bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective Antiviral Cytotoxic T Cell Memory Is Most Efficiently Maintained by Restimulation Via Dendritic Cells
Authors: Ludewig Burkhard , Oehen Stephan , Barchiesi Federica , Schwendener Reto A. , Hengartner Hans , Zinkernagel Rolf M. 
Published: January 2023

Abstract
Dendritic cells (DC) play a key role in the initiation of T cell-mediated immune responses and may therefore be successfully used in antiviral and antitumor vaccination strategies. Because both strength and duration of an immune response determines the outcome of a vaccination protocol, we evaluated the life span of DC-induced antiviral CTL memory against systemic and peripheral challenge infections with lymphocytic choriomeningitis virus (LCMV). We found that expansion and activation of CTL by DC was transient. Protection against systemic LCMV infection after DC immunization was relatively long-lived (&gt;60 days), whereas complete protection against peripheral infection via intracerebral infection or infection into the footpad with LCMV, where rapid recruitment of effector T cells to the site of infection and elimination of viral pathogen plays a major role, was short-lived (&lt;30 days). Protective immunity was most efficiently restored by administration of antigenic peptides via DC, rather than in combination with IFA or in liposomes. These results suggest that Ag presentation by DC may be crucial for both initiation and maintenance of protective CTL-mediated immunity against viruses infecting solid organs or against peripheral mesenchymal or epithelial tumors.
The Ectoenzyme γ-Glutamyl Transpeptidase Regulates Antiproliferative Effects of S-Nitrosoglutathione on Human T and B Lymphocytes
Authors: Henson Sarah E. , Nichols Timothy C. , Holers V. Michael , Karp David R. 
Published: January 2023

Abstract
Expression of the ectoenzyme γ-glutamyl transpeptidase (GGT) is regulated on T lymphocytes. It is present at a low level on naive T cells, at a high level on activated T cells, and at an intermediate level on resting memory T cells. GGT cleaves the glutamyl group from glutathione, which is the first step in the uptake of extracellular glutathione. In vitro, purified GGT also metabolizes the naturally occurring nitrosothiol, S-nitrosoglutathione (GSNO). Because of this relationship, the effects of cellular GGT on the metabolism of and cellular response to GSNO were tested. The GGT-negative lymphoblasts Ramos and SupT1 were transfected with cDNA for human GGT. In the presence of cells lacking GGT, GSNO is extremely stable. In contrast, GGT-expressing cells rapidly metabolize GSNO leading to nitric oxide release. The nitric oxide causes a rapid (&lt;2-h) inhibition of DNA synthesis. There is a concomitant decrease in the concentration of intracellular deoxyribonucleotides, suggesting that one effect of the nitric oxide generated from GSNO is the previously described inactivation of the enzyme ribonucleotide reductase. GSNO also caused a rapid, GGT-dependent cytostatic effect in Hut-78, a human T cell lymphoma, as well as in activated peripheral blood T cells. Although DNA synthesis was decreased to 16% of control values in anti-CD3-stimulated Hut-78, the production of IL-2 was unchanged by GSNO. These data show that GGT, a regulated ectoenzyme on T cells, controls the rate of nitric oxide production from GSNO and thus markedly affects the physiological response to this biologically active nitrosothiol.
Inflammatory Cytokines Synergize with the HIV-1 Tat Protein to Promote Angiogenesis and Kaposi’s Sarcoma Via Induction of Basic Fibroblast Growth Factor and the αvβ3 Integrin
Authors: Barillari Giovanni , Sgadari Cecilia , Palladino Clelia , Gendelman Rita , Caputo Antonella , Morris Cindy Bohan , Nair Bala C. , Markham Philip , Nel Andrè , Stürzl Michael , Ensoli Barbara 
Published: January 2023

Abstract
The Tat protein of HIV-1, a transactivator of viral gene expression, is released by acutely infected T cells and, in this form, exerts angiogenic activities. These have linked the protein to the pathogenesis of Kaposi’s sarcoma (KS), a vascular tumor frequent and aggressive in HIV-1-infected individuals (AIDS-KS). In this study, we show that a combination of the same inflammatory cytokines increased in KS lesions, namely IL-1β, TNF-α, and IFN-γ, synergizes with Tat to promote in nude mice the development of angioproliferative KS-like lesions that are not observed with each factor alone. Inflammatory cytokines induce the tissue expression of both basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), two angiogenic molecules highly produced in primary KS lesions. However, bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial cells to migrate, to adhere, and to grow in response to Tat in vitro. Tat angiogenic effects correlate with the expression of the αvβ3 integrin that is induced by bFGF and binds the arginine-glycine-aspartic acid (RGD) region of Tat. In contrast, no correlation is observed with the expression of αvβ5, which is promoted by VEGF and binds Tat basic region. Finally, KS lesion formation induced by bFGF and Tat in nude mice is blocked by antagonists of RGD-binding integrins. Because αvβ3 is an RGD-binding integrin that is highly expressed in primary KS lesions, where it colocalizes with extracellular Tat on vessels and spindle cells, these results suggest that αvβ3 competitors may represent a new strategy for the treatment of AIDS-KS.
Intradermal Delivery of IL-12 Naked DNA Induces Systemic NK Cell Activation and Th1 Response In Vivo That Is Independent of Endogenous IL-12 Production
Authors: Watanabe Morihiro , Fenton Robert G. , Wigginton Jon M. , McCormick Kathryn L. , Volker Kirk M. , Fogler William E. , Roessler Philip G. , Wiltrout Robert H. 
Published: January 2023

AbstractIn this study four murine IL-12 naked DNA expression plasmids (pIL-12), containing both the p35 and p40 subunits, were shown to induce systemic biological effects in vivo after intradermal injection. Three of the four IL-12 expression vectors augmented NK activity and induced expression of the IFN-γ and IFN-γ-inducible Mig genes. Both IL-12 p70 heterodimer and IFN-γ proteins were documented in the serum within 24 h after intradermal injection of the pIL-12o− plasmid, which also induced the highest level of NK activity in the spleen and liver among the IL-12 constructs. Interestingly, both p40 mRNA expression at the injection site and serum protein levels followed a biphasic pattern of expression, with peaks on days 1 and 5. Subsequent studies revealed that the ability of intradermally injected pIL-12o− to augment NK lytic activity was prevented by administration of a neutralizing anti-IL-12 mAb. Finally, injection of the pIL-12o− into BALB/c IL-12 p40−/− mice also resulted in a biphasic pattern of IL-12 p70 appearance in the serum, and induced IFN-γ protein and activated NK lytic activity in liver and spleen. These results demonstrate that injection of delivered naked DNA encoding the IL-12 gene mediates the biphasic systemic production of IL-12-inducible genes and augments the cytotoxic function of NK cells in lymphoid and parenchymal organs as a direct result of transgene expression. The results also suggest that these naked DNA plasmids may be useful adjuvants for vaccines against infectious and neoplastic diseases.
Partial IgA-Deficiency with Increased Th2-Type Cytokines in TGF-β1 Knockout Mice
Authors: Ginkel Frederik W. van , Wahl Sharon M. , Kearney John F. , Kweon Mi-Na , Fujihashi Kohtaro , Burrows Peter D. , Kiyono Hiroshi , McGhee Jerry R. 
Published: January 2023

AbstractThough it has been shown that TGF-β1 directs B cells to switch to IgA in vitro, no studies have assessed TGF-β1 effects on mucosal vs systemic immunity in vivo. When the B cell functions of TGF-β1 gene-disrupted (TGF-β1−/−) mice were analyzed, significantly decreased IgA levels and increased IgG and IgM levels in serum and external secretions were observed. Further, analysis of Ab forming cells (AFC) isolated from both mucosal and systemic lymphoid tissue showed elevated IgM, IgG, and IgE, with decreased IgA AFC. A lack of IgA-committed B cells was seen in TGF-β1−/− mice, especially in the gastrointestinal (GI) tract. Splenic T cells triggered via the TCR expressed elevated Th2-type cytokines and, consistent with this observation, a 31-fold increase in serum IgE was seen in TGF-β1−/− mice. Thus, uncontrolled B cell responses, which include elevated IgE levels, a lack of antiinflammatory IgA, and an excess of complement-binding IgG and IgM Abs, will promote inflammation at mucosal surfaces in TGF-β1−/− mice and likely contribute to pulmonary and GI tract lesions, ultimately leading to the early death of these mice.
APCs Express DCIR, a Novel C-Type Lectin Surface Receptor Containing an Immunoreceptor Tyrosine-Based Inhibitory Motif
Authors: Bates Elizabeth E. M. , Fournier Nathalie , Garcia Eric , Valladeau Jenny , Durand Isabelle , Pin Jean-Jacques , Zurawski Sandra M. , Patel Sejal , Abrams John S. , Lebecque Serge , Garrone Pierre , Saeland Sem 
Published: January 2023

Abstract
We have identified a novel member of the calcium-dependent (C-type) lectin family. This molecule, designated DCIR (for dendritic cell (DC) immunoreceptor), is a type II membrane glycoprotein of 237 aa with a single carbohydrate recognition domain (CRD), closest in homology to those of the macrophage lectin and hepatic asialoglycoprotein receptors. The intracellular domain of DCIR contains a consensus immunoreceptor tyrosine-based inhibitory motif. A mouse cDNA, encoding a homologous protein has been identified. Northern blot analysis showed DCIR mRNA to be predominantly transcribed in hematopoietic tissues. The gene encoding human DCIR was localized to chromosome 12p13, in a region close to the NK gene complex. Unlike members of this complex, DCIR displays a typical lectin CRD rather than an NK cell type extracellular domain, and was expressed on DC, monocytes, macrophages, B lymphocytes, and granulocytes, but not detected on NK and T cells. DCIR was strongly expressed by DC derived from blood monocytes cultured with GM-CSF and IL-4. DCIR was mostly expressed by monocyte-related rather than Langerhans cell related DC obtained from CD34+ progenitor cells. Finally, DCIR expression was down-regulated by signals inducing DC maturation such as CD40 ligand, LPS, or TNF-α. Thus, DCIR is differentially expressed on DC depending on their origin and stage of maturation/activation. DCIR represents a novel surface molecule expressed by Ag presenting cells, and of potential importance in regulation of DC function.
The Leukocyte Integrin αDβ2 Binds VCAM-1: Evidence for a Binding Interface Between I Domain and VCAM-1
Authors: Van der Vieren Monica , Crowe David T. , Hoekstra Denise , Vazeux Rosemay , Hoffman Patricia A. , Grayson Mitchell H. , Bochner Bruce S. , Gallatin W. Michael , Staunton Donald E. 
Published: January 2023

Abstract
The trafficking of leukocytes through tissues is supported by an interaction between the β2 (CD18) integrins CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) and their ligand ICAM-1. The most recently identified and fourth member of the β2 integrins, αDβ2, selectively binds ICAM-3 and does not appear to bind ICAM-1. We have reported recently that αDβ2 can support eosinophil adhesion to VCAM-1. Here we demonstrate that expression of αDβ2 in a lymphoid cell that does not express α4 integrins confers efficient binding to VCAM-1. In addition, a soluble form of αDβ2 binds VCAM-1 with greater efficiency relative to ICAM-3. The I domain of αD contains a binding site for VCAM-1 since recombinant αD I domain binds specifically to VCAM-1. In addition, αD mAb that block cellular binding to VCAM-1 bind the αD I domain. Using VCAM-1 mutants we have determined that the binding site on VCAM-1 for αDβ2 overlaps with that of α4 integrins. Substitution of VCAM-1 aspartate at position 40, D40, within the conserved integrin binding site, diminishes binding to αDβ2 and abrogates binding to the αD I domain. The corresponding integrin binding site residue in ICAM-3 is also essential to αDβ2 binding. Finally, we demonstrate that αDβ2 can support lymphoid cell adhesion to VCAM-1 under flow conditions at levels equivalent to those mediated by α4β1. These results indicate that VCAM-1 can bind to an I domain and that the binding of αDβ2 to VCAM-1 may contribute to the trafficking of a subpopulation of leukocytes that express αDβ2.
Localization on a Physical Map of the NKC-Linked Cmv1 Locus Between Ly49b and the Prp Gene Cluster on Mouse Chromosome 6
Authors: Brown Michael G. , Zhang Jun , Du Ying , Stoll Janis , Yokoyama Wayne M. , Scalzo Anthony A. 
Published: January 2023

Abstract
The Cmv1 locus controls NK cell-mediated resistance to infection with murine CMV. Our recent genetic analysis of backcross mice demonstrated that the NK gene complex (NKC)-linked Cmv1 locus should reside between the Ly49 and Prp gene clusters on distal mouse chromosome 6. We have aligned yeast artificial chromosome (YAC) inserts in a contig spanning the interval between the Ly49 and Prp gene clusters. This YAC contig includes 13 overlapping YAC inserts that span more than 2 megabases (Mb) in C57BL/6 (B6) mice. Since we have identified genomic clones that span the Ly49-Prp gene region, we hypothesize that at least one should contain the Cmv1 locus. To narrow the Cmv1 critical region, we developed novel NKC genetic markers and used these to genotype informative backcross and intra-NKC recombinant congenic mouse DNA samples. These data suggest that Cmv1 resides on a single YAC insert within an interval that corresponds to a physical distance of ∼390 kb. This high resolution, integrated physical and genetic NKC map will facilitate identification of Cmv1 and other NKC-linked loci that regulate NK cell-mediated immunity.
Specific Inhibition of Macrophage TNF-α Expression by In Vivo Ribozyme Treatment
Authors: Kisich Kevin O. , Malone Robert W. , Feldstein Paul A. , Erickson Kent L. 
Published: January 2023

Abstract
The overproduction of the cytokine TNF-α is associated with inflammatory and autoimmune diseases. We have developed a means to block TNF-α production with ribozymes directed against TNF-α mRNA to selectively inhibit its production in vitro and in vivo. Following cationic lipid-mediated delivery to peritoneal murine macrophages in culture, anti-TNF-α ribozymes were more effective inhibitors of TNF-α secretion than catalytically inactive ribozyme controls. Inhibition of TNF-α secretion was proportional to the concentration of ribozyme administered, with an IC50 of ∼10 nM. After i.p. injection of cationic lipid/ribozyme complexes, elicited macrophages accumulated ∼6% of the administered ribozyme. The catalytically active ribozyme suppressed LPS-stimulated TNF-α secretion by ∼50% relative to an inactive ribozyme control without inhibiting secretion of another proinflammatory cytokine produced by macrophages, IL-1α. Ribozyme-specific TNF-α mRNA degradation products were found among the mRNA extracted from macrophages following in vivo ribozyme treatment and ex vivo stimulation. Thus, catalytic ribozymes can accumulate in appropriate target cells in vivo; once in the target cell, ribozymes can be potent inhibitors of specific gene expression.
Antiinflammatory Effects of Glucocorticoids in Brain Cells, Independent of NF-κB
Authors: Bourke Emer , Moynagh Paul N. 
Published: January 2023

Abstract
Glucocorticoids are potent antiinflammatory drugs. They inhibit the expression of proinflammatory cytokines and adhesion molecules. It has recently been proposed that the underlying basis to such inhibition is the induction of the protein IκB, which inhibits the transcription factor NF-κB. The latter is a key activator of the genes encoding cytokines and adhesion molecules. The present study shows that the synthetic glucocorticoid, dexamethasone, inhibits the induction of the proinflammatory cytokine IL-8 and the adhesion molecules VCAM-1 and ICAM-1 in human 1321N1 astrocytoma and SK.N.SH neuroblastoma cells. However, dexamethasone failed to induce IκB or inhibit activation of NF-κB by IL-1 in the two cell types. EMSA confirmed the identity of the activated NF-κB by demonstrating that an oligonucleotide, containing the wild-type NF-κB-binding motif, inhibited formation of the NF-κB-DNA complexes whereas a mutated form of the NF-κB-binding motif was ineffective. In addition, supershift analysis showed that the protein subunits p50 and p65 were prevalent components in the activated NF-κB complexes. The lack of effect of dexamethasone on the capacity of IL-1 to activate NF-κB correlated with its inability to induce IκB and the ability of IL-1 to cause degradation of IκB, even in the presence of dexamethasone. The results presented in this paper strongly suggest that glucocorticoids may exert antiinflammatory effects in cells of neural origin by a mechanism(s) independent of NF-κB.
Initial Characterization of the Vitamin D Binding Protein (Gc-Globulin) Binding Site on the Neutrophil Plasma Membrane: Evidence for a Chondroitin Sulfate Proteoglycan
Authors: DiMartino Stephen J. , Kew Richard R. 
Published: January 2023

Abstract
The vitamin D binding protein (DBP) is a multifunctional plasma protein that can modulate certain immune and inflammatory responses. The diverse cellular functions of DBP appear to require cell surface binding to mediate these processes. Numerous reports have detected DBP bound to the surface of several cell types and would support the concept of a cell surface binding site for DBP. However, direct evidence for such a molecule has been lacking and essentially nothing is known about its basic biochemical properties. In the present study, radioiodinated DBP was used as a probe to characterize biochemically the neutrophil DBP binding site. Radiolabeled DBP binds to and remains associated with the plasma membrane and is not degraded. Quantitation of DBP binding to either intact cells or purified plasma membranes showed nonsaturable (linear) binding with positive cooperativity, possibly suggesting DBP oligomer formation. Solubilization of cell bound 125I-DBP with various nonionic and zwitterionic detergents demonstrated that DBP binds to a membrane macromolecule that partitions to the detergent insoluble fraction. Moreover, this molecule does not associate with the cytoskeleton. Cross-linking of radiolabeled DBP bound to plasma membranes increased the amount of protein that partitioned to the insoluble fraction, and analysis of these complexes by SDS-PAGE revealed that they may be very large since they did not enter the gel. Finally, treatment of plasma membranes with either proteases or chondroitinase ABC completely abrogated membrane binding of DBP, suggesting that the protein binds to a chondroitin sulfate proteoglycan.
Monocyte Chemoattractant Protein-1 Mediates Cockroach Allergen-Induced Bronchial Hyperreactivity in Normal But Not CCR2−/− Mice: The Role of Mast Cells
Authors: Campbell Emma M. , Charo Israel F. , Kunkel Steven L. , Strieter Robert M. , Boring Landin , Gosling Jennifa , Lukacs Nicholas W. 
Published: January 2023

Abstract
Bronchial eosinophil and mononuclear cell infiltrates are a hallmark of the asthmatic lung and are associated with the induction of reversible airway hyperreactivity. In these studies, we have found that monocyte chemotactic protein-1 (MCP-1), a CC (β) chemokine, mediates airway hyperreactivity in normal and allergic mice. Using a murine model of cockroach Ag-induced allergic airway inflammation, we have demonstrated that anti-MCP-1 Abs inhibit changes in airway resistance and attenuate histamine release into the bronchoalveolar lavage, suggesting a role for MCP-1 in mast cell degranulation. In normal mice, instillation of MCP-1 induced prolonged airway hyperreactivity and histamine release. In addition, MCP-1 directly induced pulmonary mast cell degranulation in vitro. These latter effects would appear to be selective because no changes were observed when macrophage-inflammatory protein-1α, eotaxin, or MCP-3 were instilled into the airways of normal mice or when mast cells were treated in vitro. Airway hyperreactivity was mediated by MCP-1 through CCR2 because allergen-induced as well as direct MCP-1 instilled-induced changes in airway hyperreactivity were significantly attenuated in CCR2 −/− mice. The neutralization of MCP-1 in allergic animals and instillation of MCP-1 in normal animals was related to leukotriene C4 levels in the bronchoalveolar lavage and was directly induced in pulmonary mast cells by MCP-1. Thus, these data identify MCP-1 and CCR2 as potentially important therapeutic targets for the treatment of hyperreactive airway disease.
A Putative Susceptibility Locus on Chromosome 18 Is Not a Major Contributor to Human Selective IgA Deficiency: Evidence from Meiotic Mapping of 83 Multiple-Case Families
Authors: Vořechovský Igor , Blennow Elisabeth , Nordenskjöld Magnus , Webster A. David B. , Hammarström Lennart 
Published: January 2023

Abstract
Previous reports of an association between constitutional chromosome 18 abnormalities and low levels of IgA suggested that this chromosome contains a susceptibility locus for selective IgA deficiency (IgAD), the most frequent Ig deficiency in humans. IgAD is genetically related to common variable immunodeficiency (CVID), characterized by a lack of additional isotypes. Our previous linkage analysis of 83 multiple-case IgAD/CVID families containing 449 informative pedigree members showed a significantly increased allele sharing in the chromosome region 6p21 consistent with allelic associations in family-based and case-control studies and provided the evidence for a predisposing locus, termed IGAD1, in the proximal part of the MHC. We have typed the same family material at 17 chromosome 18 marker loci with the average intermarker distance of 7 cM. A total of 7633 genotypes were analyzed in a nonparametric linkage analysis, but none of the marker loci exhibited a significantly increased allele sharing in affected family members. In addition, reverse painting and deletion mapping of a panel of constitutional chromosome 18 deletions/translocations showed the presence of IgA-deficient and IgA-proficient patients with the same abnormality and did not reveal a region commonly deleted. The linkage analysis of chromosome 8 and 21 regions involved in reciprocal translocations t(8;18) and t(18;21), which were identified in two patients lacking IgA, did not disclose a significant allele sharing. Although these results do not exclude the presence of a minor predisposing locus on this chromosome, such a putative locus would confer a population risk of developing IgAD/CVID much lower than IGAD1.