addition, these experiments demonstrate that ongoing direct alloantigen recognition within the transplanted airway tissue is necessary for the recruitment and retention of these directly alloreactive CD8+ T cells. Thus, these experiments are the first to definitively show a role for directly alloreactive CD8+ T cells in the chronic rejection that leads to OAD.
Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease
Authors: Liu Hong-biao , Loo Kyi Kyi , Palaszynski Karen , Ashouri Judith , Lubahn Dennis B. , Voskuhl Rhonda R. 
Published: April 2014

Abstract
Estrogens are known to influence a variety of autoimmune diseases, but it is not known whether their actions are mediated through classic estrogen receptor α (ERα). The presence of a functional ER was demonstrated in secondary lymphoid tissues, then ERα expression was shown at both the RNA and protein levels in these tissues. Use of ERα knockout mice revealed that both the estrogen-induced disease protection and the estrogen-induced reduction in proinflammatory cytokines were dependent upon ERα in the prototypic Th1-mediated autoimmune disease experimental autoimmune encephalomyelitis. These findings are central to the design of selective ER modifiers which aim to target biologic responses in specific organ systems.
Cutting Edge: In Vivo Induction of Integrated HIV-1 Expression by Mycobacteria Is Critically Dependent on Toll-Like Receptor 2
Authors: Báfica André , Scanga Charles A. , Schito Marco L. , Hieny Sara , Sher Alan 
Published: April 2014

AbstractMycobacterial infection has been implicated as a possible factor in AIDS progression in populations where HIV-1 and Mycobacterium tuberculosis are coendemic. In support of this concept, we have previously shown that HIV-1-transgenic (Tg) mice infected with mycobacteria display enhanced viral gene and protein expression. In this study, we demonstrate that the induction of HIV-1 observed in this model is dependent on Toll-like receptor 2 (TLR2), a pattern recognition receptor known to be involved in mycobacteria-host interaction. Spleen cells from HIV-1-Tg mice deficient in TLR2 (Tg/TLR2−/−) were found to be completely defective in p24 production induced in response to live M. tuberculosis or Mycobacterium avium as well as certain mycobacterial products. Importantly, following in vivo mycobacterial infection, Tg/TLR2−/− mice failed to display the enhanced HIV-1 gag/env mRNA and p24 protein synthesis exhibited by wild-type Tg animals. Together, these results argue that TLR2 plays a crucial role in the activation of HIV-1 expression by mycobacterial coinfections.
Baculovirus Induces an Innate Immune Response and Confers Protection from Lethal Influenza Virus Infection in Mice
Authors: Abe Takayuki , Takahashi Hitoshi , Hamazaki Hiroyuki , Miyano-Kurosaki Naoko , Matsuura Yoshiharu , Takaku Hiroshi 
Published: April 2014

Abstract
A recombinant baculovirus expressing the hemagglutinin gene of the influenza virus, A/PR/8/34 (H1N1), under the control of the chicken β-actin promoter, was constructed. To determine the induction of protective immunity in vivo, mice were inoculated with the recombinant baculovirus by intramuscular, intradermal, i.p., and intranasal routes and then were challenged with a lethal dose of the influenza virus. Intramuscular or i.p. immunization with the recombinant baculovirus elicited higher titers of antihemagglutinin Ab than intradermal or intranasal administration. However, protection from a lethal challenge of the influenza virus was only achieved by intranasal immunization of the recombinant baculovirus. Surprisingly, sufficient protection from the lethal influenza challenge was also observed in mice inoculated intranasally with a wild-type baculovirus, as evaluated by reductions in the virus titer, inflammatory cytokine production, and pulmonary consolidations. These results indicate that intranasal inoculation with a wild-type baculovirus induces a strong innate immune response, which protects mice from a lethal challenge of influenza virus.
The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-α Production in CD11c+CD11b+CD8− Dendritic Cells
Authors: Doxsee Christie L. , Riter Tony R. , Reiter Michael J. , Gibson Shelia J. , Vasilakos John P. , Kedl Ross M. 
Published: April 2014

AbstractIL-12 and TNF-α production by dendritic cells (DCs) is a critical step in the initiation of local inflammation and adaptive immune responses. We show in this study that a small molecule immune response modifier that is a Toll-like receptor 7 (TLR7) agonist induces IL-12 and TNF-α production from murine CD11c+CD11b+CD8− DCs, a subset not previously known for this activity. Stimulation of these DCs through TLR7 in vivo induces significant cytokine production even 12 h after initial stimulation, as well as migration of the DC into T cell zones of the lymphoid tissue. In contrast, stimulation through TLR4 and TLR9 induced IL-12 production predominantly from CD8+ DCs, consistent with previously published data. All TLR stimuli induced the increase in surface expression of the activation markers B7-1, B7-2, and class II in both CD8+ and CD8− DCs, demonstrating that CD8+ DCs do respond to TLR7-mediated stimuli. To date this is the only known stimuli to induce preferential cytokine production from CD8− DCs. Given the efficacy of TLR7 agonists as antiviral agents, the data collectively indicate that stimulation of CD8− DCs through TLR7 most likely plays a role in the generation of antiviral immune responses.
Early Defect Prethymic in Bone Marrow T Cell Progenitors in Athymicnu/nuMice
Authors: Chatterjea-Matthes Devavani , García-Ojeda Marcos E. , Dejbakhsh-Jones Sussan , Jerabek Libuse , Manz Markus G. , Weissman Irving L. , Strober Samuel 
Published: April 2014

Abstractnu/nu mice fail to develop a thymus and mature T cells due to a defect in the whn gene encoding a transcription factor necessary for terminal epithelial cell differentiation. We investigated whether early T cell progenitor development in the nu/nu bone marrow is also defective. We demonstrated a maturation arrest of nu/nu marrow T cell progenitors associated with a lack of pTα gene expression and a failure to give rise to mature T cells in adoptive euthymic hosts. Wild-type hemopoietic stem cells rapidly matured into functional T cell progenitors in the marrow of euthymic or thymectomized but not nu/nu hosts. We show that defects in bone marrow prethymic T cell development can also contribute to T cell deficiency in nu/nu mice.
Functional Analysis of the TCR Binding Domain of Toxic Shock Syndrome Toxin-1 Predicts Further Diversity in MHC Class II/Superantigen/TCR Ternary Complexes
Authors: McCormick John K. , Tripp Timothy J. , Llera Andrea S. , Sundberg Eric J. , Dinges Martin M. , Mariuzza Roy A. , Schlievert Patrick M. 
Published: April 2014

AbstractSuperantigens (SAGs) aberrantly alter immune system function through simultaneous interaction with lateral surfaces of MHC class II molecules on APCs and with particular variable regions of the TCR β-chain (Vβ). To further define the interface between the bacterial SAG toxic shock syndrome toxin-1 (TSST-1) and the TCR, we performed alanine scanning mutagenesis within the putative TCR binding region of TSST-1 along the central α helix adjacent to the N-terminal α helix and the β7-β9 loop as well as with two universally conserved SAG residues (Leu137 and Tyr144 in TSST-1). Mutants were analyzed for multiple functional activities, and various residues appeared to play minor or insignificant roles in the TCR interaction. The locations of six residues (Gly16, Trp116, Glu132, His135, Gln136, and Gln139), each individually critical for functional activity as well as direct interaction with the human TCR Vβ2.1-chain, indicate that the interface occurs in a novel region of the SAG molecule. Based on these data, a model of the MHC/TSST-1/TCR ternary complex predicts similarities seen with other characterized SAGs, although the CDR3 loop of Vβ2.1 is probably involved in direct SAG-TCR molecular interactions, possibly contributing to the TCR Vβ specificity of TSST-1.
Repetitive Elements in Mammalian Telomeres Suppress Bacterial DNA-Induced Immune Activation
Authors: Gursel Ihsan , Gursel Mayda , Yamada Hiroshi , Ishii Ken J. , Takeshita Fumihiko , Klinman Dennis M. 
Published: April 2014

AbstractBacterial DNA contains immunostimulatory CpG motifs that trigger an innate immune response capable of promoting host survival following infectious challenge. Yet CpG-driven immune activation may also have deleterious consequences, ranging from autoimmune disease to death. We find that repetitive elements present at high frequency in mammalian telomeres, but rare in bacteria, down-regulate CpG-induced immune activation. Suppressive activity correlates with the ability of telomeric TTAGGG repeats to form G-tetrads. Colocalization of CpG DNA with Toll-like receptor 9 in endosomal vesicles is disrupted by these repetitive elements, although cellular binding and uptake remain unchanged. These findings are the first to establish that specific host-derived molecules can down-regulate the innate immune response elicited by a TLR ligand.
Alternate Class I MHC Antigen Processing Is Inhibited by Toll-Like Receptor Signaling Pathogen-Associated Molecular Patterns:Mycobacterium tuberculosis19-kDa Lipoprotein, CpG DNA, and Lipopolysaccharide
Authors: Tobian Aaron A. R. , Potter Nicholas S. , Ramachandra Lakshmi , Pai Rish K. , Convery Marilyn , Boom W. Henry , Harding Clifford V. 
Published: April 2014

AbstractPathogen-associated molecular patterns (PAMPs) signal through Toll-like receptors (TLRs) to activate immune responses, but prolonged exposure to PAMPs from Mycobacterium tuberculosis (MTB) and other pathogens inhibits class II MHC (MHC-II) expression and Ag processing, which may allow MTB to evade CD4+ T cell immunity. Alternate class I MHC (MHC-I) processing allows macrophages to present Ags from MTB and other bacteria to CD8+ T cells, but the effect of PAMPs on this processing pathway is unknown. In our studies, MTB and TLR-signaling PAMPs, MTB 19-kDa lipoprotein, CpG DNA, and LPS, inhibited alternate MHC-I processing of latex-conjugated Ag by IFN-γ-activated macrophages. Inhibition was dependent on TLR-2 for MTB 19-kDa lipoprotein (but not whole MTB or the other PAMPs); inhibition was dependent on myeloid differentiation factor 88 for MTB and all of the individual PAMPs. Inhibition of MHC-II and alternate MHC-I processing was delayed, appearing after 16 h of PAMP exposure, as would occur in chronically infected macrophages. Despite inhibition of alternate MHC-I Ag processing, there was no inhibition of MHC-I expression, MHC-I-restricted presentation of exogenous peptide or conventional MHC-I processing of cytosolic Ag. MTB 19-kDa lipoprotein and other PAMPs inhibited phagosome maturation and phagosome Ag degradation in a myeloid differentiation factor 88-dependent manner; this may limit availability of peptides to bind MHC-I. By inhibiting both MHC-II and alternate MHC-I Ag processing, pathogens that establish prolonged infection of macrophages (&gt;16 h), e.g., MTB, may immunologically silence macrophages and evade surveillance by both CD4+ and CD8+ T cells, promoting chronic infection.
Murine Macrophages Produce Secretory Leukocyte Protease Inhibitor During Clearance of Apoptotic Cells: Implications for Resolution of the Inflammatory Response
Authors: Odaka Chikako , Mizuochi Toshiaki , Yang Jingxuan , Ding Aihao 
Published: April 2014

AbstractMacrophage-derived secretory leukocyte protease inhibitor (SLPI) can be induced locally as well as systemically in response to microbial products such as LPS and lipotechoic acid. It is not known whether phagocytosis of apoptotic cells, an essential function of macrophages, can regulate expression and secretion of SLPI. In this study, we report that exposure of peritoneal macrophages of BALB/c mice or murine macrophage cell lines RAW264.7 and J774.1 to apoptotic target cells induced an elevation in SLPI secretion. Secreted SLPI retained its antichymotrypsin activity. SLPI expression in thymuses from BALB/c mice that had been injected with anti-CD3 Ab to induce apoptosis of thymocytes was also elevated both at the mRNA and protein levels. Colchicine, a microtubular inhibitor, blocked the internalization of apoptotic cells by macrophages but not SLPI secretion, suggesting that surface recognition of apoptotic cells is sufficient for the induction of SLPI. Exposure of RAW264.7 cells to apoptotic CTLL-2 cells induced both SLPI and TNF-α, and addition of IFN-γ inhibited SLPI but augmented TNF-α production. Transfection of either the secreted or a nonsecreted form of SLPI into RAW264.7 cells led to suppression of TNF-α production in response to apoptotic cells. Thus, macrophages secrete an increased amount of SLPI when encountering apoptotic cells, which may help to attenuate potential inflammation during clearance of these cells.
Pivotal Role of Stat4 and Stat6 in the Pathogenesis of the Lupus-Like Disease in the New Zealand Mixed 2328 Mice
Authors: Jacob Chaim O. , Zang Song , Li Lily , Ciobanu Voicu , Quismorio Frank , Mizutani Akiei , Satoh Minoru , Koss Michael 
Published: April 2014

AbstractWe have developed novel genetically lupus-prone (NZB × NZW)F1-derived congenic New Zealand mixed (NZM) 2328 lines, which are either Stat4- or Stat6-deficient. Our studies show that the deficiency of Stat4 and Stat6 significantly alters the phenotype of the lupus-like disease in NZM 2328 congenic mice. Specifically, Stat4-deficient NZM mice develop accelerated nephritis and increased mortality in the absence of high levels of autoantibodies including anti-dsDNA Abs, and in the presence of relatively reduced levels of IFN-γ. In contrast, Stat6-deficient NZM mice display a significant reduction in incidence of kidney disease, with a dramatic increase in survival, despite the presence of high levels of anti-dsDNA Abs. The lack of correlation between levels of these autoantibodies and kidney disease raises the question of the direct cause-effect relationships between the presence of autoantibodies and kidney disease. Furthermore, these results also question the apparent equation of the effect of Stat deficiency with loss of secretion or response to particular cytokines.
Inhibitory Signal Override Increases Susceptibility to Mercury-Induced Autoimmunity
Authors: Zheng Yan , Monestier Marc 
Published: April 2014

AbstractAfter exposure to subtoxic doses of heavy metals such as mercury, H-2s mice develop an autoimmune syndrome consisting of the rapid production of IgG autoantibodies that are highly specific for nucleolar autoantigens and a polyclonal increase in serum IgG1 and IgE. In this study, we explore the role of two inhibitory immunoreceptors, CTLA-4 and FcγRIIB, in the regulation of mercury-induced autoimmunity. In susceptible mice treated with mercuric chloride (HgCl2), administration of a blocking anti-CTLA-4 Ab resulted in a further increase in anti-nucleolar autoantibodies and in total serum IgG1 levels. Furthermore, in some DBA/2 mice, which are normally resistant to heavy metal-induced autoimmunity, anti-CTLA-4 treatment leads to the production of anti-nucleolar Abs, thereby overcoming the genetic restriction of the disease. In mice deficient for the FcγRIIB, HgCl2 administration did not trigger autoantibody production, but resulted in an increase in IgE serum levels. Taken together, these results indicate that different inhibitory mechanisms regulate various manifestations of this autoimmune syndrome.
Enhanced Immunogenicity and Protective Efficacy Against Mycobacterium tuberculosis of Bacille Calmette-Guérin Vaccine Using Mucosal Administration and Boosting with a Recombinant Modified Vaccinia Virus Ankara
Authors: Goonetilleke Nilu P. , McShane Helen , Hannan Carolyn M. , Anderson Richard J. , Brookes Roger H. , Hill Adrian V. S. 
Published: April 2014

Abstract
Heterologous prime-boost immunization strategies can evoke powerful T cell immune responses and may be of value in developing an improved tuberculosis vaccine. We show that recombinant modified vaccinia virus Ankara, expressing Mycobacterium tuberculosis Ag 85A (M.85A), strongly boosts bacille Calmette-Guérin (BCG)-induced Ag 85A specific CD4+ and CD8+ T cell responses in mice. A comparison of intranasal (i.n.) and parenteral immunization of BCG showed that while both routes elicited comparable T cell responses in the spleen, only i.n. delivery elicited specific T cell responses in the lung lymph nodes, and these responses were further boosted by i.n. delivery of M.85A. Following aerosol challenge with M. tuberculosis, i.n. boosting of BCG with either BCG or M.85A afforded unprecedented levels of protection in both the lungs (2.5 log) and spleens (1.5 log) compared with naive controls. Protection in the lung correlated with the induction of Ag 85A-specific, IFN-γ-secreting T cells in lung lymph nodes. These findings support further evaluation of mucosally targeted prime-boost vaccination approaches for tuberculosis.
Cutting Edge: H-2DM Is Responsible for the Large Differences in Presentation Among Peptides Selected by I-Ak During Antigen Processing
Authors: Lovitch Scott B. , Petzold Shirley J. , Unanue Emil R. 
Published: April 2014

AbstractWe quantitated the amounts of peptides from hen egg-white lysozyme presented by I-Ak molecules in APC lines. The large chemical gradient of presentation of the four hen egg-white lysozyme epitopes observed in cell lines expressing HLA-DM or H-2DM (referred to in this study as DM) was significantly diminished in the T2.Ak line lacking DM. Differences in levels of presentation between wild-type and DM-deficient APC were observed for all four epitopes, but differences were most evident for the highest affinity epitope. As a result of these quantitative differences in display, presentation of all four epitopes to T cells was impaired in the line lacking DM. The binding affinity of the pool of naturally processed peptides from DM-expressing lines was higher than that from the DM-deficient line. Thus, using a direct biochemical approach in APC, we demonstrate that DM influences the selection of peptides bound to MHC class II by favoring high affinity peptides.
Systemic Overexpression of IL-10 Induces CD4+CD25+ Cell Populations In Vivo and Ameliorates Type 1 Diabetes in Nonobese Diabetic Mice in a Dose-Dependent Fashion
Authors: Goudy Kevin S. , Burkhardt Brant R. , Wasserfall Clive , Song Sihong , Campbell-Thompson Martha L. , Brusko Todd , Powers Matthew A. , Clare-Salzler Michael J. , Sobel Eric S. , Ellis Tamir M. , Flotte Terence R. , Atkinson Mark A. 
Published: April 2014

Abstract
Early systemic treatment of nonobese diabetic mice with high doses of recombinant adeno-associated virus (rAAV) vector expressing murine IL-10 prevents type 1 diabetes. To determine the therapeutic parameters and immunological mechanisms underlying this observation, female nonobese diabetic mice at 4, 8, and 12 wk of age were given a single i.m. injection of rAAV-murine IL-10 (104, 106, 108, and 109 infectious units (IU)), rAAV-vector expressing truncated murine IL-10 fragment (109 IU), or saline. Transduction with rAAV-IL-10 at 109 IU completely prevented diabetes in all animals injected at all time points, including, surprisingly, 12-wk-old animals. Treatment with 108 IU provided no protection in the 12-wk-old injected mice, partial prevention in 8-wk-old mice, and full protection in all animals injected at 4 wk of age. All other treatment groups developed diabetes at a similar rate. The rAAV-IL-10 therapy attenuated pancreatic insulitis, decreased MHC II expression on CD11b+ cells, increased the population of CD11b+ cells, and modulated insulin autoantibody production. Interestingly, rAAV-IL-10 therapy dramatically increased the percentage of CD4+CD25+ regulatory T cells. Adoptive transfer studies suggest that rAAV-IL-10 treatment alters the capacity of splenocytes to impart type 1 diabetes in recipient animals. This study indicates the potential for immunomodulatory gene therapy to prevent autoimmune diseases, including type 1 diabetes, and implicates IL-10 as a molecule capable of increasing the percentages of regulatory cells in vivo.