bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD1a and CD1b surface expression is independent from de novo synthesized glycosphingolipids
Authors: Manolova Vania , Hirabayashi Yoshio , Mori Lucia , Libero Gennaro De 
Published: February 2003

AbstractCD1 molecules resemble classical MHC molecules in structure, bind self and bacterial glycolipids and present them to T cells. Whether the CD1 antigen‐binding groove becomes filled during maturation and traffic to the cell surface is an important and still unsolved biological question. As most cell types synthesize complex glycosphingolipids (GSL), which also stimulate CD1‐restricted T cells, it could be possible that these ligands associate with nascent CD1 molecules. Here, we show that treatment of cells with drugs blocking at different levels the de novo and salvage pathways of GSL synthesis does not prevent surface expression of CD1a and CD1b. Furthermore, transfection of CD1A and CD1B genes in a mutant cell line unable to synthesize glucosylceramides and galactosylceramides showed normal surface expression of both CD1 molecules. Lack of GSL did not induce intracellular CD1 accumulation as indicated by confocal microscopy. The same results were obtained by transfecting the Lec series of mutants, which are deficient in sugar addition to glycolipids and glycoproteins. These findings demonstrate that endogenous de novo synthesized GSL are not mandatory for CD1a and CD1b negotiating surface expression.
Generation of an effective anti‐tumor immunity after immunization with xenogeneic antigens
Authors: Sioud Mouldy , Sørensen Dag 
Published: February 2003

AbstractCentral and peripheral tolerance mechanisms are expected to hamper the generation of effective immunity against tumors. To break self tolerance against malignant gliomas, we assessed the therapeutic potential of self/foreign antigen cross‐reactivity in an immunocompetent rat glioma model. Immunotherapy of tumors using xenogeneic human glioma membrane proteins (HGP) as a vaccine inhibitedtumor growth, whereas no significant effect was obtained with rat glioma membrane proteins (RGP). In contrast to RGP, HGP elicited a specific IgG immune response that cross‐reacted with RGP. This immune response was found to be mainly a Th1 type response. On tumor sections stained with hematoxylin and eosin, glioma cells are sparse and apoptotic in HGP‐immunized rats, whereas control tumors showed condensed and viable cells. Tumor‐specific CTL were induced in HGP‐immunized rats. Immunohistochemical analysis revealed that a significant number of CD8+ and CD4+ cells infiltrated into tumors from HGP‐vaccinated rats, whereas RGP vaccination led to only few tumor‐infiltrating T cells. Taken together, the data establish the in vivo applicability of the cross‐stimulation between self and foreign antigens as an alternative way to break tolerance against the poorly immunogenic gliomas.
Association of T cell antigen CD7 with type II phosphatidylinositol‐4 kinase, a key component in pathways of inositol phosphate turnover
Authors: Subrahmanyam Gosukonda , Rudd Christopher E. , Schneider Helga 
Published: February 2003

AbstractCD7 is a 40‐kDa glycoprotein that is expressed on prothymocytes and persists during T cell differentiation. CD7 has been demonstrated to generate, like other costimulatory molecules, intracellular signals that modulate T cell function. However, although it binds to phosphatidylinositol 3‐kinase (PI 3‐kinase), the signaling events mediated by CD7 are not completely understood. In this context, phosphatidylinositol 4‐kinase (PI 4‐kinase) is a key enzyme involved in a variety of events, from the modeling of the actin cytoskeleton to the activation of protein kinase C. In this study, we show for the first time that PI 4‐kinase of 55 kDa can associate with CD7. The enzyme activity was insensitive to wortmannin, but was inhibited by adenosine, a characteristic for type II PI 4‐kinase. Together, our findings demonstrate that type II PI 4‐kinases are integral components of the CD7 signaling pathway and may play a role of CD7 in co‐stimulation and thymic differentiation.
Membrane‐bound form of fractalkine induces IFN‐γ production by NK cells
Authors: Yoneda Osamu , Imai Toshio , Nishimura Miyuki , Miyaji Michihiko , Mimori Tsuneyo , Okazaki Toshiro , Domae Naochika , Fujimoto Hiroko , Minami Yasuhiro , Kono Takeshi , Bloom Eda T. , Umehara Hisanori 
Published: February 2003

AbstractNatural killer (NK) cells participate in both innate and adaptive immunity, in part by their prompt secretion of cytokines including IFN‐γ, a pro‐inflammatory cytokine with an important role in Th1 polarization. To assess the involvement of fractalkine in inflammatory processes, we examined the effect of fractalkine on IFN‐γ production by NK cells. Although soluble chemokines, including MCP‐1 and RANTES as well as fractalkine, had a negligible effect on IFN‐γ production, immobilized fractalkine markedly induced IFN‐γ production by NK cells in a dose‐dependent manner. Pretreatment of NK cells with the phosphatidylinositol 3‐kinase (PI 3‐K) inhibitor, wortmannin, completely inhibited the production of IFN‐γ induced by fractalkine, and pretreatment with the protein tyrosine kinase inhibitor, herbimycin A, partially suppressed the response, suggesting that augmentation of IFN‐γ production in response to fractalkine treatment of NK cells involves signaling through PI 3‐K and protein tyrosine kinases. Furthermore, co‐culture of NK cells with fractalkine‐transfected 293E cells markedly enhanced IFN‐γ production by NK cells compared with co‐culture with control 293E cells. These findings may indicate a paracrine feedback loop system in which endothelial cells may be activated to produce more fractalkine, and also suggest a role for fractalkine expressed on endothelial cells in Th1 polarization through the stimulation of IFN‐γ production by NK cells.
Experimental African trypanosomiasis: IFN‐γ mediates early mortality
Authors: Shi Meiqing , Pan Wanling , Tabel Henry 
Published: February 2003

AbstractIn this study, we demonstrate that Kupffer cells in the livers of highly susceptible BALB/c mice infected with Trypanosoma congolense were loaded with trypanosomal antigen and appeared highly activated. This was associated with an enlarged capillary bed in the livers and decreased blood pressure of these mice towards the terminal stage. Blocking of murine IL‐10 receptor (IL‐10R)in vivo shortened the survival time of highly susceptible T. congolense‐infected BALB/c mice. Anti‐IL‐10R treatment decreased the survival of relatively resistant T. congolense‐infected C57BL/6 mice dramatically. Blocking of the IL‐10R also significantly shortened the survival time of mice infected with T. brucei. The acute death of trypanosome‐infected mice treated with anti‐IL‐10R antibodies in vivo was associated with focal liver necrosis, with significantly increased plasma levels of IL‐6, IL‐10, IL‐12p40 and IFN‐γ and enhanced synthesis of IL‐6, IL‐12p40 and IFN‐γ by spleen cell cultures. Anti‐IL‐10R‐induced death of T. congolense‐infected C57BL/6 mice could be prevented by administration of a neutralizing antibody specific forIFN‐γ. We conclude that phagocytosis of a critical number of trypanosomes by Kupffer cells leads to a systemic inflammatory response syndrome and, depending on the degree of Kupffer cell activation, is followed by death that is mediated by IFN‐γ. The role of trypanosome‐pulsed macrophages, T cells and genetic influences is discussed in a synopsis.
Soluble HLA‐A,‐B,‐C and ‐G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation
Authors: Contini Paola , Ghio Massimo , Poggi Alessandro , Filaci Gilberto , Indiveri Francesco , Ferrone Soldano , Puppo Francesco 
Published: February 2003

AbstractThere is convincing evidence that soluble HLA‐A,‐B,‐C (sHLA‐A,‐B,‐C) and soluble HLA‐G (sHLA‐G) antigens can induce apoptosis in CD8+ activated T cells although there is scanty and conflicting information about the mechanism(s) by which sHLA‐A,‐B,‐C antigens and sHLA‐G antigens induce apoptosis. In this study we have compared the apoptosis‐inducing ability of sHLA‐A,‐B,‐C antigens with that of sHLA‐G1 antigens in CD8+ T lymphocytes and CD8+ NK cells. Furthermore we have compared the inhibitory effect of sHLA‐A,‐B,‐C antigens and of sHLA‐G1 antigens on theactivity of EBV‐specific CD8+ cytotoxic T lymphocytes (CTL). sHLA molecules were purified from serum and from the supernatant of HLA class I‐negative cells transfected with one gene encoding either classical or non‐classical HLA class I antigens. Both classical and non‐classical sHLA class I molecules trigger apoptosis in CD8+ T lymphocytes and in CD8+ NK cells, which lack the T cell receptor, and their apoptotic potency is comparable. The binding of sHLA‐A,‐B,‐C and sHLA‐G1 molecules to CD8 leads to Fas ligand (FasL) up‐regulation, soluble FasL (sFasL) secretion and CD8+ cell apoptosis by Fas/sFasL interaction. Moreover, classical and non‐classical sHLA class I molecules inhibit the cytotoxic activity of EBV‐specific CD8+ CTL. As the amount ofsHLA‐G molecules detectable in normal serum is significantly lower than that of sHLA‐A,‐B,‐C molecules, the immunomodulatory effects of sHLA class I molecules purified from serum are likely to be mainly attributable to classical HLA class I antigens. As far as the potential in vivo relevance of these findings is concerned, we suggest that classical sHLA class I molecules may play a major immunoregulatory role in clinical situations characterized by activation of the immune system and elevated sHLA‐A,‐B,‐C serum levels. In contrast, non‐classical HLA class I molecules may exert immunomodulatory effects in particular conditions characterized by elevated sHLA‐G levels such as pregnancy and some neoplastic diseases.
Anti‐CD28 has a potent adjuvant effect on the antibody response to soluble antigens mediated through CTLA‐4 by‐pass
Authors: Carlring Jennifer , Barr Tom A. , Buckle Anne‐Marie , Heath Andrew W. 
Published: February 2003

AbstractWith the surge in potential new vaccines produced as recombinant proteins or synthetic peptides has come a pressing need to identify safe, potent immunological adjuvants to enhance immunogenicity of these antigens. CD28 is an important costimulatory molecule for T cells, and it has been shown that cell surface expression of its ligands, CD80 and CD86, can enhance cellular immune responses against tumor cells, however, these tumor cells do not normally express the ligands. Many new vaccines will be based upon soluble recombinant antigens, and in vaccination with these antigens CD80 and CD86 would normally be expressed on activated antigen‐presenting cells and additional stimulation through CD28 would not be predicted to enhance responses further. However, we show here that, surprisingly, CD28 antibody can very strongly enhance immune responses against soluble proteins, but only when directly attached to the antigen. The mode of action of CD28 antibodies appears to be linked to their ability to signal through CD28, but not to bind the negative feedback regulatory antigen, CTLA‐4. CD28 stimulants may represent novel, highly effective and safe immunological adjuvants for usewith a wide range of prophylactic and therapeutic vaccines.
NKT cells are dispensable in the induction of oral tolerance but are indispensable in the abrogation of oral tolerance by prostaglandin E
Authors: Ishimitsu Ryotaro , Yajima Toshiki , Nishimura Hitoshi , Kawauchi Hideyuki , Yoshikai Yasunobu 
Published: February 2003

AbstractNK1.1+ α β T cells (NKT cells) regulate the Th1/Th2 balance in response to dietary Ag, which may be involved in regulation of oral tolerance. OVA‐specific IgE and IgG1 Ab levels were significantly lower following an i.p. injection of OVA (in CFA) in C57BL/6 mice orally given a single, high dose (25 mg) of OVA than in those orally given PBS. The oral tolerance was normally induced in Jα281–/– mice which lack Vα14+ NKT cells, suggesting that NKT cells are dispensable for induction of oral tolerance. Treatment with PGE1 or PGE2 abrogated the oral tolerance in Jα281+/+ mice; this abrogation was accompanied by an OVA‐specific Th2‐dominant response. The abrogation of oral tolerance by PGE1 was not evident in Jα281–/– mice. Treatment with PGE1 induced an early increase in IL‐4 production by liver NKT cells in normal mice and neutralization of the early IL‐4 by administration of anti‐IL‐4 mAb abolished PGE1‐induced abrogation of oral tolerance. These results suggest that liver NKT cells producing IL‐4 are responsible for the down‐regulation of oral tolerance that is caused by the PGE molecules.
Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein
Authors: Welte Stefan A. , Sinzger Christian , Lutz Stefan Z. , Singh‐Jasuja Harpreet , Sampaio Kerstin Laib , Eknigk Ute , Rammensee Hans‐Georg , Steinle Alexander 
Published: February 2003

AbstractHuman cytomegalovirus (HCMV) has evolved a multitude of molecular mechanisms to evade the antiviral immune defense of the host. Recently, using soluble recombinant molecules, the HCMV UL16 glycoprotein was shown to interact with some ligands of the activating immunoreceptor NKG2D and, therefore, may also function as a viral immunomodulator. However, the role of UL16 during the course of HCMV infection remained unclear. Here, we demonstrate that HCMV infection of fibroblasts induces expression of all known NKG2D ligands (NKG2DL). However, solely MICA and ULBP3 reach the cellular surface to engage NKG2D, whereas MICB, ULBP1 and ULBP2 are selectively retained in the endoplasmic reticulum by UL16. UL16‐mediated reduction of NKG2DL cell surface density diminished NK cytotoxicity. Thus, UL16 functions by capturing activating ligands for cytotoxic lymphocytes that are synthesized in response to HCMV infection.
Intramuscular transfer of naked calcitonin gene‐related peptide gene prevents autoimmune diabetes induced by multiple low‐dose streptozotocin in C57BL mice
Authors: Sun Wei , Wang Liuyi , Zhang Zhenmin , Chen Mingzhe , Wang Xian 
Published: February 2003

AbstractThe imbalance of Th1/Th2 subsets is an important pathogenic mechanism for insulin‐dependent diabetes mellitus (IDDM). Calcitonin gene‐related peptide (CGRP) has been found to play important roles in the regulation of T lymphocytes. We hypothesize that exogenous CGRP administration during insulitis may modulate the balance of Th lymphocytes, thereby providing a therapeutic intervention for IDDM. We established CGRP gene transfer by naked plasmid injection into the skeletal muscles with electroporation enhancement. The effect of CGRP gene transfer on pathogenesis of IDDM was observedin autoimmune diabetic C57BL mice induced by multiple low‐dose streptozotocin (MLDS) administration. The treatment significantly decreased morbidity of diabetes, ameliorated hyperglycemia and insulin deficiency, and inhibited lymphocyte infiltration into the islets, indicating the protection of β cells against autoimmune destruction. CGRP gene transfer significantly inhibited T cell proliferation and secretion of the Th1 cytokine IFN‐γ, increased the level of the Th2 cytokine IL‐10, but had no effect on IL‐4 and TGF‐β1 secretion. CGRP gene transfer also decreased IL‐12 and IFN‐γ levels in peritoneal effusion. Our results demonstrate that CGRP gene transfer selectively suppresses the pro‐inflammatory Th1 subsets and promote anti‐inflammatory Th2 subsets, resulting in amelioration of β cell destruction and reduction of IDDM occurrence in mice with MLDS‐induced diabetes.
Differential requirements for JAK2 and TYK2 in T cell proliferation and IFN‐γ production induced by IL‐12 alone or together with IL‐18
Authors: Sugimoto Naotoshi , Nakahira Masakiyo , Ahn Hyun‐Jong , Micallef Mark , Hamaoka Toshiyuki , Kurimoto Masashi , Fujiwara Hiromi 
Published: February 2003

AbstractIL‐12 activates TYK2 and Janus kinase (JAK)‐2 to induce the phosphorylation of various signal transducers and activators of transcription (STAT) proteins. However, little is known regarding how these JAK exhibit the distinct biological effects of IL‐12. Using two JAK inhibitors, tyrphostin A1 (A1) for TYK2 and tyrphostin B42 (B42) for JAK2, we investigated the involvement of JAK2 and TYK2 in IL‐12‐induced T cell proliferation and IFN‐γ production. B42, but not A1, inhibited T cell proliferation along with down‐regulation of IL‐12‐induced c‐Myc expression and STAT5 phosphorylation. In contrast, A1 but not B42 inhibited STAT4/STAT3 phosphorylation and IFN‐γ production. IL‐18, but not IL‐12, induced activator protein‐1 (AP‐1) responsible for high levels of IFN‐γ promoter activation. However, this IL‐18 effect depended on the interaction of AP‐1 with STAT4. A1 prevented AP‐1 binding by inhibiting STAT4 involvement and down‐regulated synergistic IFN‐γ promoter activation. These results indicate that JAK2 activation is required for IL‐12‐mediated T cell growth, whereas the TYK2‐STAT4 signaling pathway is critical for IFN‐γ expression that is mediated by IL‐12 alone and enhanced synergistically by combination with IL‐18.
Double‐edged effect of Vγ9/Vδ2 T lymphocytes on viral expression in an in vitro model of HIV‐1/mycobacteria co‐infection
Authors: Biswas Priscilla , Ferrarini Marina , Mantelli Barbara , Fortis Claudio , Poli Guido , Lazzarin Adriano , Manfredi Angelo A. 
Published: February 2003

AbstractA reciprocal influence exists between mycobacteria and HIV: HIV‐infected individuals are more susceptible to mycobacterial infections and, on the other hand, mycobacterial infection results inacceleration of HIV disease progression. Vγ9/Vδ2 T lymphocytes are known to participate in the defense against intracellular pathogens, including Mycobacterium tuberculosis. Indeed, they kill mycobacteria‐infected macrophages and, upon recognition of mycobacterial Ag, release TNF‐α and IFN‐γ, which are also up‐regulators of HIV expression. To assess whether mycobacteria‐activated γ δ T lymphocytes contribute to the enhancement of HIV replication, we established an in vitro model mimicking HIV and mycobacteria co‐infection with the latently HIV‐infected promonocytic U1 cell line and Vγ9/Vδ2 peripheral lymphocytes stimulated with mycobacterial Ag. γ δ T cell activation determined two distinct, but connected effects, namely U1cell death and HIV expression. Both effects were mainly mediated by release of TNF‐α and IFN‐γ from activated γ δ lymphocytes, although Fas‐FasL interaction also contributed to U1 apoptosis. The final outcome on U1 survival, and thus, on HIV expression, highly depended on mycobacterial Ag concentration coupled to the differential secretory potency of γ δ cells. In particular, the induction of viral expression prevailed at low Ag concentration and with lower cytokine production by mycobacteria‐activated γ δ cells. Notably, during the course of HIV infection, Vγ9/Vδ2 lymphocytes are reported to be functionally impaired and may thus indirectly influence the progression of HIV disease. In addition, a predominant inhibition of viral replication was encountered when mycobacteria‐activated γ δ T cells were co‐cultured with primary HIV‐infected macrophages. Thus, we suggest that specific recognition of mycobacterial Ag by γ δ T lymphocytes in co‐infected individuals may modulate viral replication through the complex array of soluble factors released.
A major role for tapasin as a stabilizer of the TAP peptide transporter and consequences for MHC class I expression
Authors: Garbi Natalio , Tiwari Neeraj , Momburg Frank , Hämmerling Günter J. 
Published: February 2003

AbstractTapasin is a member of the MHC class I loading complex where it bridges the TAP peptide transporter to class I molecules. The main role of tapasin is assumed to be the facilitation of peptide loading and optimization of the peptide cargo. Here, we describe another important function for tapasin. In tapasin‐deficient (Tpn–/–) mice the absence of tapasin was found to have a dramatic effect on the stability of the TAP1/TAP2 heterodimeric peptide transporter. Steady‐state expression of TAP protein was reduced more than 100‐fold from about 3×104 TAP molecules per wild‐type splenocyte to about 1×102 TAP per Tpn–/– splenocyte. Thus, a major function of murine tapasin appears to be the stabilization of TAP. The low amount of TAP moleculesin Tpn–/– lymphocytes is likely to contribute to the severe impairment of MHC class I expression. Surprisingly, activation of Tpn–/– lymphocytes yielded strongly enhanced class I expression comparable to wild‐type levels, although TAP expression remained low and in the magnitude of several hundred molecules per cell. The high level of class I on activated Tpn–/– cells depended on peptides generated by the proteasome as indicated by blockade with the proteasome‐specific inhibitor lactacystin. Lymphocyte activation induced an increase in ubiquitinated proteins that are cleaved into peptides by the proteasome. These findings suggest that in the presence of a large peptide pool in the cytosol, a small number of TAP transporters is sufficient to translocate enough peptides for high class I expression. However, these class I molecules were less stable than those of wild‐type cells, indicating that tapasin is not only required for stabilization of TAP butalso for optimization of the spectrum of bound peptides.
Computation and analysis of multiple structural change models
Authors: Bai Jushan , Perron Pierre 
Published: February 2003

AbstractIn a recent paper, Bai and Perron (1998) considered theoretical issues related to the limiting distribution of estimators and test statistics in the linear model with multiple structural changes. In this companion paper, we consider practical issues for the empirical applications of the procedures. We first address the problem of estimation of the break dates and present an efficient algorithm to obtain global minimizers of the sum of squared residuals. This algorithm is based on the principle of dynamic programming and requires at most least‐squares operations of orderO(T2) for any number of breaks. Our method can be applied to both pure and partial structural change models. Second, we consider the problem of forming confidence intervals for the break dates under various hypotheses about the structure of the data and the errors across segments. Third, we address the issue of testing for structural changes under very general conditions on the data and the errors. Fourth, we address the issue of estimating the number of breaks. Finally, a few empirical applications are presented to illustrate the usefulness of the procedures. All methods discussed are implemented in a GAUSS program. Copyright © 2002 John Wiley & Sons, Ltd.
A simple framework for analysing bull and bear markets
Authors: Pagan Adrian R. , Sossounov Kirill A. 
Published: February 2003

AbstractBull and bear markets are a common way of describing cycles in equity prices. To fully describe such cycles one would need to know the data generating process (DGP) for equity prices. We begin with a definition of bull and bear markets and use an algorithm based on it to sort a given time series of equity prices into periods that can be designated as bull and bear markets. The rule to do this is then studied analytically and it is shown that bull and bear market characteristics depend upon the DGP for capital gains. By simulation methods we examine a number of DGPs that are known to fit the data quite well—random walks, GARCH models, and models with duration dependence. We find that a pure random walk provides as good an explanation of bull and bear markets as the more complex statistical models. In the final section of the paper we look at some asset pricing models that appear in the literature from the viewpoint of their success in producing bull and bear markets which resemble those in the data. Copyright © 2002 John Wiley & Sons, Ltd.