bluuebunny/crossref_metadata_2025_split huggingface dataset:
B7-1 is superior to B7-2 costimulation in the induction and maintenance of T cell-mediated antileukemia immunity. Further evidence that B7-1 and B7-2 are functionally distinct.
Authors: Matulonis U , Dosiou C , Freeman G , Lamont C , Mauch P , Nadler L M , Griffin J D 
Published: December 2022

Abstract
Although intact, viable tumor cells rarely induce a clinically significant immune response in vivo, immunogenicity can be elicited by irradiated tumor cells that protect against subsequent challenge with wild-type intact viable tumor cells. Genetic modification of murine tumor cells, by transfection of cDNAs encoding either cytokines, MHC molecules, or costimulatory molecules, has been capable of inducing antitumor immunity. We and others have previously demonstrated that expression of the B7-1 costimulatory molecule, in either immunogenic or nonimmunogenic tumors, can protect against subsequent challenge with wild-type tumor cells. In this work, using a murine model of acute myeloid leukemia, we demonstrate that the B7-1 costimulatory molecule is superior to the B7-2 molecule in its capacity to protect against wild-type tumor challenge and eradicate minimal residual disease. These results provide compelling evidence that the B7-1 and B7-2 costimulatory signals are functionally distinct, thus resulting in clinically significant differences in the induction of antitumor immunity in vivo.
Bacterial lipopolysaccharide induces the association and coordinate activation of p53/56lyn and phosphatidylinositol 3-kinase in human monocytes.
Authors: Herrera-Velit P , Reiner N E 
Published: December 2022

Abstract
p53/56lyn and other src family tyrosine kinases become activated in monocytes treated with LPS. In a variety of systems, phosphatidylinositol 3-kinase (PI 3-kinase) is believed to be a downstream effector of tyrosine kinases, and activation of PI 3-kinase results in increased levels of D3-phosphorylated metabolites of phosphatidylinositol (PtdIns). To examine whether LPS activates PI 3-kinase, freshly isolated human, peripheral blood monocytes were labeled in vitro with [32P]orthophosphate, and inositol phospholipids were detected after extraction and separation of lipids by TLC. Levels of PtdIns 3,4,5-trisphosphate (PtdIns 3,4,5-P3) were elevated within minutes of exposure of cells to LPS. Analysis of 32P-labeled lipid extracts of U937 cells by HPLC confirmed that levels of PtdIns 3,4,5-P3 increased rapidly following LPS treatment. Increased levels of PtdIns 3,4,5-P3 in LPS-treated cells resulted from an increase in the specific activity of PI 3-kinase. Thus, anti-PI 3-kinase immunoprecipitates prepared from unlabeled monocytes and assayed in an in vitro phosphorylation assay, using PtdIns as substrate, showed higher enzymatic activity when these were prepared from lysates of LPS-treated cells as compared with control cells. PI 3-kinase activity in immunoprecipitates was elevated as early as 2 min after LPS exposure and was dose dependent, with increased activity being observed at LPS concentrations as low as 10 pg/ml. Activation of PI 3-kinase involved signaling through the monocyte cell surface molecule CD14, since pretreatment of cells with Abs to CD14 abrogated LPS-induced increases in PtdIns 3,4,5-P3. Immunoprecipitates of p53/56lyn from LPS-treated cells showed a time-dependent and transient increase in PI 3-kinase activity assayed in vitro, coordinate with activation of p53/56lyn, indicating that LPS induces the association and simultaneous activation of these two enzymes in vivo. These findings indicate that monocytes respond to LPS with the rapid activation of PI 3-kinase, resulting in transient increases in levels of PtdIns 3,4,5-P3. This process is CD14 dependent and involves the physical association of PI 3-kinase with activated p53/56lyn.
Study of complement-mediated anaphylaxis in humans. The role of IgG subclasses (IgG1 and/or IgG4) in the complement-activating capacity of immune complexes.
Authors: Bergamaschini L , Santangelo T , Faricciotti A , Ciavarella N , Mannucci P M , Agostoni A 
Published: December 2022

Abstract
The role of Ig classes and subclasses in complement activation has been investigated both in vitro and in experimental animals, but not in humans. This study was conducted to determine the immunologic events of post-transfusion anaphylaxis in humans, and the effects of immune complexes of different IgG subclass compositions on complement activation. The ability of immune complexes containing mixed IgG1 and IgG4 or IgG4 Ab only to activate complement was investigated in two patients with von Willebrand's disease (a congenital bleeding disorder). This disease was complicated by precipitating IgG alloantibodies to von Willebrand factor (vWF), which triggered complement-mediated anaphylaxis after infusion of vWF-containing preparations. Complement activation was greater in the presence of mixed IgG1- and IgG4-vWF complexes than with IgG4-vWF alone. In one patient, the generation of large amounts of C4a, C3a, and terminal complement complexes following the formation of mixed IgG1- and IgG4-vWF was associated with life-threatening anaphylaxis. In this patient, IgG4 appeared to have no inhibitory effect on antigen-bound IgG1-mediated complement activation. In the other patient, formation of IgG4-vWF led to a lesser degree of complement activation and was associated with moderately severe anaphylaxis. Since neither patient showed any biochemical alterations indicating the involvement of mast cells or the contact phase of coagulation at any time, it is probable that the pathogenetic mechanism of the clinical syndrome was a direct effect of complement anaphylatoxins on vascular permeability and smooth muscle contraction. In both patients, IgG-vWF bound C4 and C3 (IgG4-vWF to a lesser extent than mixed IgG1- and IgG4-vWF), and this probably prevented serum sickness as a complication.
HIV glycoprotein 120 enhances intercellular adhesion molecule-1 gene expression in glial cells. Involvement of Janus kinase/signal transducer and activator of transcription and protein kinase C signaling pathways.
Authors: Shrikant P , Benos D J , Tang L P , Benveniste E N 
Published: December 2022

Abstract
It is well established that the two major glial cells in the central nervous system (CNS), astrocytes and microglia, are key participants in mediating the neurologic dysfunction associated with HIV infection of the CNS. In this study, we investigated the ability of the major envelope glycoprotein of HIV, glycoprotein 120 (gp120), to regulate intercellular adhesion molecule-1 (ICAM-1) expression in glial cells, because ICAM-1 is important in mediating immune responsiveness in the CNS, facilitating entry of HIV-infected cells into the CNS, and promoting syncytia formation. Our results indicate that gp120 enhances ICAM-1 gene expression in primary rat astrocytes, primary human astrocytes, a human astroglioma cell line CRT, and primary rat microglia. The signal transduction events involved in gp120-mediated enhancement of ICAM-1 appear to involve activation of both protein kinase C and tyrosine kinase, because inhibitors of protein kinase C and tyrosine kinase abrogate gp120-mediated ICAM-1 expression in both astrocytes and microglia. Moreover, gp120 induces tyrosine phosphorylation of signal transducer and activator of transcription (STAT-1 alpha) as well as the Janus kinase (JAK2) in glial cells. We also demonstrate that gp120-mediated ICAM-1 expression has functional significance, as it enhances the ability of monocytic cells to bind to gp120-stimulated human astrocytes in an ICAM-1/beta 2 integrin-dependent fashion. These results provide new insights into how gp120 can influence the involvement of glial cells in the pathogenesis of AIDS dementia complex.
CD28-mediated up-regulation of beta 1-integrin adhesion involves phosphatidylinositol 3-kinase.
Authors: Zell T , Hunt S W , Mobley J L , Finkelstein L D , Shimizu Y 
Published: December 2022

Abstract
Cross-linking of the CD28 Ag on T cells results in increased beta 1-integrin-mediated adhesion to fibronectin. Chimeric contructs containing the CD28 cytoplasmic domain fused to the extracellular and transmembrane regions of CD2 were expressed in HL60 cells to investigate CD28-mediated regulation of adhesion. Ab cross-linking of the CD2/28 chimera resulted in increased beta 1-dependent adhesion of HL60 transfectants to fibronectin. Induced binding was completely inhibited by the phosphatidylinositol 3-kinase (PI 3-K) inhibitor wortmannin. Cross-linking of the CD2/28 chimera also induced association of the p85 subunit of PI 3-K with the CD2/28 cytoplasmic domain. In contrast, cross-linking of a CD2/28 chimera containing a tyrosine to phenylalanine substitution in the YMNM motif did not result in increased adhesion to fibronectin and did not lead to association of the chimera with PI 3-K. These results directly implicate the YMNM motif and PI 3-K in the regulation of beta 1-integrin activity by the CD28 Ag.
Chemokines regulate T cell adherence to recombinant adhesion molecules and extracellular matrix proteins.
Authors: Lloyd A R , Oppenheim J J , Kelvin D J , Taub D D 
Published: December 2022

Abstract
Chemokines are a family of structurally related, low m.w. proteins that regulate leukocyte migration both in vitro and in vivo. By virtue of their target cell specificity, chemokines have the potential to selectively recruit leukocyte subpopulations into sites of inflammation during the genesis of an immune response. Chemokines have been shown to induce leukocyte adhesion to endothelium, to facilitate trans-endothelial passage, and to direct cell migration along a protein gradient (chemotaxis). The chemokines (macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, RANTES, and IFN-inducible protein-10) have recently been reported to be chemotactic for T cells. We have investigated the potential activity of these proteins in regulation of T cell adhesion. These chemokines induce T cell adhesion to purified, recombinant human adhesion molecules (rhICAM-1, rhVCAM-1) and to ECM proteins: fibronectin, collagen, and laminin. The chemokine-induced adhesion process occurs rapidly, is dose-dependent, and appears to be mediated via beta 1 and beta 2 integrins. The enhanced T cell adhesion is not associated with an increased surface expression of adhesion proteins, suggesting that chemokines stimulate the development of a high affinity state in the integrin molecules. Our findings provide in vitro evidence of a critical role for chemokines in T cell adhesion to endothelial adhesion molecules and ECM proteins, thereby promoting haptotactic migration of T cells to sites of inflammation in vivo.
Requirement for phosphatidylinositol 3'-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor.
Authors: Minshall C , Arkins S , Freund G G , Kelley K W 
Published: December 2022

Abstract
Hemopoietic growth factors promote survival of progenitor cells by preventing their apoptotic death. Recently, phosphatidylinositol 3'-kinase (PI 3-kinase) has been shown to be integral in the pathway by which insulin and nerve growth factor prevent apoptosis. In this work, we show that IL-3-dependent FDCP-1/Mac-1 murine hemopoietic progenitors express receptors for another growth factor, insulin-like growth factor-I (IGF-I), and that both IL-3 and IGF-I stimulate PI 3-kinase activity. We then demonstrate that IGF-I shares with IL-3 the properties of significantly promoting proliferation and enhancing survival of myeloid progenitor cells at concentrations as low as 3 ng/ml. IL-3 and IGF-I efficiently promote cell survival in the presence of inhibitors of either RNA synthesis (actinomycin D) or mitosis (mitomycin C), suggesting that both ligands promote survival by a process that is largely independent of RNA synthesis. To determine whether PI 3-kinase mediates IL-3- and IGF-I-induced inhibition of apoptosis, FDCP-1/Mac-1 cells were incubated with the PI 3-kinase inhibitor, wortmannin. While wortmannin inhibited both basal and IGF-I- and IL-3-induced PI 3-kinase enzyme activity, it did not affect the ability of IL-3 to protect FDCP-1/Mac-1 cells from apoptosis, even though it abrogated the IGF-I-induced inhibition of apoptosis. These data demonstrate that even though activation of PI 3-kinase is a pleiotropic feature of both IL-3 and IGF-I receptors in myeloid progenitors, prevention of apoptosis by IL-3 but not IGF-I is independent of PI 3-kinase. Survival of hemopoietic progenitors is therefore maintained by at least two different intracellular signaling pathways, one requiring PI 3-kinase and one that does not.
Thymic stromal cells can support B cell differentiation from intrathymic precursors.
Authors: Montecino-Rodriguez E , Johnson A , Dorshkind K 
Published: December 2022

Abstract
T lineage cells are the predominant intrathymic population, but low numbers of thymic B cells are also present in the thymus. Recent studies describing the contribution of thymic B cells to the shaping of the T cell repertoire have raised the question as to whether they are produced intrathymically and the potential role of the thymic stroma in this process. During the course of studies aimed at testing the B cell developmental potential of CD4-CD8-CD3/TCR- triple-negative thymocytes present in a newly developed, stromal cell-dependent, long term culture system, the ability of selected thymic stromal cells to support distinct stages of B cell development was revealed. Some thymic stromal cell lines maintained cells with B cell developmental potential but could not support their differentiation, while other selected lines efficiently supported the development of surface IgM-expressing cells from triple-negative precursors. Thymic surface IgM+ B cells were generated most efficiently from thymocytes harvested from relatively young mice. Taken together, the results of this study demonstrate that the thymic microenvironment exhibits a functional heterogeneity in its ability to support different stages of B cell development.
IL-7 differentially modulates the expression of IFN-gamma and IL-4 in activated human T lymphocytes by transcriptional and post-transcriptional mechanisms.
Authors: Borger P , Kauffman H F , Postma D S , Vellenga E 
Published: December 2022

Abstract
We investigated the role of IL-7 on the expression of IFN-gamma and IL-4 in human T lymphocytes. IL-7 alone did not induce IFN-gamma or IL-4 mRNA. However, IL-7 dose-dependently up-regulates the anti-CD3- or anti-CD3/anti-CD28-induced IFN-gamma and IL-4 mRNA expression. Used at an optimal concentration, IL-7 (5 ng/ml) increased the accumulation of IFN-gamma (eightfold) and IL-4 (2.5-fold) mRNAs, which could not be blocked by anti-IL-12 treatment. The enhanced IFN-gamma mRNA accumulation was observed within 3 to 6 h, without altering the pattern of the kinetics. However, longer exposure (&gt; 12 h) did not result in different IFN-gamma expression for anti-CD3/anti-CD28 vs anti-CD3/anti-CD28 plus IL-7-stimulated T lymphocytes. mRNA stability studies revealed that IL-7 stabilizes both IFN-gamma and IL-4 mRNA transcripts: 40 and 60 min in anti-CD3/anti-CD28-stimulated T cells vs 120 and 90 min in T cells costimulated with anti-CD3/anti-CD28 plus IL-7. Nuclear run-on assays revealed that the transcription rate of the IFN-gamma gene increased approximately twofold in the presence of IL-7, without affecting the transcription rate of the IL-4 gene. The IL-7-mediated IFN-gamma up-regulation could not be inhibited by cycloheximide treatment, in contrast to IL-4 gene expression. However, the promotive effect of IL-7 on IFN-gamma and IL-4 gene expression could be blocked by genistein and cyclosporin A. Finally, it was demonstrated that the effect of IL-7 on IFN-gamma mRNA accumulation was also reflected at the protein level. In summary, these data demonstrate that IL-7 preferentially up-regulates IFN-gamma expression in activated T lymphocytes, which is accomplished at transcriptional and post-transcriptional levels.
Role of the TCR binding region of the HLA class I alpha 2 domain in regulation of cell adhesion and proliferation.
Authors: Pettersen R D , Hestdal K , Lie S O , Gaudernack G 
Published: December 2022

Abstract
In addition to Ag presentation for T cell surveillance, MHC molecules have been implicated in mediating regulatory signals. We have assessed biologic responses following engagement of the TCR accessible region of the HLA class I alpha 2 domain. mAbs directed to this domain specifically induced cell aggregation of normal hematopoietic and leukemic cells. The functional consequences were unique since other mAbs reactive with HLA class I residues outside the TCR binding domain did not induce cell aggregation. The adhesion response required ATP, mRNA, protein, and actin synthesis and did not depend on LFA-1/ICAM interactions. Cell aggregation was also induced when all but four of the intracytoplasmic residues of the class I molecule were deleted, indicating that transduction of signals leading to cell adhesion does not require this portion of the molecule. mAbs directed to HLA class I alpha 2 amino acid residues within the TCR binding domain were also able to inhibit proliferation of normal mitogen-stimulated T cells. Growth inhibition correlated with down-regulated expression of CD25, CD28, and CD95, suggesting that reduced transduction of costimulatory signals is involved. Although HLA class I signals inducing cell aggregation required engagement of positions within the TCR binding region, growth inhibitory signals could be generated through positions both within and adjacent to this domain. Taken together, engagement of specific positions within the TCR binding domain of the class I alpha 2 helix results in active cellular responses. Thus, this region may be directly involved in signal transduction following CTL recognition of target cells.
Contribution of nitric oxide to the host parasite equilibrium in toxoplasmosis.
Authors: Hayashi S , Chan C C , Gazzinelli R , Roberge F G 
Published: December 2022

Abstract
We studied the effect of nitric oxide (NO) production on the evolution of toxoplasmosis in C57BL/6 mice. Infection was induced by i.p. injection of Toxoplasma gondii strain ME49. NO synthesis was inhibited by treatment with aminoguanidine, a structural analogue of L-arginine. The severity of infection was evaluated by histopathologic examination of the brain. In the infected mice treated for 2 wk with aminoguanidine, we observed an increase in the number of toxoplasma tachyzoites and intracellular cysts accompanied by an exacerbated inflammation of the brain tissue compared with that in controls. When spleen cells from infected mice were stimulated in culture with toxoplasma Ag, there was a marked cytotoxic effect on cells collected during the acute stage of infection and an inhibition of proliferation of the remaining viable lymphocytes. These effects were correlated with high levels of NO and PGE2 production. The suppression of NO synthesis prevented cell death and restored the lymphocyte proliferative response as well as lymphokine production. The neutralization of IFN-gamma or TNF-alpha had no effect on NO production in the cultures of infected mouse spleen cells. Cultures in which purified macrophages and lymphocytes from infected and naive mice were mixed indicated that the production of NO was dependent on lymphocyte activation. In the later stages of infection, when the production of NO was abating, preventing PGE2 secretion with indomethacin also increased the lymphocyte proliferative response. We conclude that the opposing effects of NO in toxoplasmosis, which protects against Toxoplasma gondii and at the same time limits the immune response, probably contribute to the establishment of the characteristic chronic state of host parasite equilibrium.
Acute phase levels of C-reactive protein enhance IL-1 beta and IL-1ra production by human blood monocytes but inhibit IL-1 beta and IL-1ra production by alveolar macrophages.
Authors: Pue C A , Mortensen R F , Marsh C B , Pope H A , Wewers M D 
Published: December 2022

Abstract
C-reactive protein (CRP), the major acute phase protein in humans, was purified free of endotoxin (LPS) (&lt; 10 pg of LPS/mg of purified CRP) and evaluated for its ability to modulate LPS-induced production of IL-1 beta and IL-1 receptor antagonist (IL-1ra) from human PBMC and lung macrophages. PBMC (5 x 10(6)/ml) released low levels of IL-1 beta in response to either CRP (250 micrograms/ml) or LPS (100 ng/ml) for 18 h (0.3 +/- 0.1 and 1.5 +/- 0.7 ng/ml, respectively). However, when CRP (250 micrograms/ml) and LPS (100 ng/ml) were combined, PBMC released 9.7 +/- 2.9 ng/ml (p &lt; 0.001 vs LPS alone). This synergy was removed by immunodepletion of CRP before stimulation. With respect to IL-1ra, although CRP induced IL-1ra production from PBMC (0.8 +/- 0.3 ng/ml control, 2.6 +/- 1.3 ng/ml with CRP), CRP did not synergize with LPS for IL-1ra production (15.0 +/- 0.7 ng/ml LPS alone vs 15.4 +/- 1.4 ng/ml LPS and CRP). In contrast, lung macrophages responded to CRP quite differently than PBMC. Macrophages (10(6)/ml) were not stimulated to produce IL-1 beta or IL-1ra by CRP alone. When combined with LPS, CRP inhibited IL-1 beta and IL-1ra release induced by LPS (for IL-1 beta release, LPS induced 3.0 +/- 1.7 ng/ml vs 1.1 +/- 0.4 for combined LPS and CRP; for IL-1ra release, LPS induced 12.9 +/- 2.3 ng/ml vs 7.6 +/- 2.3 ng/ml for combined LPS and CRP). These data suggest that acute phase levels of CRP may have divergent effects depending on the target population. CRP may be largely proinflammatory to blood monocytes responding to LPS since IL-1 beta production is augmented over IL-1ra production. However, in tissue compartments the effects of CRP may be largely immunosuppressive to LPS-induced tissue macrophage IL-1 beta production.
Ligand-independent activation of the glucocorticoid receptor by ursodeoxycholic acid. Repression of IFN-gamma-induced MHC class II gene expression via a glucocorticoid receptor-dependent pathway.
Authors: Tanaka H , Makino Y , Miura T , Hirano F , Okamoto K , Komura K , Sato Y , Makino I 
Published: December 2022

Abstract
The therapeutic effectiveness of ursodeoxycholic acid (UDCA) for various autoimmune liver diseases strongly indicates that UDCA possesses immunomodulatory activities. Experimental evidence also supports this notion, since, for example, UDCA has been shown to suppress secretion of IL-2, IL-4, and IFN-gamma from activated T lymphocytes, and Ig production from B lymphocytes. To investigate the mechanical background of UDCA-mediated immunomodulation, we asked whether UDCA interacts with the intracellular signal transduction pathway, especially whether it is involved in immunosuppressive glucocorticoid hormone action. For this purpose, we used a cloned Chinese hamster ovary cell line, CHOpMTGR, in which glucocorticoid receptor cDNA was stably integrated. In immunocytochemical analysis, we found that treatment with UDCA promoted the nuclear translocation of the glucocorticoid receptor in a ligand-independent fashion, which was further confirmed by immunoprecipitation assays. Moreover, the translocated glucocorticoid receptor demonstrated sequence-specific DNA binding activity. Transient transfection experiments revealed that treatment of the cells with UDCA marginally enhanced glucocorticoid-responsive gene expression. We also showed that UDCA suppressed IFN-gamma-mediated induction of MHC class II gene expression via the glucocorticoid receptor-mediated pathway. Together, UDCA-dependent promotion of translocation of the glucocorticoid receptor may be associated with, at least in part, its immunomodulatory action through glucocorticoid receptor-mediated gene regulation.