bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Dendritic Cell (DC)-Based Anti-Infective Therapy: Engineering DCs to Secrete Functional IFN-γ and IL-12
Authors: Ahuja Seema S. , Mummidi Srinivas , Malech Harry L. , Ahuja Sunil K. 
Published: December 2022

AbstractAn imbalance in the Th1- and Th2-type cytokine responses may allow certain microbes to modify the host response to favor their own persistence. We now show that infection/pulsing of human CD34+ peripheral blood hemopoietic progenitor cell-derived dendritic cells (DCs) with Leishmania donovani promastigotes, Histoplasma capsulatum, and Mycobacterium kansasii impairs the constitutive production of IL-12 from these cells. Thus, strategies aimed at modulating a dysregulated Th1/Th2 response to infection would be of great interest. To both augment the host immune response and deliver potent immunomodulatory cytokines such as IL-12 and IFN-γ, our goal is to develop a therapeutic strategy using genetically modified, microbial Ag-pulsed DCs. Toward developing such immunotherapies, we used retrovirus-mediated somatic gene transfer techniques to engineer human DCs to secrete biologically active IL-12 and IFN-γ. DCs pulsed with microbial antigens (e.g., leishmania and histoplasma Ags) were capable of inducing proliferative responses in autologous CD4+ lymphocytes. CD4+ lymphocytes cocultured with IL-12-transduced autologous DCs had enhanced Ag-specific proliferative responses compared with CD4+ lymphocytes cocultured with nontransduced or IFN-γ- transduced DCs. In this cell culture model system we demonstrate that IL-12 has a negative effect on IL-4 secretion that is independent of its ability to induce IFN-γ secretion. Taken together, these results indicate that IL-12-transduced DCs may be specifically suited in inducing or down-modulating Ag-specific Th1 or Th2 responses, respectively, and thus may be useful as adjunctive therapy in those intracellular infections in which a dominant Th1 response is critical for the resolution of infection.
T Cell-Mediated, IFN-γ-Facilitated Rejection of Murine B16 Melanomas
Authors: Böhm Waltraud , Thoma Stefan , Leithäuser Frank , Möller Peter , Schirmbeck Reinhold , Reimann Jörg 
Published: December 2022

AbstractThe murine melanoma cell line B16.F10 (H-2b) was used to study specific T cell responses that reject tumors. Stable B16 transfectants were established that express viral Ags, either the hepatitis B surface Ag (HBsAg) or the large tumor Ag (T-Ag) of SV40. B16 cells and their transfected sublines were CD40+CD44+ but expressed no (or low levels of the) costimulator molecules CD154 (CD40L), CD48, CD54, CD80, and CD86. Surface expression of MHC class I (Kb, Db) and class II (I-Ab) molecules by B16 cells was low, but strikingly up-regulated by IFN-γ. CD95 (Fas) and CD95 ligand (CD95L (FasL)) were “spontaneously” expressed by B16 cells growing in vitro in serum-free medium; these markers were strikingly up-regulated by IFN-γ. B16 cells coexpressing CD95 and CD95L were irreversibly programed for apoptosis. In vitro, noninduced B16 transfectants stimulated a specific IFN-γ release response, but no cytolytic response (in a 4-h assay) in MHC class I-restricted CTL; in contrast, IFN-γ-induced B16 targets were efficiently and specifically lysed by CTL. In vivo, B16 transfectants were specifically rejected by DNA-vaccinated syngeneic hosts through a T-dependent immune effector mechanism. The tumors showed evidence of massive apoptosis in vivo during the rejection process. The data suggest that CTL-derived IFN-γ enhances an intrinsic suicide mechanism of these tumor cells in addition to facilitating lytic interactions of effectors with tumor targets.
Secondary Lymphoid-Tissue Chemokine (SLC) Stimulates Integrin α4β7-Mediated Adhesion of Lymphocytes to Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) Under Flow
Authors: Pachynski Russell K. , Wu Steve W. , Gunn Michael D. , Erle David J. 
Published: December 2022

AbstractThe attachment of leukocytes to the endothelium is a multistep process that depends upon a very rapid increase in the adhesive activity of leukocyte integrins. A pertussis toxin-sensitive pathway stimulates integrin-dependent lymphocyte adhesion to Peyer’s patch high endothelial venules in vivo, but the factors responsible for activating this pathway have not been identified previously. We now report that secondary lymphoid-tissue chemokine (SLC) (also known as 6Ckine, Exodus-2, and thymus-derived chemotactic agent 4), a recently described CC chemokine that is expressed in Peyer’s patches and lymph nodes, rapidly activates integrin-mediated lymphocyte adhesion. Immobilized SLC increased the adhesion of HUT-78 T cells and human PBLs to mucosal addressin cell adhesion molecule-1, a protein that is expressed on Peyer’s patch and mesenteric lymph node high endothelial venules. This effect of SLC was seen in both static and flow chamber adhesion assays, was mediated by integrin α4β7, and was inhibited by pertussis toxin. The other CC chemokines tested did not increase adhesion to mucosal addressin cell adhesion molecule-1. SLC had a greater effect on naive CD4+ T cells than on memory CD4+ T cells; CD8+ T cells, B cells, and NK cells were also responsive to SLC. SLC is likely to play an important role in regulating the recruitment of lymphocytes to Peyer’s patches and lymph nodes.
Cutting Edge: Curative Treatment of an Experimentally Induced Colitis by a CD44 Variant V7-Specific Antibody
Authors: Wittig Bianca , Schwärzler Christoph , Föhr Nicole , Günthert Ursula , Zöller Margot 
Published: December 2022

Abstract
Inflammatory bowel disease is a quite severe chronic inflammation, treated mainly by immunosuppression, which often has serious side effects. As CD44 is important in lymphocyte activation and migration, we asked whether Abs against CD44 isoforms influence trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice. A lethal colitis (73/111 mice) could be prevented in 69 of 97 mice by anti-CD44v7 (CD44 variant isoform v7), whereas anti-CD44s (CD44 standard isoform) and anti-CD44v6 had no effect. Upon receiving anti-CD44v7 after the disease had been fully exacerbated, &gt;90% of the mice recovered. TNBS plus anti-CD44v7-treated mice developed early signs of inflammation, with infiltration of leukocytes in the lamina propria and increased IFN-γ production. However, while control mice developed a severe pancolitis, the intestine fully regenerated in anti-CD44v7-treated mice. Locally and systemically, a strong increase in IL-10 production was noted. Thus, anti-CD44v7 can be regarded as a highly efficient and specific therapeutic reagent in chronic colitis, which probably functions by regulating an overshooting Th1 reaction.
Cutting Edge: Differential Regulation of Chemokine Receptors During Dendritic Cell Maturation: A Model for Their Trafficking Properties
Authors: Sozzani Silvano , Allavena Paola , D’Amico Giovanna , Luini Walter , Bianchi Giancarlo , Kataura Motoji , Imai Toshio , Yoshie Osamu , Bonecchi Raffaella , Mantovani Alberto 
Published: December 2022

AbstractUpon exposure to immune or inflammatory stimuli, dendritic cells (DC) migrate from peripheral tissues to lymphoid organs, where they present Ag. CC chemokines induce chemotactic and transendothelial migration of immature DC, in vitro. Maturation of DC by CD40L, or by LPS, IL-1, and TNF, induces down-regulation of the two main CC chemokine receptors expressed by these cells, CCR1 and CCR5, and abrogates chemotaxis to their ligands. Inhibition was rapid (&lt;1 h) and included the unrelated agent FMLP. Concomitantly, the expression of CCR7 and the migration to its ligand EBI1 ligand chemokine (ELC)/macrophage inflammatory protein (MIP)-3β, a chemokine expressed in lymphoid organs, were strongly up-regulated, though with slower kinetics (24–48 h). Rapid inhibition of responsiveness to chemoattractants present at sites of inflammation and immune reaction may be permissive for leaving peripheral tissues. Conversely, the slower acquisition of responsiveness to ELC/MIP-3β may guide subsequent localization of DC in lymphoid organs.
Dendritic Cell Heterogeneity In Vivo: Two Functionally Different Dendritic Cell Populations in Rat Intestinal Lymph Can Be Distinguished by CD4 Expression
Authors: Liu LiMing , Zhang ManHua , Jenkins Chris , MacPherson G. Gordon 
Published: December 2022

AbstractDC derived from rat pseudo-afferent lymph (L-DC) vary in CD4, CD11b/c, Thy1, and OX41 expression. CD4 and OX41 are expressed by the same subpopulation (50–60%) of L-DC. CD4+/OX41+ L-DC express short fine processes and low nonspecific esterase, whereas CD4− DC/OX41− express long pseudopodia, high nonspecific esterase, and many cytoplasmic inclusions. These differences are stable in culture. Both populations express similar amounts of MHC class II, ICAM-1, CD11b/c and OX62. Most CD4−/OX41− L-DC are strongly positive for B7, but CD4+ L-DC express less B7, and some may be negative. Both populations express invariant chain, but both the absolute numbers and levels of expression were higher for CD4− DC. Surprisingly, CD4+ L-DC are more potent APC than CD4− cells in MLRs, for sensitized T cells in vitro and for naive T cells in vivo. Cultured CD4+/OX41+ DC can still process and present native Ag. Cultured CD4−/OX41− cells cannot present native Ag but can stimulate strong MLRs. CD4− DC invariant chain expression decreases in culture, whereas expression by CD4+ DC is stable for 48 h. CD4+ and CD4− L-DC have similar turnover times in vivo, suggesting that one population is not the precursor of the other. Thus, two separate DC populations that differ functionally and phenotypically migrate from intestine to mesenteric nodes. This may reflect distinct DC lineages or differentiation modulated by different microenvironmental stimuli.
Down-Modulation of a Novel Bax-Associated Protein During Apoptosis in Normal Mature B Lymphocytes
Authors: He Huiling , Hershberger Pamela A. , McCarthy Susan A. 
Published: December 2022

AbstractWe have recently characterized a novel 16-kDa Bax-associated protein. In this study, we investigate the regulation of this protein’s expression during in vitro induction of apoptosis in mature splenic B cells. A panel of biochemically distinct apoptotic stimuli induced the dramatic down-modulation of the 16-kDa protein in B cells; this down-modulation was rapid, and did not require DNA fragmentation. Reciprocally, stimuli that induced protection from apoptosis prevented down-modulation of the 16-kDa protein. These regulatory effects were specific, since Bcl-2 and Bax protein levels were not similarly modulated. Stimuli that reduce expression of the 16-kDa protein may therefore act indirectly to increase the proapoptotic activity of Bax, perhaps by altering Bax binding to other cellular proteins.
Induction of Acute Inflammation In Vivo by Staphylococcal Superantigens. II. Critical Role for Chemokines, ICAM-1, and TNF-α
Authors: Tessier Philippe A. , Naccache Paul H. , Diener Kerrilyn R. , Gladue Ronald P. , Neote Kuldeep S. , Clark-Lewis Ian , McColl Shaun R. 
Published: December 2022

AbstractSuperantigens such as staphylococcal enterotoxin A and B (SEA and SEB) activate the immune system by stimulating a large proportion of T lymphocytes through specific Vβ regions of the TCR and activating macrophages by binding to MHC class II molecules. While the mechanisms by which superantigens activate T lymphocytes have been elucidated, their role in the generation of local immune responses to bacterial invasion is still unclear. In this study we have examined the ability of the superantigens SEA and SEB to elicit an inflammatory reaction in vivo, in s.c. air pouches in the mouse. Upon injection into the s.c. air pouch, the two superantigens stimulated a time-dependent increase in the number of leukocytes appearing in the pouch exudate. The leukocytes migrating into the pouch exudate were predominantly neutrophils, with some mononuclear phagocytes and eosinophils present. No T lymphocytes were detected either in the pouch lining tissue or in the exudate cells. Injection of SEA resulted in increased ICAM-1 expression, as detected by immunohistochemistry, on endothelial cells in the tissue surrounding the air pouch and accumulation of TNF-α and the chemokines macrophage inflammatory protein-2 (MIP-2), MIP-1α, and JE in the pouch exudate. In addition, pretreatment of mice with Abs raised against ICAM-1, TNF-α, MIP-2, MIP-1α, KC, or JE inhibited leukocyte accumulation induced by SEA. These data demonstrate that bacterial superantigens may promote inflammation at extravascular sites in vivo, and that this response is secondary to the generation of inflammatory mediators, including chemokines.
IL-4-Producing NK1.1+ T Cells Are Resistant to Glucocorticoid-Induced Apoptosis: Implications for the Th1/Th2 Balance
Authors: Tamada Koji , Harada Mamoru , Abe Koichiro , Li Tieli , Nomoto Kikuo 
Published: December 2022

AbstractTo elucidate the mechanisms by which glucocorticoids promote Th2-type responses, we investigated the influence of dexamethasone (DEX) on both cytokine production and viability of NK1.1+ T cells. The in vivo administration of DEX enhanced the IL-4 production of spleen cells and liver mononuclear cells in wild-type mice, but not in β2m-deficient mice. DEX reduced the cellularity of conventional T cells, but not that of NK1.1+ T cells, in both spleen and liver, suggesting an increased proportion of NK1.1+ T cells. Moreover, the proportion of IL-4-producing NK1.1+ T cells increased in the DEX-injected mice. These results suggest that DEX induced IL-4 production through the preferential survival of IL-4-producing NK1.1+ T cells. In investigating the reason for the preferential survival of NK1.1+ T cells, we found that NK1.1+ T cells were resistant to DEX-induced apoptosis and expressed a higher level of intracellular Bcl-2 compared with conventional NK1.1− T cells. In addition, splenic and hepatic NK1.1+ T cells were resistant to radiation-induced apoptosis. Collectively, our findings revealed an important role for NK1.1+ T cells in the regulation of Th1/Th2 balance by glucocorticoids and their possible functions under various apoptotic stimuli.
Staphylococcal Enterotoxin A Induces Survival of VH3-Expressing Human B Cells by Binding to the VH Region with Low Affinity
Authors: Domiati-Saad Rana , Lipsky Peter E. 
Published: December 2022

AbstractStaphylococcal enterotoxins (SE) are bacterial superantigens that bind to MHC class II molecules and to the Vβ-chain of the TCR, and subsequently activate T cells expressing specific Vβ regions. In this study, we have studied the effects of SEA on human B cell activation, and specifically the capacity of SEA to function as a B cell superantigen in vitro. We show herein that SEA failed to induce B cell proliferation and differentiation in the absence of T cells. However, SEA induced survival of B cells uniquely expressing VH3-containing IgM, independently of light chain utilization. The sequences of VH3 IgM gene products were determined and found to include a number of members of the VH3 family with a variety of different D and JH gene segments. Analysis of the sequences of VH3 gene products revealed possible sites in framework region 1 and/or framework region 3 that could be involved in SEA-mediated activation of VH3-expressing B cells. Binding studies showed that SEA interacts with the VH3 domain of Ig with low, but detectable affinity. These results indicate that SEA functions as a B cell superantigen by interacting with VH3 gene segments of Ig.
Characterization and Differentiation of an Early Murine Yolk Sac-Derived IL-7-Independent Pre-Pro-B Cell Line
Authors: Lu Li-Sheng , Auerbach Robert 
Published: December 2022

AbstractWe describe a unique, stable pre-pro-B cell line (YS-PPB) derived from AA4.1+ yolk sac cells from day 10 mouse embryos. This cell line, discovered fortuitously during the course of studies of in vitro B cell differentiation, is independent of IL-7 supplementation for long term expansion in vitro. YS-PPB cells as well as clonal sublines expressed AA4.1, CD43, B220, Sca-1, CD19, heat stable antigen, MHC class I, IL-7R, and FcγR, but did not express cytoplasmic μ-chain, surface IgM (sIgM), or MHC class II molecules. PCR analysis showed that the cells expressed TdT, λ5, and RAG-1 genes, but that their Ig genes were still in germline configuration. The cell line was dependent on direct contact with S17 stromal cells for growth, but, in contrast to bone marrow stem cells, required no additional growth factors for maintenance and expansion. When stimulated with IL-7 and LPS, YS-PPB cells and cells from all tested clonal sublines differentiated into sIgM+ B cells in vitro. Irradiated mice reconstituted with YS-PPB cells yielded spleens containing 38% sIgM+ donor-derived B cells, demonstrating that YS-PPB cells, although stably arrested in development at the boundary between pre-pro-B and pro-B stages of B cell differentiation, still retain their competence to differentiate into mature, Ig-producing B cells when transferred to a normal host environment. Thus, this new cell line can provide a reproducible source of B cell precursors arrested at that critical time in B cell differentiation when the machinery for Ig gene rearrangement is in place but rearrangement has not yet occurred.
Cytokine-Like Factor-1, a Novel Soluble Protein, Shares Homology with Members of the Cytokine Type I Receptor Family
Authors: Elson Greg C. A. , Graber Pierre , Losberger Christophe , Herren Suzanne , Gretener Denise , Menoud Laurent N. , Wells Timothy N. C. , Kosco-Vilbois Marie H. , Gauchat Jean-François 
Published: December 2022

AbstractIn this report we describe the identification, cloning, and expression pattern of human cytokine-like factor 1 (hCLF-1) and the identification and cloning of its murine homologue. They were identified from expressed sequence tags using amino acid sequences from conserved regions of the cytokine type I receptor family. Human CLF-1 and murine CLF-1 shared 96% amino acid identity and significant homology with many cytokine type I receptors. CLF-1 is a secreted protein, suggesting that it is either a soluble subunit within a cytokine receptor complex, like the soluble form of the IL-6R α-chain, or a subunit of a multimeric cytokine, e.g., IL-12 p40. The highest levels of hCLF-1 mRNA were observed in lymph node, spleen, thymus, appendix, placenta, stomach, bone marrow, and fetal lung, with constitutive expression of CLF-1 mRNA detected in a human kidney fibroblastic cell line. In fibroblast primary cell cultures, CLF-1 mRNA was up-regulated by TNF-α, IL-6, and IFN-γ. Western blot analysis of recombinant forms of hCLF-1 showed that the protein has the tendency to form covalently linked di- and tetramers. These results suggest that CLF-1 is a novel soluble cytokine receptor subunit or part of a novel cytokine complex, possibly playing a regulatory role in the immune system and during fetal development.
Sequence-Based Typing Provides a New Look at HLA-C Diversity
Authors: Turner Seán , Ellexson Mary E. , Hickman Heather D. , Sidebottom David A. , Fernández-Viña Marcelo , Confer Dennis L. , Hildebrand William H. 
Published: December 2022

AbstractAlthough extensive HLA-A and HLA-B polymorphism is evident, the true diversity of HLA-C has remained hidden due to poor resolution of HLA-C Ags. To better understand the polymorphic nature of HLA-C molecules, 1823 samples from the National Marrow Donor Program research repository in North America have been typed by DNA sequencing and interpreted in terms of HLA-C diversification. Results show that HLA-Cw*0701 was the most common allele with a frequency of 16%, whereas 28% of the alleles typed as Cw12-18 (serologic blanks). The frequency of homozygotes was 9.8% as compared with previous studies of 18% for sequence-specific primers and 50% for serology. Most startling was the frequency at which new alleles were detected; 19 new HLA-C alleles were detected, representing a rate of ∼1 in 100 samples typed. These new HLA-C alleles result from 29 nucleotide substitutions of which 4 are silent, such that coding substitutions concentrated about the Ag-binding groove predominate. Polymorphism at the HLA-C locus therefore resembles that at the HLA-A and HLA-B loci more than previously believed, indicating that antigenic stress is driving HLA-C evolution. However, sequence conservation in the α-helix of the first domain and a clustering of unique amino acids around the B pocket indicate that HLA-C alleles respond to antigenic pressures differently than HLA-A and HLA-B. Finally, because the samples characterized were predominantly from Caucasians, we hypothesize that HLA-C polymorphism will equal or exceed that of the HLA-A and -B loci as DNA sequence-based typing is extended to include more non-Caucasian individuals.
Secretory IgA Induces Degranulation of IL-3-Primed Basophils
Authors: Iikura Motoyasu , Yamaguchi Masao , Fujisawa Takao , Miyamasu Misato , Takaishi Toshiaki , Morita Yutaka , Iwase Takashi , Moro Itaru , Yamamoto Kazuhiko , Hirai Koichi 
Published: December 2022

AbstractWe examined whether secretory IgA (sIgA), known to mediate eosinophil stimulation, has an effect on basophil functions. An immobilized preparation of sIgA, but not of monomeric IgA, induced histamine release (approximately 15% of total histamine contents) from human basophils in vitro. sIgA-induced basophil histamine release was totally dependent on pretreatment with IL-3. IL-5 and granulocyte-macrophage CSF also primed basophils for sIgA-mediated release. Exogenous divalent ions, i.e., Ca2+ and Mg2+, were essential for sIgA-mediated basophil degranulation, and the degranulation was completed within 45 min. A newly synthesized lipid mediator, leukotriene C4, was also liberated from IL-3-primed, sIgA-stimulated basophils. Enzyme digestion experiments revealed that the (Fc)2·secretory component portion of sIgA is important for sIgA-mediated basophil activation, but the functional binding sites of sIgA on basophils were surmised to be different from FcαR. These observations reveal the novel finding that sIgA is able to stimulate basophils as well as eosinophils. Since sIgA is the most abundant Ig isotype in the secretions from mucosal tissues, and basophils are active participants in allergic late-phase reactions, sIgA-mediated basophil mediator release is potentially involved in exacerbation of the inflammation associated with allergic disorders.
Sustained Phosphorylation of Cytosolic Phospholipase A2 Accompanies Cycloheximide- and Adenovirus-Induced Susceptibility to TNF
Authors: O’Brien Jennifer B. , Piddington Debra L. , Voelkel-Johnson Christina , Richards Debra J. , Hadley Leslie A. , Laster Scott M. 
Published: December 2022

Abstract
In this report we examine the phosphorylation state of cytosolic phospholipase A2 (cPLA2) in C3HA fibroblasts that have been treated with TNF, cycloheximide (CHI), or a combination of both compounds. Our experiments show that TNF and CHI, when used independently, caused the rapid phosphorylation of cPLA2 (within 10 min). In both cases, cPLA2 was subsequently dephosphorylated to pretreatment levels by 40 min. In addition, under these conditions [3H]arachidonic acid was not released, and we could not detect a change in the activity of cPLA2 in vitro. In contrast, in cells treated with a combination of TNF and CHI, we found that the dephosphorylation of cPLA2 was inhibited, and cPLA2 remained phosphorylated for up to 2 h. In vitro we found that sustained phosphorylation of cPLA2 was accompanied by a 60 to 80% increase in the activity of cPLA2. The sustained phosphorylation of cPLA2 also occurred in cells infected with the adenovirus mutant dl309, suggesting that sustained phosphorylation may be a general requirement for the activation of cPLA2 in apoptotic cells. We also found that sustained phosphorylation of phosphoproteins is not a general consequence of apoptotic death, since the phosphorylation of p42 mitogen-activated protein kinase was not sustained. Finally, we show that the phosphatase inhibitor orthovanadate acts as does CHI to render cells susceptible to TNF, suggesting that resistance to TNF may depend on TNF’s ability to induce the expression of tyrosine or dual specificity phosphatase(s).