bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Peroxisome Proliferator-Activated Receptors in Human Airway Smooth Muscle Cells Has a Superior Anti-inflammatory Profile to Corticosteroids: Relevance for Chronic Obstructive Pulmonary Disease Therapy
Authors: Patel Hema J. , Belvisi Maria G. , Bishop-Bailey David , Yacoub Magdi H. , Mitchell Jane A. 
Published: April 2014

Abstract
Airway smooth muscle is actively involved in the inflammatory process in diseases such as chronic obstructive pulmonary disease and asthma by 1) contributing to airway narrowing through hyperplasia and hypertrophy and 2) the release of GM-CSF and G-CSF, which promotes the survival and activation of infiltrating leukocytes. Thus, the identification of novel anti-inflammatory pathways in airway smooth muscle will have important implications for the treatment of inflammatory airway disease. This study identifies such a pathway in the activation of peroxisome proliferator-activated receptors (PPARs). PPAR ligands are known therapeutic agents in the treatment of diabetes; however, their role in human airway disease is unknown. We demonstrate, for the first time, that human airway smooth muscle cells express PPARα and -γ subtypes. Activation of PPARγ by natural and synthetic ligands inhibits serum-induced cell growth more effectively than does the steroid dexamethasone, and induces apoptosis. Moreover, PPARγ activation, like dexamethasone, inhibits the release of GM-CSF. However, PPARγ ligands, but not dexamethasone, similarly inhibits G-CSF release. These results reveal a novel anti-inflammatory pathway in human airway smooth muscle, where PPARγ activation has additional anti-inflammatory effects to those of steroids. Hence, PPAR ligands might act as potential treatments in human respiratory diseases.
Divergence of Mechanisms Regulating Respiratory Burst in Blood and Sputum Eosinophils and Neutrophils from Atopic Subjects
Authors: Lacy Paige , Latif Dalia Abdel , Steward Melissa , Musat-Marcu Sorin , Man S. F. Paul , Moqbel Redwan 
Published: April 2014

Abstract
Eosinophil respiratory burst is an important event in asthma and related inflammatory disorders. However, little is known concerning activation of the respiratory burst NADPH oxidase in human eosinophils. Conversely, neutrophils are known to assemble NADPH oxidase in intracellular and plasma membranes. We hypothesized that eosinophils and neutrophils translocate NADPH oxidase to distinct intracellular locations, consistent with their respective functions in O2−-mediated cytotoxicity. PMA-induced O2– release assayed by cytochrome c was 3.4-fold higher in atopic human eosinophils than in neutrophils, although membrane-permeable dihydrorhodamine-123 showed similar amounts of release. Eosinophil O2– release was dependent on Rac, in that it was 54% inhibited by Clostridium difficile toxin B (400–800 ng/ml). In eosinophils stimulated with PMA, a pronounced shift of cytosolic Rac to p22phox-positive plasma membrane was observed by confocal microscopy, whereas neutrophils directed Rac2 mainly to intracellular sites coexpressing p22phox. Similarly, ex vivo sputum eosinophils from asthmatic subjects exhibited predominantly plasma membrane-associated immunoreactivity for Rac, whereas sputum neutrophils exhibited cytoplasmic Rac2 staining. Thus, activated sputum eosinophils, rather than neutrophils, may contribute significantly to the pathogenesis of asthma by extracellular release of tissue-damaging O2–. Our findings suggest that the differential modes of NADPH oxidase assembly in these cells may have important implications for oxidant-mediated tissue injury.
T Cell Repertoire Development in Humans with SCID After Nonablative Allogeneic Marrow Transplantation
Authors: Sarzotti Marcella , Patel Dhavalkumar D. , Li Xiaojing , Ozaki Daniel A. , Cao Shui , Langdon Scott , Parrott Roberta E. , Coyne Katherine , Buckley Rebecca H. 
Published: April 2014

Abstract
Transplantation of HLA-identical or haploidentical T cell-depleted allogeneic bone marrow (BM) into SCID infants results in thymus-dependent T cell development in the recipients. Immunoscope analysis of the TCR Vβ repertoire was performed on 15 SCID patients given BM transplants. Before and within the first 100 days after bone marrow transplantation (BMT), patients’ PBMC displayed an oligoclonal or skewed T cell repertoire, low TCR excision circles (TREC) values, and a predominance of CD45RO+ T cells. In contrast, the presence of high numbers of CD45RA+ cells in the circulation of SCID patients &gt;100 days post-BMT correlated with active T cell output by the thymus as revealed by high TREC values and a polyclonal T cell repertoire demonstrated by a Gaussian distribution of Vβ-specific peaks. Ten years after BMT, we observed a decrease of the normal polyclonal T cell repertoire and an increase of a more skewed T cell repertoire. A decline of TREC levels and a decrease in the number of CD45RA+ cells beyond 10 years after BMT was concomitant with the detection of oligoclonal CD3+CD8+CD45RO+ cells. The switch from a polyclonal to a more skewed repertoire, observed in the CD3+CD8+CD45RO+ T cell subset, is a phenomenon that occurs normally with decreased thymic output during aging, but not as rapidly as in this patient population. We conclude that a normal T cell repertoire develops in SCID patients as a result of thymic output and the repertoire remains highly diverse for the first 10 years after BMT. The TCR diversity positively correlates in these patients with TREC levels.
Celiac Disease Association with CD8+ T Cell Responses: Identification of a Novel Gliadin-Derived HLA-A2-Restricted Epitope
Authors: Gianfrani Carmen , Troncone Riccardo , Mugione Patrizia , Cosentini Elena , De Pascale Mariateresa , Faruolo Clementina , Senger Stefania , Terrazzano Giuseppe , Southwood Scott , Auricchio Salvatore , Sette Alessandro 
Published: April 2014

AbstractOne of the diagnostic hallmarks of the histological lesions associated with celiac disease is the extensive infiltration of the small intestinal epithelium by CD8+ T cells of unknown Ag specificity. In this study, we report recognition of the gliadin-derived peptide (A-gliadin 123–132) by CD8+ T lymphocytes from celiac patients. A-gliadin 123–132-specific IFN-γ production and cytotoxic activity were detected in PBMCs derived from patients on gluten-free diet, but not from either celiac patients on gluten-containing diet or healthy controls. In contrast, A-gliadin 123–132-specific cells were isolated from small intestine biopsies of patients on either gluten-free or gluten-containing diets. Short-term T cell lines derived from the small intestinal mucosa and specific for the 123–132 epitope recognized human APC pulsed with either whole recombinant α-gliadin or a partial pepsin-trypsin gliadin digest. Finally, we speculate on a possible mechanism leading to processing and presentation of class I-restricted gliadin-derived epitopes in celiac disease patients.
Synergistic Anti-Tumor Responses After Administration of Agonistic Antibodies to CD40 and IL-2: Coordination of Dendritic and CD8+ Cell Responses
Authors: Murphy William J. , Welniak Lisbeth , Back Timothy , Hixon Julie , Subleski Jeff , Seki Naoko , Wigginton Jon M. , Wilson Susan E. , Blazar Bruce R. , Malyguine Anatoli M. , Sayers Thomas J. , Wiltrout Robert H. 
Published: April 2014

Abstract
In cancer, the coordinate engagement of professional APC and Ag-specific cell-mediated effector cells may be vital for the induction of effective antitumor responses. We speculated that the enhanced differentiation and function of dendritic cells through CD40 engagement combined with IL-2 administration to stimulate T cell expansion would act coordinately to enhance the adaptive immune response against cancer. In mice bearing orthotopic metastatic renal cell carcinoma, only the combination of an agonist Ab to CD40 and IL-2, but neither agent administered alone, induced complete regression of metastatic tumor and specific immunity to subsequent rechallenge in the majority of treated mice. The combination of anti-CD40 and IL-2 resulted in significant increases in dendritic cell and CD8+ T cell number in advanced tumor-bearing mice compared with either agent administered singly. The antitumor effects of anti-CD40 and IL-2 were found to be dependent on CD8+ T cells, IFN-γ, IL-12 p40, and Fas ligand. CD40 stimulation and IL-2 may therefore be of use to promote antitumor responses in advanced metastatic cancer.
T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts
Authors: Yi Shounan , Hawthorne Wayne J. , Lehnert Anne M. , Ha Hong , Wong Jeferey Kwok Wah , van Rooijen Nico , Davey Kelly , Patel Anita T. , Walters Stacey N. , Chandra Abhilash , O’Connell Philip J. 
Published: April 2014

Abstract
Macrophages have been proposed as the major effector cell in T cell-mediated xenograft rejection. To determine their role in this response, NOD-SCID mice were transplanted with fetal pig pancreas (FPP) before reconstitution with CD4+ T cells from BALB/c mice. Twelve days after CD4+ T cell reconstitution, purified macrophages (depleted of T cells) were isolated from CD4+ T cell-reconstituted FPP recipient mice and adoptively transferred to their nonreconstituted counterparts. After adoptive macrophage transfer, FPP recipient mice transferred with macrophages from CD4+ T cell-reconstituted mice demonstrated xenograft destruction along with massive macrophage infiltration at day 4 and complete graft destruction at day 8 postmacrophage transfer. By contrast, FPP recipients that received macrophages from nonreconstituted mice showed intact FPP xenografts with few infiltrating macrophages at both days 4 and 8 after macrophage transfer. The graft-infiltrating macrophages showed increased expression of their activation markers. Depletion of endogenous macrophages or any remaining CD4+ T cells did not delay graft rejection in the macrophage-transferred FPP recipients, whereas depletion of transferred macrophages with clodronate liposomes prevented graft rejection. Our results show that macrophages primed by FPP and activated by CD4+ T cells were attracted from the peripheral circulation and were capable of specific targeting and destruction of FPP xenografts. This suggests that in xenograft rejection, there are macrophage-specific recognition and targeting signals that are independent of those received by T cells.
Host Response to Malaria During Pregnancy: Placental Monocyte Recruitment Is Associated with Elevated β Chemokine Expression
Authors: Abrams Elizabeth T. , Brown Heidi , Chensue Stephen W. , Turner Gareth D. H. , Tadesse Eyob , Lema Valentino M. , Molyneux Malcolm E. , Rochford Rosemary , Meshnick Steven R. , Rogerson Stephen J. 
Published: April 2014

Abstract
Malaria during pregnancy is associated with poor birth outcomes, particularly low birth weight. Recently, monocyte infiltration into the placental intervillous space has been identified as a key risk factor for low birth weight. However, the malaria-induced chemokines involved in recruiting and activating placental monocytes have not been identified. In this study, we determined which chemokines are elevated during placental malaria infection and the association between chemokine expression and placental monocyte infiltration. Placental malaria infection was associated with elevations in mRNA expression of three β chemokines, macrophage-inflammatory protein 1 (MIP-1) α (CCL3), monocyte chemoattractant protein 1 (MCP-1; CCL2), and I-309 (CCL1), and one α chemokine, IL-8 (CXCL8); all correlated with monocyte density in the placental intervillous space. Placental plasma concentrations of MIP-1α and IL-8 were increased in women with placental malaria and were associated with placental monocyte infiltration. By immunohistochemistry, we localized placental chemokine production in malaria-infected placentas: some but not all hemozoin-laden maternal macrophages produced MIP-1β and MCP-1, and fetal stromal cells produced MCP-1. In sum, local placental production of chemokines is increased in malaria, and may be an important trigger for monocyte accumulation in the placenta.
Cutting Edge: CD40 Engagement Eliminates the Need for Bruton’s Tyrosine Kinase in B Cell Receptor Signaling for NF-κB
Authors: Mizuno Takuya , Rothstein Thomas L. 
Published: April 2014

Abstract
The Tec kinase Bruton’s tyrosine kinase (Btk) represents a key intermediary for B cell receptor (BCR) signaling. Btk mutation produces B cell deficiency in mice with X-linked immunodeficiency (xid), and surface Ig-mediated responses of mature B cells are seriously deranged. The central role that Btk plays in directing downstream events produced by BCR engagement is demonstrated by the complete failure of NF-κB induction and cellular proliferation following anti-Ig treatment of B cells obtained from xid mice. In this study, we report that the block in BCR signaling produced by Btk mutation is reversed by CD40 engagement. Prior treatment with CD40 ligand normalized subsequent responses of xid B cells to BCR cross-linking, so that typical outcomes of BCR signaling such as NF-κB activation and cell cycle progression occurred in a Btk-independent fashion. These results demonstrate that a specific genetic lesion interrupting BCR-mediated intracellular signaling is circumvented through stimulation of CD40.
Forced Expression of the Fc Receptor γ-Chain Renders Human T Cells Hyperresponsive to TCR/CD3 Stimulation
Authors: Nambiar Madhusoodana P. , Fisher Carolyn U. , Kumar Anil , Tsokos Christos G. , Warke Vishal G. , Tsokos George C. 
Published: April 2014

Abstract
High level expression of FcεRIγ chain replaces the deficient TCR ζ-chain and contributes to altered TCR/CD3-mediated signaling abnormalities in T cells of patients with systemic lupus erythematosus. Increased responsiveness to Ag has been considered to lead to autoimmunity. To test this concept, we studied early signaling events and IL-2 production in fresh cells transfected with a eukaryotic expression vector encoding the FcεRIγ gene. We found that the overexpressed FcεRIγ chain colocalizes with the CD3ε chain on the surface membrane of T cells and that cross-linking of the new TCR/CD3 complex leads to a dramatic increase of intracytoplasmic calcium concentration, protein tyrosine phosphorylation, and IL-2 production. We observed that overexpression of FcεRIγ is associated with increased phosphorylation of Syk kinase, while the endogenous TCR ζ-chain is down-regulated. We propose that altered composition of the CD3 complex leads to increased T cell responsiveness to TCR/CD3 stimulation and sets the biochemical grounds for the development of autoimmunity.
Detection of Suppressor T Lymphocytes and Estimation of Their Frequency in Limiting Dilution Assays by Generalized Linear Regression Modeling
Authors: Bonnefoix Thierry , Bonnefoix Philippe , Mi Jian-Qing , Lawrence Jean-Jacques , Sotto Jean-Jacques , Leroux Dominique 
Published: April 2014

Abstract
The estimate of the frequency of suppressor T lymphocytes in unfractionated cell populations remains challenging, mainly because these regulatory cells do not display specific immunophenotypic markers. In this paper, we describe a novel theoretical approach for quantifying the frequency of suppressor cells. This method is based on limiting dilution data modeling, and allows the simultaneous estimation of the frequencies of both proliferating and suppressor cells. We used previously published biological data, characterizing the inhibiting activity of suppressor T cell clones. Starting from these data, we propose a mathematical model describing the interaction between suppressor and proliferating T cells, and applied to a Poisson process. Limiting dilution data corresponding to this non-single-hit, suppressor two-target Poisson model were artificially generated, then modeled according to a generalized linear regression procedure. Deviation from the single-hit Poisson model was revealed by a statistical slope test, and a stepwise analysis of the regression appeared to be an efficient method that strongly argued in favor of the presence of suppressor cells. By using the frequency of proliferating T cells calculated in the first step of the regression, we demonstrated the possibility to provide a reasonable estimate of the frequency of suppressor T cells. Based on these findings, a practical decision-making procedure is given to perform standard analyses of limiting dilution data.
Acute Alcohol Inhibits TNF-α Processing in Human Monocytes by Inhibiting TNF/TNF-α-Converting Enzyme Interactions in the Cell Membrane
Authors: Zhao Xue-Jun , Marrero Luis , Song Kejing , Oliver Peter , Chin So Yeon , Simon Harriet , Schurr Jill R. , Zhang Zili , Thoppil Deepu , Lee Sharon , Nelson Steve , Kolls Jay K. 
Published: April 2014

Abstract
Alcohol abuse has long been known to adversely affect innate immune responses and predispose to infections. One cellular mechanism responsible for this effect is alcohol-induced suppression of TNF-α by mononuclear phagocytes. We undertook experiments to better understand the cellular mechanisms by which alcohol dose-dependently suppresses TNF elaboration by human monocytes. Here we show in human primary monocytes and cell lines that alcohol suppresses LPS-induced TNF secretion post-transcriptionally by inhibiting cellular processing by TNF-α-converting enzyme (TACE). Using fluorescent resonance energy transfer microscopy, physiological relevant levels of alcohol resulted in a reversible dose-dependent decrease in fluorescent resonance energy transfer efficiency between TNF and TACE. These data demonstrate that alcohol inhibits interactions between TNF and its converting enzyme, TACE, possibly by affecting membrane fluidity. These data in part explain the cellular mechanisms by which alcohol impairs monocyte function and may identify immunotherapeutic targets aimed at restoring immune function in this at-risk patient population.
A Threshold for Central T Cell Tolerance to an Inducible Serum Protein
Authors: Haribhai Dipica , Engle Deborah , Meyer Michelle , Donermeyer David , White J. Michael , Williams Calvin B. 
Published: April 2014

AbstractWe report an inducible system of self Ag expression that examines the relationship between serum protein levels and central T cell tolerance. This transgenic approach is based on tetracycline-regulated expression of a secreted form of hen egg lysozyme, tagged with a murine hemoglobin (Hb) epitope. In the absence of the tetracycline-regulated transactivator, serum levels of the chimeric protein are extremely low (≤0.1 ng/ml) and the mice show partial tolerance to both Hb(64–76) and lysozyme epitopes. In the presence of the transactivator, expression increases to 1.5 ng/ml and the mice are completely tolerant. Partial tolerance was further investigated by crossing these mice to strains expressing transgenic TCRs. At the lowest Ag levels, 3.L2tg T cells (specific for Hb(64–76)/I-Ek) escape the thymus and ∼10% of CD4+ splenocytes express the 3.L2 TCR. In contrast, 3A9 T cells (specific for hen egg lysozyme(46–61)/I-Ak) are completely eliminated by negative selection. These data define a tolerogenic threshold for negative selection of Ag-specific T cells by circulating self proteins that are 100-fold more sensitive than previously demonstrated. They suggest that partial tolerance at extremely low levels of self Ag exposure is the result of a restricted repertoire of responding T cells, rather than a simple reduction in precursor frequency; tolerogenic thresholds are T cell specific.
CD40 Ligand Trimer Enhances the Response of CD8+ T Cells to Mycobacterium tuberculosis
Authors: Samten Buka , Wizel Benjamin , Shams Homayoun , Weis Stephen E. , Klucar Peter , Wu Shiping , Vankayalapati Ramakrishna , Thomas Elaine K. , Okada Satoshi , Krensky Alan M. , Barnes Peter F. 
Published: April 2014

Abstract
We investigated the effect of recombinant CD40 ligand trimer (CD40LT) on the functional capacity of peripheral blood CD8+ T cells from healthy tuberculin reactors that were cultured with Mycobacterium tuberculosis-infected autologous monocytes. CD40LT enhanced the capacity of M. tuberculosis-responsive CD8+ T cells to produce IFN-γ by increasing the number of IFN-γ-producing CD8+ T cells and the amount of IFN-γ produced per cell. CD40LT-induced IFN-γ production was dependent on production of IL-12 and IL-18, but did not require IL-15. CD40LT up-regulated expression of the transcription factors phosphorylated CREB and c-Jun, both of which have been previously shown to stimulate IFN-γ mRNA transcription by binding to the IFN-γ promoter. CD40LT also enhanced the capacity of CD8+ T cells to lyse M. tuberculosis-infected monocytes, and increased CTL activity was associated with higher expression of perforin and granulysin, but not of Fas ligand. We conclude that CD40LT can enhance CD8+ T cell effector function in response to M. tuberculosis.
IFN-γ Reverses the Stop Signal Allowing Migration of Antigen-Specific T Cells into Inflammatory Sites
Authors: Tay Szun S. , McCormack Ann , Lawson Charlotte , Rose Marlene L. 
Published: April 2014

Abstract
In humans the majority of endothelial cells (EC) constitutively express MHC class II Ags. We know that in vitro ECs can activate CD45RO+ B7-independent CD4+ T cells to proliferate and produce IL-2. The in vivo correlate of this T cell response is not known, and here we have explored whether endothelial expression of MHC class II Ags affects the transendothelial migration of alloreactive CD4+ CD45RO+ B7-independent T cells. Alloreactive CD4+ T cell clones and lines were generated against HLA-DR11, DR13, DR4, and DR1 MHC Ags, and their rates of migration across untreated EC line Eahy.926 (MHC class II negative) or Eahy.926 transfected with CIITA (EahyCIITA) to express DR11 and DR13 were investigated. The migrations of EahyCIITA-specific T cell clones and lines were retarded in a DR-specific manner, and retardation was reversed in the presence of mAb to DR Ag. When investigating the ability of T cells to proliferate in response to EahyCIITA before and after transmigration, migrated cells were still able to proliferate, but the frequency of EahyCIITA-specific cells was much reduced compared with that of nonmigrated cells. The use of fluorescently labeled T cells revealed that specific cells become trapped within the endothelial monolayer. Pretreatment of EahyCIITA with IFN-γ restored the ability of DR11- or DR13-specific T cells to transmigrate and proliferate, thus abrogating DR-specific retardation. We conclude that cognate interaction between T cells and endothelial MHC class II initiates a stop signal possibly similar to an immunological synapse, but this is overcome in an inflammatory milieu.
IL-8 Directly Enhanced Endothelial Cell Survival, Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis
Authors: Li Aihua , Dubey Seema , Varney Michelle L. , Dave Bhavana J. , Singh Rakesh K. 
Published: April 2014

Abstract
IL-8, a member of the chemokine family, has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to determine the mechanism of IL-8-mediated angiogenesis. We examined the direct role of IL-8 in angiogenesis by examining IL-8 receptor expression on endothelial cells and their proliferation, survival, and matrix metalloproteinases (MMPs) production. We demonstrate that HUVEC and human dermal microvascular endothelial cells constitutively express CXCR1 and CXCR2 mRNA and protein. Recombinant human IL-8 induced endothelial cell proliferation and capillary tube organization while neutralization of IL-8 by anti-IL-8 Ab blocks IL-8-mediated capillary tube organization. Incubation of endothelial cells with IL-8 inhibited endothelial cell apoptosis and enhanced antiapoptotic gene expression. Endothelial cells incubated with IL-8 had higher levels of Bcl-xL:Bcl-xS and Bcl-2:Bax ratios. Furthermore, incubation of endothelial cells with IL-8 up-regulated MMP-2 and MMP-9 production and mRNA expression. Our data suggest that IL-8 directly enhanced endothelial cell proliferation, survival, and MMP expression in CXCR1- and CXCR2-expressing endothelial cells and regulated angiogenesis.