bluuebunny/crossref_metadata_2025_split huggingface dataset:
A polymorphic CD40 ligand (CD154) molecule mediates CD40‐dependent signalling but interferes with the ability of soluble CD40 to functionally block CD154 : CD40 interactions
Authors: Barnhart B. , Ford G. S. , Bhushan A. , Song C. , Covey L. R. 
Published: March 2003

SummaryWe report the characterization of a naturally occurring polymorphism in CD40 ligand (CD40L, CD154) expressed by activated T cells from a young female patient. This polymorphism encodes a nonconservative Gly → Arg substitution in amino acid 219 in the extracellular, CD40 binding domain of the molecule. Studies carried out with 293 epithelial cells ectopically expressing the polymorphic protein (CD154/G219R) revealed reduced levels of binding to different anti‐CD154 monoclonal antibodies (mAb) and CD40‐immunoglobulin (CD40‐Ig). However, recognition of the polymorphic and wild‐type CD154 molecules by a polyclonal antiserum was comparable, suggesting that the polymorphism affects the ability of the protein to interact with CD40 but does not significantly alter its surface expression. To determine if reduced cross‐linking of CD40 mediated decreased functional effects, three CD40‐dependent properties were measured. We found that pathways leading to the induction of surface CD23, CD80, and Iγ transcription were activated in response to CD154/G219R signalling. However, the decrease in affinity for CD40 by the mutated CD154 affected the ability of CD40‐Ig to efficiently interfere with the binding and effectively block induced CD80 expression. In contrast, we found that the 5c8 mAb, which recognized the polymorphic molecule to a similar extent as wild‐type CD154, effectively blocked the interaction between CD154/G219R and CD40 as measured by CD80 expression. These findings suggest that naturally occurring polymorphisms in the CD154 molecule may affect the ability of CD40‐mediated functions to be blocked by soluble CD40 or anti‐CD154 mAb in the therapeutic treatment of disease and graft rejection.
Increasing the frequency of T‐cell precursors specific for a cryptic epitope of hen‐egg lysozyme converts it to an immunodominant epitope
Authors: Thatcher T. H. , O'brien D. P. , Altuwaijri S. , Barth R. K. 
Published: March 2003

SummaryEfforts to understand the mechanisms that govern how immunodominant T‐cell epitopes are selected from protein antigens have focused mostly on differences in the efficiency of processing and presentation of peptide/major histocompatibility complex (MHC) complexes by antigen‐presenting cells, while little attention has been directed at the role of the T‐cell repertoire. In this report, the influence of the T‐cell repertoire on immunodominance was investigated using transgenic mice that express the β chain from a T‐cell receptor specific for a cryptic Ek restricted epitope of hen‐egg lysozyme, HEL85‐96. In these mice, the frequency of HEL85‐96‐specific T‐cell precursors is increased 10–20‐fold over non‐transgenic mice. Transgenic mice respond as well as non‐transgenic controls to intact HEL, even though they respond poorly or not at all to a variety of other antigens, including the dominant H‐2k restricted epitopes of HEL. Following immunization with native HEL, the only HEL peptide that could recall a response in vitro in the transgenic mice was HEL85‐96. Therefore, this normally cryptic epitope is the sole immunodominant epitope in the transgenic mice, and this alteration in immune response is due solely to an increase in the frequency of specific T‐cell precursors. An analysis of four additional H‐2k restricted cryptic epitopes of HEL suggests that three are similarly limited by T‐cell frequency, and that only one is consistent with a defect in efficient antigen presentation. This indicates that there are at least two different types of cryptic epitopes, one in which crypticity is caused by inefficient processing or presentation, and another in which the frequency of specific T‐cell progenitors is limiting.
The route of administration of an immunodominant peptide derived from heat‐shock protein 65 dramatically affects disease outcome in pristane‐induced arthritis
Authors: Francis J. N. , Lamont A. G. , Thompson S. J. 
Published: March 2003

SummaryPrevious studies have shown that immunization of mice with an immunodominant epitope from heat‐shock protein 65 (hsp 65) (amino acids 261–271) can protect from the development of pristane‐induced arthritis (PIA) and this protection is mediated by an antigen‐specific T helper type 2 (Th2) cytokine response. Here we confirm these findings and show that frequent intranasal administration of this peptide exacerbates disease. In naive mice given peptide intranasally an antigen‐specific T‐cell population is systemically activated similar to that induced by peptide immunization in incomplete Freund’s adjuvant. Thus, a paradox exists whereby apparently similar peptide‐specific populations are either associated with protection from, or exacerbation of, PIA. However, comparison of cytokine profiles reveals differences between these two cell populations. Peptide inhalation induces the production of Th1‐type cytokines (interferon‐γ) whereas intraperitoneal immunization leads to the production of Th2‐type cytokines (interleukin‐4, interleukin‐5 and interleukin‐10) by splenic T cells upon stimulation with peptide. Thus, for the application of nasal ‘tolerance’ in clinical medicine, it is important to identify antigens and dosing regimes that counteract but do not activate adverse immune responses.
Mice lacking tartrate‐resistant acid phosphatase (Acp 5) have disordered macrophage inflammatory responses and reduced clearance of the pathogen, Staphylococcus aureus
Authors: Bune A. J. , Hayman A. R. , Evans M. J. , Cox T. M. 
Published: March 2003

SummaryTartrate‐resistant acid phosphatase (TRAP) is a lysosomal di‐iron protein of mononuclear phagocytes and osteoclasts. Hitherto, no role for the enzyme in immunity has been identified; however, knockout mice lacking TRAP have a skeletal phenotype caused by an intrinsic osteoclast defect. To investigate a putative function for TRAP in macrophages (Mφ), we investigated proinflammatory responses and systemic microbial clearance in knockout mice compared with age‐ and gender‐matched congenic wild‐type mice. Phorbol 12‐myristate 13‐acetate (PMA)‐stimulated and interferon‐γ (IFN‐γ)‐induced superoxide formation was enhanced in peritoneal Mφ lacking TRAP; nitrite production in response to stimulation with lipopolysaccharide (LPS) and IFN‐γ was also increased. In addition, secretion of the proinflammatory cytokines, tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐1β and IL‐12, was significantly greater in TRAP‐deficient Mφ when stimulated with LPS, with or without addition of either TNF‐α or IFN‐γ. The activity of tartrate‐sensitive (lysosomal) acid phosphatase was increased in Mφ from the knockout mice but activities of the lysosomal hydrolases N‐acetyl β‐glucosaminidase and acid β‐glucuronidase were unchanged, indicating selective activation of compensatory acid phosphatase activity. Evidence of impaired Mφ function in vivo was obtained in TRAP knockout mice, which showed delayed clearance of the microbial pathogen, Staphylococcus aureus, after sublethal intraperitoneal inoculation. After microbial challenge, peritoneal exudates obtained from TRAP knockout mice had a reduced population of Mφ. As peritoneal Mφ and neutrophils lacking TRAP were able to phagocytose and kill S. aureus normally in vitro, TRAP may directly or indirectly influence recruitment of Mφ to sites of microbial invasion. Our study shows that TRAP participates in the inflammatory response of the Mφ and influences effector signalling pathways in innate immunity.
Reduced herpes simplex virus type 1 latency in Flt‐3 ligand‐treated mice is associated with enhanced numbers of natural killer and dendritic cells
Authors: Smith J. R. , Thackray A. M. , Bujdoso R. 
Published: March 2003

SummaryWe have investigated the effect of Flt‐3 ligand (Flt‐3L) on the resistance to herpes simplex virus type‐1 (HSV‐1) infection in BALB/c mice which are normally highly susceptible to challenge with this virus. We have confirmed data by others that in vivo treatment with Flt‐3L causes an increase in dendritic cells (DC) and natural killer (NK) cells in lymphoid tissue. Increasing doses of Flt‐3L caused a corresponding increase in liver and spleen CD11c+ DC which were increased up to 20‐fold compared with control levels. A significant expansion of NK cells was seen in the spleen of Flt‐3L‐treated mice where the number of DX5+ cells was increased by up to fivefold. We subsequently tested the hypothesis that Flt‐3L treatment, at the time of viral infection, might lead to enhanced immunity and protection against viral pathogenesis. Two murine models of HSV‐1 (SC16) infection were used. In the first model, mice were injected with Flt‐3L daily for 9 days. Control mice received mouse serum albumin (MSA). On day 7 of the Flt‐3L treatment 106 plaque‐forming units (PFU) of SC16 was inoculated into the ear pinna. Flt‐3L treatment significantly reduced mortality following virus inoculation, with 80% survivors in this group compared with 20% survivors in the MSA‐treated group. In the second model, Flt‐3L‐treated mice were scarified with 104 PFU of SC16. In this case there was 60% survival in the Flt‐3L‐treated group of mice compared with 10% survival in the MSA‐treated group. Assessment by in situ hybridization for latency‐associated transcripts showed that Flt‐3L treatment reduced the amount of latent virus within infected neurons. These studies show that in vivo treatment with Flt‐3L results in protection against challenge with live HSV‐1, which may be a consequence of enhanced numbers of DC and/or NK.
Mechanisms of interleukin‐10‐mediated immune suppression
Authors: Akdis Cezmi A. , Blaser Kurt 
Published: March 2003

SummarySpecific immune suppression and induction of anergy are essential processes in the regulation and circumvention of immune defence. Interleukin‐10 (IL‐10), a suppressor cytokine of T‐cell proliferative and cytokine responses, plays a key regulatory role in tolerizing exogenous antigens during specific immunotherapy (SIT) of allergy and natural exposure to antigens. Specific T‐cell tolerance is directed against the T‐cell epitopes of an antigen and characterized by suppressed proliferative and T helper type 1 (Th1) and type 2 (Th2) cytokine responses. IL‐10 elicits tolerance in T cells by selective inhibition of the CD28 co‐stimulatory pathway and thereby controls suppression and development of antigen‐specific immunity. IL‐10 only inhibits T cells stimulated by low numbers of triggered T‐cell receptors and which therefore depend on CD28 co‐stimulation. T cells receiving a strong signal from the T‐cell receptor alone, and thus not requiring CD28 co‐stimulation, are not affected by IL‐10. IL‐10 inhibits CD28 tyrosine phosphorylation, the initial step of the CD28 signalling pathway, and consequently the phosphatidylinositol 3‐kinase p85 binding to CD28. Together these results demonstrate that IL‐10‐induced selective inhibition of the CD28 co‐stimulatory pathway acts as a decisive mechanism in determining whether a T cell will contribute to an immune response or become anergic.
The role of donor T cells for target organ injuries in acute and chronic graft‐versus‐host disease
Authors: Kataoka Yasuro , Iwasaki Tsuyoshi , Kuroiwa Takanori , Seto Yoshifumi , Iwata Nobuo , Hashimoto Naoaki , Ogata Atsushi , Hamano Teruaki , Kakishita Eizo 
Published: March 2003

SummaryDonor T cells are crucial for target organ injury in graft‐versus‐host disease (GVHD). We examined the effects of donor T cells on the target organs using a parent‐into‐F1 model of acute and chronic GVHD. Donor T cells showed engraftment in the spleen, small intestine and liver of mice with acute GVHD, causing typical GVHD pathology in these organs. Interferon‐γ and Fas ligand expression were up‐regulated, and host lymphocytes were depleted in the target organs of these mice. In contrast, donor T cells did not show engraftment in the small intestine of mice with chronic GVHD, and no GVHD pathology was observed in this organ. However, both donor T‐cell engraftment and GVHD pathology were observed in the spleen and liver of chronic GVHD mice, along with the up‐regulation of interleukin‐4 (IL‐4) and IL‐10 expression plus the expansion of host lymphocytes such as splenic B cells and hepatic natural killer (NK) 1.1+ T cells. Donor anti‐host cytotoxic T‐lymphocyte activity was observed in spleen cells from mice with acute GVHD, but not in spleen cells from mice with chronic GVHD. Transplantation of Fas ligand‐deficient (gld) spleen cells did not induce host lymphocyte depletion in target organs. These results indicate that donor T cells augment type 1 T helper immune responses and deplete the host lymphocytes from target organs mainly by Fas‐mediated pathways in acute GVHD, while donor T cells augment type 2 T helper immune responses and expand host splenic B cells and hepatic NK1.1+ T cells in chronic GVHD.
Lack of evidence for aggregation‐dependent enhancement of p56lck in the signal transduction upon major histocompatibility complex recognition by mature T cells
Authors: Eshima Koji , Suzuki Harumi , Shinohara Nobukata 
Published: March 2003

SummaryThe kinase activity of lymphocyte‐specific tyrosine kinase p56lck (Lck) upon physiological major histocompatibility complex (MHC) recognition by normal mature T cells was examined. Recognition of the target MHC molecules by T cells induced phosphorylation of the ζ‐chain without obvious enhancement of the background Lck activity. There was no sign of enhancement of Lck through putative T‐cell receptor (TCR)‐independent class II MHC/CD4 interactions either. As has been reported, cross‐linking of CD4 molecules by antibodies induced a marked enhancement of Lck activity. However, it did not have an immediate relevance to TCR‐mediated signal transduction, as judged from the lack of detectable de novo phosphorylation of ζ‐chain and the absence of functional responses of T cells. These results strongly favour the model in which TCR‐mediated signal transduction does not involve aggregation‐dependent enhancement of Lck, suggesting that the signal can be triggered simply by the recruitment of already active Lck with basal kinase activity through the formation of a TCR/MHC/CD4 ternary complex.
Differential expansion of T‐cell receptor variable beta subsets after antigenic stimulation in patients with different outcomes of hepatitis C infection
Authors: Woitas Rainer P. , Sippel Martin , Althausen Eva‐Maria , Brackmann Hans H. , Kochan Bettina , Matz Bertfried , Rockstroh Jürgen K. , Sauerbruch Tilman , Spengler Ulrich 
Published: March 2003

SummaryPersistent antigenic stimulation during chronic hepatitis C may alter the T‐cell receptor variable chain beta (TCR BV) repertoire as well as the cytokine responses of hepatitis C virus (HCV)‐specific T lymphocytes. We analysed the distribution of the TCR BV subsets 2.1, 3.1, 5.1, 6.1, 8, 13.1, 13.6, 14.1, 17.1, 21.3 in relation to intracytoplasmic expression of interleukin‐2, interferon‐γ, interleukin‐4 and interleukin‐10. Using flow cytometry, CD45RO+ memory T cells of 27 patients with chronic hepatitis C, eight patients with resolved HCV infection and 16 non‐HCV‐related controls were studied with and without stimulation by the HCV core, NS3, NS4, NS5a and NS5b proteins. Patients with chronic and resolved hepatitis C differed by larger basal TCR BV2.1+, BV6.1+, BV17.1+ and BV21.3+ subsets in chronic hepatitis C, which were correlated to the numbers of T cells with spontaneous interleukin‐2 and interferon‐γ production (r=0·51–0·73, P<0·05). Upon HCV‐specific stimulation these subsets did not expand, whereas a marked in vitro expansion of TCR BV8+ T cells in response to all HCV proteins was selectively noted in chronic hepatitis C (P<0·05). This expansion of TCR BV8+ memory T cells was significantly correlated to HCV‐induced interleukin‐10 expression (r=0·58–0·98, P<0·01). Thus, differential involvement of selected TCR BV subsets may be related to the outcome of HCV infection.
In vivo tolerance breakdown with dendritic cells pulsed with U1A protein in non‐autoimmune mice: the induction of a high level of autoantibodies but not renal pathological changes
Authors: Suen Jau‐Ling , Chuang Ya‐Hui , Chiang Bor‐Luen 
Published: March 2003

SummaryOne of the hallmarks of systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), is the immune response to nuclear autoantigens. Several studies have proposed that dendritic cells may acquire the nuclear autoantigens from the apoptotic cells to initiate the systemic autoimmune responses. To examine the immune response to a nuclear autoantigen induced by dendritic cells, bone marrow‐derived dendritic cells (BMDCs) pulsed with U1 small nuclear ribonucleoprotein (snRNP)‐A protein (U1A) were intravenously injected into non‐autoimmune mice. The results showed that BMDCs pulsed with U1A proteins by intravenous injection into BALB/c (H‐2d) and DBA‐2×NZW F1 (H‐2d/u) mice were capable of activating the autoreactive T cells and inducing a high titre of immunoglobulin G (IgG) anti‐U1A antibodies. Both groups of mice with a high anti‐U1A autoantibody titre also transiently developed IgG against double‐stranded (ds) DNA. However, unlike NZB×NZW F1 (BWF1) (H‐2d/u) mice, no obviously histopathological changes to the glomeruli were noted in the mice treated either with BMDCs or with U1A‐pulsed BMDCs. Several months after immunization, all mice treated with U1A‐pulsed BMDCs did develop IgG, but not the complement C3 deposit in the glomeruli. The cytokine profile produced by the U1A‐specific T cells of primed DBA‐2×NZW F1 mice was skewed toward the T helper type 1 phenotype compared with that of BWF1 mice. The model we describe here adds to the further understanding of the pathogenic mechanisms, such as self‐antigen shifting, and the mechanisms that account for the different responses to self‐antigens when in a normal or an autoimmune state.
Augmented expression of tumour necrosis factor‐α induced by lipopolysaccharide in spleen of human monocyte chemoattractant protein‐1 transgenic mouse enhances the lipopolysaccharide sensitivity of the marginal zone macrophages
Authors: Ato Manabu , Iwabuchi Kazuya , Shimada Shigeki , Mukaida Naofumi , Onoé Kazunori 
Published: March 2003

SummaryMonocyte chemoattractant protein‐1 (MCP‐1) is a protective cytokine in murine endotoxaemia induced by lipopolysaccharide (LPS). In this study, LPS‐induced pathophysiology in the human (h) MCP‐1 transgenic mouse (Tgm) line was investigated. The hMCP‐1 Tgm showed a marked increase in the mortality and weight loss following LPS administration. In the Tgm spleens, disappearance of marginal zone macrophages (MZMφ) and dendritic cells (DC) was induced by a smaller amount of LPS than that required for the disappearance in non‐transgenic littermates. A significant number of apoptotic cells were seen in these areas. Furthermore, expressions of tumour necrosis factor‐α (TNF‐α), interleukin‐1α (IL‐1α), and IL‐6 mRNA were enhanced and sustained in the LPS‐treated Tgm. Neutralization of TNF‐α considerably depressed the LPS‐sensitivity of Tgm. These findings demonstrate that the continuous and systemic presence of MCP‐1 is no more protective toward endotoxaemia and suggest that the high sensitivity of the MZMφ and DC to LPS is attributed to the enhanced TNF‐α production in the hMCP‐1 Tgm.
Maternal and newborn immunization with a human immunodeficiency virus‐1 immunogen in a rodent model
Authors: Moss Ronald B. , Savary Jay R. , Diveley Jocelyn P. , Jensen Fred , Carlo Dennis J. 
Published: March 2003

SummaryWe examined immunization with an inactivated, gp120‐depleted human immunodeficiency virus (HIV) antigen in incomplete Freund's adjuvant (IFA), also containing a sequence of immunostimulatory (ISS) DNA, during the last trimester of pregnancy and neonatally in a rat model. Pregnant rats were immunized in the third trimester and their litters were immunized during the newborn period. In addition, litters of rats from non‐immunized mothers were immunized during the neonatal period. As another control, pregnant rats were immunized and their litters analysed. Supernants from peripheral blood mononuclear cells (PBMCs) were assayed from newborns at 4 weeks of age for HIV‐specific interferon‐γ (IFN‐γ), HIV‐specific regulated on activation, normal, T‐cell expressed, and secreted (RANTES), and serum for p24 antigen‐specific immunoglobulin G (IgG) production. In the animals whose pregnant mothers were immunized and were also immunized during the neonatal period, we observed HIV‐specific IFN‐γ production and HIV‐specific RANTES production, but weak p24 IgG antibody production. Animals immunized only during the neonatal period developed the highest levels of HIV‐specific IFN‐γ production, but somewhat lower levels of HIV‐specific RANTES and p24 IgG antibody production. The group of animals whose mothers had received immunizations during the last trimester of pregnancy, but were not immunized during the neonatal period, developed the strongest p24 IgG antibody levels, but little or undetectable HIV‐specific IFN‐γ or RANTES production. Neonatal immunization resulted primarily in cell‐mediated immune responses, while animals born to mothers who were immunized during the last trimester had primarily an antibody‐mediated immune response. Immunization of pregnant animals followed by neonatal immunization resulted in a mixed cell‐mediated/antibody type profile in the neonatal animal. Future studies should provide insights into neonatal immunity and potential vaccine approaches to prevent neonatal infection and perinatal transmission.
A conceptual framework for understanding business processes and business process modelling
Authors: Melão Nuno , Pidd Michael 
Published: March 2003

AbstractIt is increasingly common to describe organizations as sets of business processes that can be analysed and improved by approaches such as business process modelling. Successful business process modelling relies on an adequate view of the nature of business processes, but there is a surprising divergence of opinion about the nature of these processes. This paper proposes a conceptual framework to organize different views of business processes under four headings. It also aims at providing an integrated discussion of the different streams of thought, their strengths and limitations, within business process modelling. It argues that the multifaceted nature of business processes calls for pluralistic and multidisciplinary modelling approaches.
Cloning and analysis of cDNAs encoding the hypusine‐containing protein eIF5A of two lepidopteran insect species
Authors: Van Oers Monique M. , Van Marwijk Mireille , Kwa Marcel S. G. , Vlak Just M. , Thomas Adri A. M. 
Published: March 2003

AbstractEukaryotic initiation factor eIF5A is essential for cell viability and contains a characteristic post‐translational modification of a specific lysine residue into a hypusine. cDNAs with similarity to eIF5A sequences were derived from Spodoptera exigua and S. frugiperda cDNA libraries. The deduced amino acid sequences are identical for both species and predict a protein with a molecular mass of 17.5 kDa. The Drosophila melanogaster eIF5A cDNA sequence was retrieved from the Drosophila EST Project. The predicted protein is 80% similar to Spodoptera eIF5A. A single eIF5A gene copy is present in the S. frugiperda genome, which is transcribed into four different transcripts. Infection of S. frugiperda cells with a baculovirus resulted in a strong decline of all four transcripts already at 12 h after infection. In contrast, the eIF5A protein was fairly stable up to 48 h post infection.