bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies.
Authors: Kornberg A , Blank M , Kaufman S , Shoenfeld Y 
Published: December 2022

Abstract
Anti-cardiolipin Abs (ACLA) are present in the sera of patients with antiphospholipid syndrome (APLS) and are associated with high incidence of thromboembolic phenomena, fetal loss, thrombocytopenia, and prolongation of the phospholipid-dependent coagulation assays (lupus anticoagulant). Recently, it has been shown that APLS can be induced experimentally by using ACLA. However, the pathophysiology of thrombus formation in this syndrome is unknown. Monocytes generate a potent procoagulant activity (PCA) after stimulation with various substances. Increased PCA has been found in monocytes from patients with diseases that are associated with high incidence of thromboembolic phenomena. In the present study, we report that the monoclonal ACLA that were shown previously by us to induce APLS stimulate mononuclear cells to generate a potent PCA. The PCA resembled tissue factor (TF) in that it accelerated clotting through the extrinsic coagulation pathway, was abolished by phospholipase C, and was inhibited by anti-TF mAbs. The induction of TF-like activity by ACLA in monocytes was dose- and time-dependent. It was induced in monocytes and monocytic cell lines, but not in lymphoid or myeloid cells, and did not require T lymphocytes for expression. The generation of PCA was dependent on protein synthesis inasmuch as it was prevented by adding puromycin to the system and was not affected by cytarabine. The TF-like activity that is induced by ACLA in monocytes may activate coagulation and thereby play a major role in the pathogenesis of thrombus formation in APLS.
Specific stimulation of Graves' disease thyrocytes by the natural anti-Gal antibody from normal and autologous serum.
Authors: Winand R J , Devigne J W , Meurisse M , Galili U 
Published: December 2022

Abstract
Anti-Gal is a natural Ab abundantly produced in humans. It interacts specifically with the carbohydrate epitope Gal alpha 1-3Gal beta 1-4GlcNAc-R (termed the alpha-galactosyl epitope). This epitope is expressed in large amounts on thyrocytes of nonprimate mammals, but not of humans. We have previously found that binding of anti-Gal to alpha-galactosyl epitopes on porcine thyrocytes results in stimulatory effects similar to those exerted by thyroid-stimulating hormone (thyrotropin). In the present study, we tested the hypothesis that anti-Gal may contribute to Graves' disease (GD) pathogenesis by stimulation of the thyrocytes of patients with this autoimmune disorder. Anti-Gal binding and stimulatory effects were assessed in primary thyrocyte cultures. Anti-Gal specifically bound to GD thyrocytes and induced an increase in cAMP synthesis, 125I uptake, and DNA synthesis in these cells. Furthermore, the stimulatory effects of autologous sera on GD thyrocytes were greatly reduced after specific depletion of anti-Gal from these sera. No binding and no stimulatory effects of anti-Gal were observed, however, with normal human thyrocytes and with thyrocytes from thyrotoxic patients who lack thyroid-stimulating Igs or thyrotropin binding inhibiting Igs. These in vitro stimulatory effects of anti-Gal on GD thyrocytes suggest that this natural Ab may contribute to the in vivo continuous stimulation of thyrocytes in GD patients. The possibility that anti-Gal may stimulate GD thyrocytes via interaction with aberrantly expressed alpha-galactosyl epitopes on the thyroid-stimulating hormone receptor is discussed.
Interaction between endothelium and CD4+CD45RA+ lymphocytes. Role of the human CD38 molecule.
Authors: Dianzani U , Funaro A , DiFranco D , Garbarino G , Bragardo M , Redoglia V , Buonfiglio D , De Monte L B , Pileri A , Malavasi F 
Published: December 2022

Abstract
CD38 is a type II transmembrane glycoprotein, which is widely used as a marker for immature and activated lymphocytes, as well as plasma cells. Although its functional role and natural ligand are not known, CD38 has been shown to transduce activation signals to lymphocytes. Our work shows that CD38 is preferentially expressed by CD4+CD45RA+ cells, but not by CD4+CD45R0+ cells. CD4+CD45RA+ cells are reported to respond poorly to stimuli acting through the CD3/TCR in vitro and to display unique migration pathways in vivo. Cross-linking of CD38 by mAb did not overcome the hyporesponsiveness of CD4+ resting/naive cells to several activation stimuli; in contrast, CD38 engagement by mAb specifically inhibited their binding with human vein endothelial cells. These data suggest that CD38 may play a role in lymphocyte migration. The same inhibitory effect was detected on the (human x mouse) hybrid cell line CP410.A10, which expresses human CD38, but not on its CD38- subclone CP14. CD38 mAb did not inhibit the conventional binding assay between endothelium and several human CD38+ T and B cell lines. However, the inhibition was apparent when the binding assay was performed at 4 degrees C on a rocking shelf, conditions that minimized integrin function. These data suggest that CD38 mediates weak cell binding to endothelium, which is effective even in dynamic conditions. These features are reminiscent of those exerted by selectins, which are adhesion molecules that account for leukocyte rolling on vascular endothelial cells and play an important role in lymphocyte homing.
Engagement of CD14 on monocytes inhibits the synthesis of human Igs, including IgE.
Authors: Jabara H H , Vercelli D 
Published: December 2022

Abstract
Engagement of CD14 on normal human monocytes results in monocyte activation and, furthermore, delivers a negative signal that terminates T cell proliferation. We show herein that engagement of selected CD14 epitopes by specific mAbs inhibited PWM-induced IgM and IgG synthesis, as well as IL-4-dependent IgE synthesis by human PBMCs. Inhibition by anti-CD14 mAb was still evident when the Ab was added after 6 days of culture, suggesting that inhibition targets a late B cell activation event. In experiments that focused on the role of CD14 in IgE regulation, suppression of IgE synthesis after CD14 engagement did not result from the release of inhibitory monokines (IL-10, TGF-beta, and PG). In fact, neutralizing Abs and specific inhibitors did not restore the IgE response and anti-CD14-conditioned monocyte supernatants did not inhibit IgE synthesis. On the other hand, inhibition of IgE synthesis by anti-CD14 mAb was not likely to be caused by the lack of soluble factors with amplificatory effects on the IgE response, because addition of either rIL-6 or rTNF-alpha did not overcome CD14-dependent inhibition of IgE production. IgE inhibition after CD14 engagement was exerted at the B cell level, inasmuch as it was observed not only in T cell-dependent IgE induction i.e., mononuclear cells stimulated with IL-4, but also in T cell-independent systems, i.e., T cell-depleted populations stimulated with IL-4 plus anti-CD40 mAb or IL-4 plus hydrocortisone. These data indicate that CD14 plays a regulatory role in B cell responses.
Function of bone marrow stromal cell lines derived from nude mice.
Authors: Dong Z , Wortis H H 
Published: December 2022

Abstract
We previously reported that in double deficient nude.xid mice B cells failed to develop and their bone marrow did not produce mature B cells in vitro. However, when progenitors from nude.xid bone marrow were placed on a preestablished normal stromal cell line (AC6) they differentiated into surface IgM+ cells. This raised the possibility of a deficiency of nude and nude.xid stromal cells such that they were incapable of supporting the maturation of X-linked immune deficiency (xid) B cells. Here we ask whether bone marrow stromal cells from nude and nude.xid mice have the ability to support xid B cell lymphopoiesis. A primary stromal cell layer derived from nude mice supported xid B cell differentiation in vitro. We derived panels of stromal cell lines by transfection of primary stromal cell layers with a retrovirus encoding SV40 large T Ag. Several bone marrow stromal cell lines derived from nude and nude.xid mice supported xid B cell differentiation from CD43+/CD45 (B220-) to CD45 (B220+) and from CD45 (B220+)/surface IgM- to surface IgM+. Supporting cell lines expressed both IL-7 and insulin-like growth factor I. The frequencies of bone marrow stromal cells capable of supporting xid B cell differentiation were similar in normal, xid, nude, and nude.xid mice. These results demonstrate that nude and nude.xid mice have bone marrow stromal cells with normal abilities to support B cell maturation.
Biologic activity of low dosage IL-2 treatment in vivo. Molecular assessment of cytokine network interaction.
Authors: Hladik F , Tratkiewicz J A , Tilg H , Vogel W , Schwulera U , Krönke M , Aulitzky W E , Huber C 
Published: December 2022

Abstract
The sequence of activation of the components of the cytokine network subsequent to in vivo application of different dosages of IL-2 is still poorly understood. Although side effects of IL-2 therapy are dose dependent, the dose-response relationship for induction of potentially beneficial or harmful cytokine genes still remains to be studied. We examined the patterns of cytokine gene expression after treatment of chronic hepatitis B patients with various doses of IL-2 in a phase 1 trial. Total RNAs were isolated from PBMC harvested at various time points after s.c. injection of natural IL-2 ranging from 30,000 to 1,000,000 U. Dose-dependent effects on mRNA expression of IL-2, GM-CSF, IFN-gamma, TNF-alpha, and IL-6 were assessed using Northern blotting and slot blotting techniques. A single application of 30,000 U nIL-2 induced selective and long-lasting expression of IL-2, IFN-gamma, and GM-CSF genes, which was not accompanied by accumulation of TNF-alpha and IL-6 mRNAs. Larger dosages of IL-2 induced activation of monokine genes and were associated with systemic side effects. mRNA levels of the different cytokines related to biologic activity and correlated with expression of specific proteins and cellular parameters: IL-2 mRNA with soluble IL-2R serum levels and induction of lymphopenia, GM-CSF mRNA with induction of neutrophilia, and IL-6 mRNA with c-reactive protein serum concentrations. Taken together these data indicate unexpected immunoregulatory activities of very low and nontoxic dosages of IL-2 in vivo.
In vitro potentiation of lymphocyte activation by dehydroepiandrosterone, androstenediol, and androstenetriol.
Authors: Padgett D A , Loria R M 
Published: December 2022

Abstract
Dehydroepiandrosterone (5-androstene-3 beta-ol-17-one, DHEA) has been shown to protect mice from lethal viral and bacterial infections. However, recently, androstenediol (5-androstene-3 beta-17 beta-diol, AED) and androstenetriol (5-androstene-3 beta-7 beta-triol, AET), metabolites of DHEA, have each shown to be more potent endocrine regulators of the immune response. In contrast to glucocorticosteroids, in vivo, these steroid hormones up-regulated the cellular immune response of the host to limit virus-mediated pathology. These experiments first examined the in vitro influences of DHEA, and AED, or AET on mitogen-stimulated activation of murine lymphocytes. From physiologic to pharmacologic doses, DHEA suppressed proliferation of mixed splenocyte cultures activated with Con A or LPS by 20 to 70% whereas AED had little influence on the response. In sharp contrast, AET potentiated the response with both mitogens to 50 to 70% above control. Analogous to these observations was the regulation of IL-2 and IL-3 secretion from Con A-activated lymphocytes by each of these hormones which again was depressed analyzed. The suppressive effects of hydrocortisone on Con A-induced lymphocyte proliferation and cytokine production were strongly counteracted by coculture with AET. DHEA did not counteract hydrocortisone activity whereas AED showed moderate antiglucocorticoid function.
Tumor-induced regulation of suppressor macrophage nitric oxide and TNF-alpha production. Role of tumor-derived IL-10, TGF-beta, and prostaglandin E2.
Authors: Alleva D G , Burger C J , Elgert K D 
Published: December 2022

Abstract
In vitro-activated macrophages (Mphi) co-express cytotoxicity for tumor cells and suppression of lymphocyte proliferation. These Mphi functions increase during tumor growth and are mediated by soluble molecules. Because Mphi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Meth-KDE) growth increased Mphi-mediated suppression of T cell proliferation by increasing Mphi NO and TNF-alpha production. Tumor-bearing host peritoneal Mphi produced more NO and TNF-alpha than normal host Mphi when activated with IFN-gamma or LPS, respectively. This tumor-induced increase in Mphi NO and TNF-alpha production mediated suppression of alloantigen-driven T cell proliferation, because treatment with either NG-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bearing host Mphi-mediated suppression. TNF-alpha did not directly suppress T cells, but it induced Mphi NO production that down-regulated proliferation. When non-tumor-infiltrating peritoneal Mphi were cultured with Meth-KDE cell supernatants, Mphi production of NO and TNF-alpha was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta 1, and prostaglandin E2. The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Recombinant forms of these cytokines suppressed NO and TNF-alpha production. 3) Ab-mediated absorption of these cytokines from tumor cell supernatants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TGF-beta 1 Ab addition to IFN-gamma-stimulated Mphi restored NO production. Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed Mphi NO and TNF-alpha production, which was partly mediated by TGF-beta 1 and prostaglandin E2. Collectively, these results suggest that tumor growth promotes distal Mphi suppressor activity by increasing Mphi production of cytotoxic molecules and concomitantly down-regulating the local production of these antitumor molecules.
IL-12 inhibits Th2 cytokine responses induced by eggs of Schistosoma mansoni.
Authors: Oswald I P , Caspar P , Jankovic D , Wynn T A , Pearce E J , Sher A 
Published: December 2022

Abstract
In the mouse, infection with the helminth parasite Schistosoma mansoni results in the selective induction of CD4+ T lymphocytes belonging to the Th2 subset. Schistosome ova are responsible for the development of Th2 responses seen in patently infected animals and the injection of eggs s.c. into the footpad leads to the development of elevated Th2 cytokine production by T cells in the draining popliteal lymph node. Using the egg injection model, we have shown that IL-12 suppresses schistosome egg-induced Th2 responses as evidenced by decreased IL-4, IL-5, and IL-10 secretion in vitro while increasing the production of the Th1 cytokine IFN-gamma. Similar responses were obtained using either total lymph node cells or purified CD4+ T cells, indicating that IL-12 acts at the T cell level. When given as a single injection IL-12 was most effective at inhibiting Th2 responses when administered 2 days after egg inoculation, a time when T cells are still in a Th0 phase. The suppression of Th2 responses induced by IL-12 was blocked when the animals were simultaneously injected with neutralizing anti-IFN-gamma mAb, either systemically or systemically plus locally. Anti-IFN-gamma also inhibited the enhancement of IFN-gamma responses induced by IL-12 but only if the mAb was administered systemically plus locally. NK cells are likely to be a major source of the immunoregulatory IFN-gamma, because the effects of IL-12 on Th2 cytokine production were suppressed in mice treated with anti-asialo-GM1 Abs. Together these results suggest that IL-12 may have potential use in preventing or treating parasite-induced pathology resulting from Th2 cytokine production.
Human polymorphonuclear leukocytes lack detectable nitric oxide synthase activity.
Authors: Yan L , Vandivier R W , Suffredini A F , Danner R L 
Published: December 2022

Abstract
Nitric oxide regulates polymorphonuclear leukocyte (PMN) function, but whether or not human PMNs express nitric oxide synthase (NOS) activity is controversial. We studied NOS activity in human PMNs by using human aortic endothelial cells (HAECs) for comparison. The conversion of L-arginine to L-citrulline, a relatively specific measure of NOS activity, was easily measured and inducible in fractionated HAECs, and &gt; 90% of all L-arginine conversion was blocked by the NOS inhibitor, N omega-amino-L-arginine (L-NAA). In fractionated PMNs, L-arginine conversion was low and was unaffected by L-NAA. In addition, NOS activity was not induced in PMNs by LPS, IL-1 beta, or IFN-gamma. In a whole-cell assay, total L-arginine conversion was much lower in human PMNs compared with HAECs (3.38 +/- 0.21 vs 157.5 +/- 10.28 pmol/h/10(6) cells, respectively; p &lt; 0.01). This conversion in whole PMNs was not increased in vitro by LPS, IFN-gamma, IL-1 beta, or TNF-alpha nor decreased by W13, a calmodulin inhibitor. Furthermore, PMNs isolated from four volunteers before and after challenge with i.v. LPS (4 ng/kg) showed no increase in L-arginine to L-citrulline conversion. Nitrite and nitrate release from human PMNs was 35-fold lower than for HAECs and was not inhibited by L-NAA. These data suggest that human PMNs do not express NOS activity.
A cultured malignant B-1 line serves as a model for Richter's syndrome.
Authors: Peng B , Sherr D H , Mahboudi F , Hardin J , Wu Y H , Sharer L , Raveché E S 
Published: December 2022

Abstract
Human chronic lymphocytic leukemia (CLL) is a malignancy of B-1 cells characterized by the accumulation of mature appearing, long lived, slow growing B-1 cells in peripheral blood. CLL occasionally evolves into an aggressive large cell lymphoma termed Richter's syndrome. NZB mice can be used to model the early stage of CLL because aged NZB mice can spontaneously develop slow growing malignant B-1 cell clones. The malignant NZB B-1 clones fail to grow in culture and are typically carried in vivo as passaged lines. During serial passage, an aggressive lymphoma developed as a result of a continued transformation of the original B-1 clone, similar to the development of Richter's syndrome. An in vitro cell line was established from the aggressive lymphoma, which was stromal dependent and could rapidly metastasize when passaged into recipient animals. Analysis of adhesion molecules did not reveal any consistent characteristics that could account for the metastatic potential of the Richter's-like cells. In addition, the aggressive in vitro line had the identical heavy chain sequence as the slow growing NZB malignant B-1 clones. The in vitro and in vivo aggressive B-1 cells had very high levels of IL-10 message, and underwent more apoptosis in response to anti-IgM than did nonaggressive B-1 clones. Taking these characteristics together, we have composed a comprehensive animal model system for human CLL that includes both the aged NZB mice for the early stage and the recipients of the in vitro B-1 line for the late stage or Richter's syndrome. This model system can be used to study, not only the ontogeny and genetic linkage of CLL, but also the regulatory factors involved in transformation and growth both in vivo and in vitro.
IFN-gamma receptor-deficient mice generate antiviral Th1-characteristic cytokine profiles but altered antibody responses.
Authors: Schijns V E , Haagmans B L , Rijke E O , Huang S , Aguet M , Horzinek M C 
Published: December 2022

Abstract
The lymphokine IFN-gamma is a pleiotropic immunomodulator and possesses intrinsic antiviral activity. We studied its significance in the development of antiviral immune responses by using IFN-gamma receptor-deficient (IFN-gamma R-/-) mice. After inoculation with live attenuated pseudorabies virus (PRV), the mutant mice showed no infectivity titers in various tissues, and transient viral Ag expression only in the spleen, similar as in wild-type mice. However, the absence of the IFN-gamma R resulted in increased proliferative splenocyte responses. The PRV-immune animals showed a normal IFN-gamma and IL-2 production, without detectable IL-4, and with decreased IL-10 secretion in response to viral Ag or Con A. Immunohistochemically, an increased ratio of IFN-gamma:IL-4-producing spleen cells was found. After immunization with either live attenuated or inactivated PRV, IFN-gamma R-/- mice produced significantly less antiviral Ab, and more succumbed to challenge infection than the intact control animals. The reduction in Ab titers in the mutant mice correlated with lower protection by their sera in transfer experiments. Our data demonstrate that ablation of the IFN-gamma receptor surprisingly does not inhibit the generation of antiviral Th1-type and increase Th2-type cytokine responses. However, it profoundly impairs the generation of protective antiviral Ab.
NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene.
Authors: Ueda A , Okuda K , Ohno S , Shirai A , Igarashi T , Matsunaga K , Fukushima J , Kawamoto S , Ishigatsubo Y , Okubo T 
Published: December 2022

Abstract
Expression of the human monocyte chemoattractant protein-1 (hMCP-1) is ubiquitous in various cell types and is increased by a wide variety of stimuli. We initially found that the effects of various stimuli, including IL-1 beta, TNF-alpha, and 2-O-tetradecanoylphorbol 13-acetate, on the expression of hMCP-1 mRNA were quite different among A172 glioblastoma cells, HT1080 fibrosarcoma cells, and SKLMS1 leiomyosarcoma cells. These findings suggested that hMCP-1 expression is regulated both in a stimulus-specific and a tissue-specific manner. To elucidate the mechanism underlying this stimulus-specific and tissue-specific regulation, we isolated a hMCP-1 5'-flanking genomic DNA fragment and sequenced it extensively up to bp 3011 upstream from the transcriptional start site. Among many putative cis-elements, we identified two cis-elements critical for the transcription of the hMCP-1 gene. The first element is a remote kappa B binding site located far upstream between bp -2612 and -2603 that was important for IL-1 beta-, TNF-alpha-, and 2-O-tetradecanoylphorbol 13-acetate-induced enhancer activity. Mutation at the kappa B consensus site resulted in a complete loss of these stimulus-induced enhancer activities. The second element is a GC box located between bp -64 and -59 that was important for the maintenance of basal transcriptional activity. Overexpression of rSp1 resulted in increased hMCP-1 transcriptional activity, possibly suggesting the role of Sp1 in controlling basal hMCP-1 transcription via this GC box. These results together indicate that hMCP-1 expression is controlled by at least two distinct regulatory elements: a kappa B site and a GC box that seem to be associated with stimulus-specific and tissue-specific regulation, respectively.