bluuebunny/crossref_metadata_2025 huggingface dataset:
The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation
Authors: Suter Tobias , Biollaz Gregoire , Gatto Dominique , Bernasconi Luca , Herren Tobias , Reith Walter , Fontana Adriano
Published: October 2003

Dendritic cells (DC) are unique in their ability to prime naive T cells and initiate adaptive immunity. In recent years, DC were identified in the inflamed central nervous system (CNS), but their role in the initiation or regulation of the tissue specific immune response is unknown. As shown here, DC isolated from mice with experimental autoimmune encephalomyelitis (EAE) exhibit a maturational phenotype similar to immature bone marrow‐derived DC or splenic DC as characterized by intermediate surface MHC class II and low expression of the costimulatory molecule CD80. However, they are unable to prime naive T cells. Moreover, they inhibit T cell proliferation stimulated by mature bone marrow‐derived DC. TGFβ, IL‐10 and TRAIL were found to significantly contribute to the CNS‐DC‐mediated inhibition of allo‐T cell proliferation. Thus CNS‐DC may be the key responsibles for maintaining immune privilege within the inflamed CNS.
Intrapulmonary targeting of RANTES/CCL5‐responsive cells prevents chronic fungal asthma
Authors: Schuh Jane M. , Blease Kate , Brühl Hilke , Mack Matthias , Hogaboam Cory M.
Published: October 2003

Regulated upon activation in normal T cells, expressed, and secreted (RANTES)/CCL5 is abundantly expressed during atopic asthma, suggesting that it is an important mediator of this disease. The contribution of intrapulmonary RANTES/CCL5‐sensitive cells during Aspergillus fumigatus‐induced airway disease in mice was assessed in this study. The intranasal delivery of a chimeric protein comprised of RANTES/CCL5 and a truncated version of Pseudomonas exotoxin A (RANTES‐PE38) significantly attenuated serum IgE, peribronchial eosinophilia, and airway hyperreactivity when it was administered from day 0 to 15 after intratracheal conidia challenge in A. fumigatus‐sensitized mice but had little effect when delivered from day 15 to 30 after conidia challenge. Intranasal RANTES‐PE38 treatment enhanced macrophage recruitment and accelerated fungal clearance in the lungs of RANTES‐PE38‐treated mice. These data reveal a major role for RANTES/CCL5 and its receptors in the development of fungal asthma yet reveal only a modest role in the chronic remodeling of the allergic airway in this disease.
The cyclin‐dependent kinase inhibitors p27Kip1 and p21Cip1 are not essential in T cell anergy
Authors: Verdoodt Berlinda , Blazek Tino , Rauch Pia , Schuler Gerold , Steinkasserer Alexander , Lutz Manfred B. , Funk Jens Oliver
Published: October 2003

Recent evidence suggests that the cyclin‐dependent kinase (Cdk) inhibitors p27Kip1 and p21Cip1 are important factors in T cell anergy, but it has remained unclear whether anergy can be induced in their absence. We therefore induced anergy by stimulation of purified T cells from wild‐type, p21Cip1–/–, and p27Kip1–/– mice with anti‐CD3 antibodies. Anergic wild‐type T cells were arrested in the G1 phase of the cell cycle with a high p27Kip1 protein level and low Cdk2 activity. In p27–/– and p21–/– T cells, the pattern of protein expression was preserved, but Cdk2 activity was increased. To confirm the in vivo relevance of these data, anergy was induced by repeated injection of mice with staphylococcal enterotoxin B (SEB), which leads to partial deletion of the responsive Vβ8+ T cell population and anergy in the remaining T cells. p21–/– mice and wild‐type mice reacted similarly tothis treatment. p27–/– mice showed reduced deletion of SEB‐responsive T cells, but persisting T cells were anergic. These data indicate that other cell cycle regulators contribute to the cell cycle arrest of anergic T cells, as neither Cdk inhibitor is required for the induction of anergy.
IFN‐γ production in human NK cells through the engagement of CD8 by soluble or surface HLA class I molecules
Authors: Spaggiari Grazia Maria , Contini Paola , Negrini Simone , Dondero Alessandra , Carosio Roberta , Ghio Massimo , Puppo Francesco , Indiveri Francesco , Zocchi Maria Raffaella , Poggi Alessandro
Published: October 2003

The engagement of CD8 on NK cell surface by either surface or soluble HLA class I (sHLA‐I) molecules induces synthesis and secretion of IFN‐γ. HLA‐I‐mediated effects were inhibited by the covering of CD8 with specific anti‐CD8 monoclonal antibodies, indicating a direct interaction of HLA‐I and CD8. That CD8 ligation induces IFN‐γ production was further supported by the finding that cross‐linking of CD8 led to release of IFN‐γ at similar levels to those obtained with HLA‐I. The sHLA‐I‐induced IFN‐γ production via CD8 was strongly down‐regulated by the engagement of the inhibitory isoforms of either CD94/NKG2 complex by sHLA‐I‐non‐(A,B,C,G) (putative sHLA‐E) or CD158b by sHLA‐I‐Cw3 allele. Ligation of CD8 did not elicit, different from other activating NK cell surface molecules such as CD16 or CD69, triggering of NK cell‐mediated cytolysis. Cyclosporin A, but not concanamycin A, an H+‐ATPase vacuolar inhibitor which affects perforin and granzyme release, strongly reduced the sHLA‐I‐mediated CD8‐dependent IFN‐γ production but did not affect cytolytic activity of NK cells, suggesting that different biochemical pathways are involved. Altogether, these findings indicate that CD8 engagement by sHLA‐I activates a cyclosporin A‐dependent pathway leading to production and secretion of IFN‐γ which may play a role in the regulation of innate immune responses in humans.
In vivo expression of recombinant pregnancy‐specific glycoprotein 1a induces alternative activation of monocytes and enhances Th2‐type immune response
Authors: Motrán Claudia C. , Diaz Fernando López , Montes Carolina L. , Bocco José Luis , Gruppi Adriana
Published: October 2003

It has been proposed that pregnancy‐specific factors could be responsible for shift the balance of cytokine profiles during maternal immune response from Th1‐type reactivity into a "less‐damaging" Th2‐type reactivity. In the present work, we investigated the in vivo function of human pregnancy‐specific glycoprotein (PSG)1a, the major variant of PSG polypeptides released into thecirculation during pregnancy, on the modulation of the innate and adaptive immune response. For this, BALB/c mice were injected with a vaccinia virus‐based vector harboring the human PSG1a cDNA (Vac‐PSG1a) 4 days before immunization with ovalbumin (OVA) in complete Freund's adjuvant, and the early specific T cell response against OVA was evaluated 8 days post‐immunization. We also studied the activation status of spleen and peritoneal monocytes/macrophages (Mo) populations from Vac‐PSG1a‐treated mice, and explored whether PSG1a‐targeted Mo could affect the Th‐type commitment by investigating their impact on the differentiation of naive T cells. Our data show that the treatment with Vac‐PSG1a is able to induce a state of alternative activation on Mo. Furthermore, the generation of the immune response in the context of these alternatively activated antigen‐presenting cells may shift T cell differentiation to Th2‐type immunity which is more compatible with a successful pregnancy.
T cell stimulation in the absence of exogenous antigen: a T cell signal is induced by both MHC‐dependent and ‐independent mechanisms
Authors: Bettini Matthew , Xi Hongkang , Kersh Gilbert J.
Published: October 2003

Mature T cells residing in peripheral lymphoid organs have frequent contact with antigen presenting cells (APC). Such contact may be required for T cell survival, but the degree to which signals in mature T cells are induced by TCR recognition of self peptide/MHC complexes is unclear. We have used induction of the early growth response gene 1 (Egr1) as an indicator of signal transductionin 3.L2 (I‐Ek‐restricted) T cells interacting with APC in the absence of exogenous antigen. The data show that Egr1 can be induced in 3.L2 T cells by TCR recognition of self peptides presented by I‐Ek. However, a more transient induction of Egr1 can be induced in 3.L2 T cells interacting with dendritic cells derived from class II/β2m double‐deficient mice. Egr1 inductionafter T cell‐APC contact was also observed in a freshly isolated polyclonal CD4 T cell population. The data suggest that self peptide/MHC recognition by the TCR induces a signal in T cells and that dendritic cells can also induce a more transient T cell signal by an MHC‐independent mechanism.
Macrophage colony‐stimulating factor‐dependent macrophage proliferation is mediated through a calcineurin‐independent but immunophilin‐dependent mechanism that mediates the activation of external regulated kinases
Authors: Comalada Monica , Valledor Annabel F. , Sanchez‐Tilló Ester , Umbert Ignacio , Xaus Jordi , Celada Antonio
Published: October 2003

Calcineurin is constitutively expressed in bone marrow‐derived macrophages. However, macrophage response to macrophage colony‐stimulating factor (M‐CSF) was not impaired by the use of either calcineurin inhibitors (W‐13, chlorpromazine and trifluoperazine), calcium chelators (BAPTA‐AM) or Ca2+ channel antagonists (verapamil, nifedipine and diltiazem). Inhibition of calcineurin expression by inhibitory antisense RNA treatment did not result in an inhibition of M‐CSF‐dependent proliferation. Only very high doses of cyclosporin A and FK506 inhibited macrophage proliferation induced by growth factors, such as M‐CSF, granulocyte‐macrophage (GM)‐CSF or IL‐3. This inhibitory action is mediated by the peptidylprolyl isomerase activity of the immunophilins, as demonstrated bythe use of specific inhibitors (rapamycin and sanglifehrin A). These isomerase inhibitors exerted a negative effect on a key element involved in macrophage proliferation, namely the M‐CSF‐dependent activation of the extracellular signal‐regulated kinases (ERK). In summary, the data presented here provide new insights in the mechanism of macrophage proliferation, which may have relevant consequences. First, we showed that in M‐CSF‐dependent proliferation calcineurin is not involved, and second, that immunophilins play a key role and their activation blocks ERK activation.
Pituitary adenylate cyclase‐activating polypeptide inhibits cutaneous immune function
Authors: Kodali Sreedevi , Friedman Ilyse , Ding Wanhong , Seiffert Kristina , Wagner John A. , Granstein Richard D.
Published: October 2003

Epidermal nerves are closely associated with Langerhans cells (LC) and may be able to release factors, such as calcitonin gene‐related peptide and epinephrine, that affect LC function. LC and the LC‐like cell line XS106 express mRNA for the pituitary adenylate cyclase‐activating polypeptide (PACAP) receptors VPAC1 and VPAC2. We examined whether PACAP regulates cutaneous immunity. Intradermal administration of PACAP prior to application of a contact sensitizer at the injected site inhibited the induction of contact hypersensitivity. Pretreatment of murine epidermal cells enriched for LC content (∼12% LC) with PACAP inhibited their ability to elicit delayed‐type hypersensitivity in previously immunized mice. In vitro, PACAP suppressed the ability of both murine epidermal cells and highly purified LC (∼95%) to present antigen to a T cell clone and hybridoma. Furthermore, in LC and the XS106 cell line, PACAP inhibited the
LPS/GM‐CSF‐induced stimulation of IL‐1β secretion and augmented IL‐10 production. PACAP also down‐regulated CD86 expression in LPS/GM‐CSF‐stimulated XS106 cells. The immunosuppressive effects of PACAP may be due to modulation ofcytokine production and CD86 expression.
Cholera toxin activates dendritic cells through dependence on GM1‐ganglioside which is mediated by NF‐κB translocation
Authors: Kawamura Yuki I. , Kawashima Rei , Shirai Yuko , Kato Rie , Hamabata Takashi , Yamamoto Masafumi , Furukawa Koichi , Fujihashi Kohtaro , McGhee Jerry R. , Hayashi Hideo , Dohi Taeko
Published: October 2003

Cholera toxin (CT) is a potent adjuvant; however, the mechanism for its ability to enhance mucosal immunity has not been fully elucidated. We report here that CT exerts its adjuvant propertiesby signaling through the GM1 ganglioside receptor. When ganglioside‐defective mice were given the antigen (Ag) ovalbumin (OVA) with CT by the oral route, CT failed to support either OVA‐specific antibody or CD4+ T cell responses. In vitro treatment of murine bone marrow‐derived dendritic cells (DC) with CT induced full maturation as evidenced by up‐regulation of the costimulatory molecules, as well as by an enhanced ability to effectively present OVA for Ag‐specific T cell responses. On the other hand, ganglioside‐defective DC failed to differentiate to full function as Ag‐presenting cells in response to CT. Since ganglioside‐defective DC showed a mature phenotype after stimulation with lipopolysaccharide (LPS), the effects of CT on DC was independent of signal transduction through adjuvant receptor for LPS, the Toll‐like receptor 4. Furthermore, CT also induced nuclear translocation of nuclear factor (NF)‐κB in DC in a GM1‐dependent fashion. These results highlight gangliosides expressed by DC for recognition of the non‐self protein bacterial enterotoxin, which employ a unique signaling pathway to induce both innate and adaptive immunity.
Microbial Toll‐like receptor ligands differentially regulate CXCL10/IP‐10 expression in fibroblasts and mononuclear leukocytes in synergy with IFN‐γ and provide a mechanism for enhanced synovial chemokine levels in septic arthritis
Authors: Proost Paul , Vynckier An‐Katrien , Mahieu Frank , Put Willy , Grillet Bernard , Struyf Sofie , Wuyts Anja , Opdenakker Ghislain , Damme Jo Van
Published: October 2003

The CXC chemokine IFN‐γ‐inducible protein‐10 (IP‐10/CXCL10) activates CXC chemokine receptor 3 (CXCR3) and attracts activated T cells and natural killer cells. Peripheral blood mononuclearcells (PBMC) produce low but significant amounts of IP‐10/CXCL10 protein upon stimulation with double‐stranded (ds) RNA, the Toll‐like receptor 3 (TLR3) ligand. IFN‐γ is a superior IP‐10/CXCL10inducer. The bacterial TLR4 and TLR2 ligands, LPS and peptidoglycan (PGN), inhibit IFN‐γ‐ or dsRNA‐dependent IP‐10/CXCL10 production in PBMC, whereas IL‐8/CXCL8 production was enhanced. In fibroblasts a different picture emerges with IFN‐γ inducing moderate and dsRNA provoking strong IP‐10/CXCL10 production. Furthermore, treatment of fibroblasts with IFN‐γ in combination with bacterial LPS or PGN results in a synergistic production of IP‐10/CXCL10 and IL‐8/CXCL8. The synergistic induction of IP‐10/CXCL10 in fibroblasts is reflected by significantly enhanced IP‐10/CXCL10 concentrations in synovial fluids of septic compared to osteoarthritis patients to reach on average higher levels than those of IL‐8/CXCL8. These high amounts of IP‐10/CXCL10 produced by connective tissue fibroblasts not only attract CXCR3 expressing activated Th1 cells and natural killer cells to sites of infection but may also antagonize the CCR3 dependent attraction of Th2 lymphocytes and exert CXCR3‐independent, defensin‐like antibacterial activity.
Identification of a CTL‐directed epitope encoded by an intron of the putative tumor suppressor gene Testin of the common fragile site 7G region: a peptide vaccine candidate for HLA‐B52+ and HLA‐62+ cancer patients
Authors: Ohkouchi Shinya , Kawamoto Naoki , Koga Makoto , Sakanashi Fumi , Shichijo Shigeki , Saijo Yasuo , Nukiwa Toshihiro , Itoh Kyogo , Yamada Akira
Published: October 2003

Although cytotoxic T lymphocyte (CTL)‐directed epitopes binding to human histocompatibility leukocyte antigen (HLA)‐A molecules have been well characterized, those binding to HLA‐B molecules have not, largely due to their large diversity. In this study we report a unique cancer antigen gene, tentatively named Testin‐related gene (TRG), which encodes CTL‐directed epitopes on the HLA‐B52 molecules most frequently expressed in Asians. TRG is located in an intron of the putative tumor suppressor gene Testin in the common fragile site 7G region at 7q31.2. TRG mRNA was expressed in the majority of cancer cells and cancer tissue tested, whereas it was scarcely expressed in the majority of normal tissues, and only low‐level expression of TRG was detected in the heart, liver, and pancreas. One TRG peptide had the ability to induce HLA‐B52‐restricted CTL cytotoxic to TRG+ tumor cells in peripheral blood mononuclear cells (PBMC) of epithelial cancer patients. This peptidealso induced HLA‐B62‐restricted and tumor‐reactive CTL in PBMC of cancer patients. Therefore, this TRG‐derived peptide might be appropriate for use in peptide‐based immunotherapy for relatively large numbers of cancer patients throughout the world, given that 34% of Japanese, 27% of Chinese, and 13% of Caucasians express either HLA‐B52 or HLA‐B62 molecules
The B subunit of Escherichia coli heat labile enterotoxin abrogates oral tolerance, promoting predominantly Th2‐type immune responses
Authors: Plant Andrea , Williams Rachel , Jackson Michelle E. , Williams Neil A.
Published: October 2003

Mucosal antigen encounter usually results in a state of systemic non‐responsiveness (tolerance). This failure to mount a protective response is a major hurdle to mucosal vaccine development. Hence, the identification of safe and effective mucosal adjuvants promoting protective immunity is of critical importance. The non‐toxic B subunit of Escherichia coli heat labile enterotoxin(EtxB) is a potent nasal adjuvant; however, its usefulness following oral delivery is unconfirmed. We used DO11.10 chimeric mice to assess whether EtxB could abrogate tolerance to oral OVA. We showthat admixing EtxB with OVA for oral immunization abrogates oral tolerance and results in a weak anti‐OVA immune response. Importantly, EtxB profoundly modulated the nature of the response to subsequent parenteral challenge, promoting IgG1 in favor of IgG2a antibodies and depressing IFN‐γ production while elevating TGF‐β secretion. The addition of EtxB promoted T cell division, as assessed by loss of staining with carboxyfluorescein diacetate succinimidyl ester. Enhanced cell division promoted by EtxB was associated with T cell differentiation (increased numbers of CD45RBlow cells) in vivo, although dividing OVA‐specific T cells were CD25–. These data suggest that although EtxB is a weak oral adjuvant, it can profoundly modulate the nature of the immune response to admixed antigen.
Post‐translational and cell type‐specific regulation of CXCR4 expression by cytokines
Authors: Brühl Hilke , Cohen Clemens D. , Linder Stefan , Kretzler Matthias , Schlöndorff Detlef , Mack Matthias
Published: October 2003

We have investigated the regulation and function of the chemokine receptor CXCR4 on neutrophils. CXCR4 is hardly detectable on neutrophils in the peripheral blood. However, overnight culture strongly up‐regulates CXCR4 expression on the cell surface. The functional activity of CXCR4 on cultured neutrophils was confirmed by stromal cell‐derived factor (SDF)‐induced migration and up‐regulation of the integrins CD11b and CD11c. CXCR4 surface expression on neutrophils but not on lymphocytes and monocytes is rapidly down‐regulated after stimulation with TNF‐α and IFN‐γ, resulting in significantly decreased SDF‐induced functional responses of neutrophils. In contrast to surface expression, CXCR4 mRNA expression was several‐fold increased in cytokine‐stimulated neutrophils, suggesting a post‐translational regulation. By confocal microscopy we demonstrate that CXCR4 is internalized after stimulation with TNF‐α and IFN‐γ. The down‐modulation of CXCR4 surface expression in response to TNF‐α and IFN‐γ was fully reversible after cytokine removal. Further, CXCR4 down‐modulation could be completely blocked by hypertonic sucrose and significantly reduced by chlorpromazine indicating the involvement of clathrin‐coated pits. Internalization of CXCR4 by cytokines in a cell type‐specific manner is a novel and functionally important mechanism of chemokine receptor regulation.
Two highly divergent ancient allelic lineages of the transporter associated with antigen processing (TAP) gene in Xenopus: further evidence for co‐evolution among MHC class I region genes
Authors: Ohta Yuko , Powis Simon J. , Lohr Rebecca L. , Nonaka Masaru , Pasquier Louis Du , Flajnik Martin F.
Published: October 2003

In the frog Xenopus, MHC class I antigen presentation and processing genes (the immunoproteasome LMP2 and LMP7 and the transporter TAP1 and TAP2) seemto be closely linked in a primordial organization. Two distinct lineages of class Ia and LMP7 loci were previously identified, thus strongly suggesting co‐evolution among ‘class I region’ genes. We now show that the Xenopus MHC ‘class I region’ lies between class II and class III genes and we have isolated two distinct alleles at both the TAP1 and TAP2 loci. The alleles at each locus are remarkably divergent from each other and phylogenetic tree analysis revealed in both cases that they diverged from each other 60–100 million years ago (MYA). For lineage‐frequency and linkage analysis, 25 wild‐caught X. laevis and 16 X. tropicalis were examined. The two lineages were present in different frequencies for X. laevis and X. tropicalis. Nevertheless, in all cases, the LMP7, TAP1, and TAP2 lineages were found in a set comprising one of the two lineages. Furthermore, like the LMP7 lineages, the TAP lineages were detected in most Xenopus species that diverged from a common ancestor 80–100 MYA, suggesting that the ‘class I region’ biallelic lineages are under balancing selection.
Structural and kinetic basis for low affinity cross‐reactivity in T cell allorecognition
Authors: Guimezanes Annick , Montero‐Julian Félix , Schmitt‐Verhulst Anne‐Marie
Published: October 2003

The alloreactive BM3.3TCR interacts with high affinity with H‐2Kb loaded with the endogenous peptide pBM1 (INFDFNTI), and shows low affinity cross‐reactivity for H‐2Kb loadedwith a viral peptide VSV8 (RGYVYQGL), CTL activity requiring 103‐fold higher peptide concentration and being highly sensitive to inhibition by anti‐CD8 monoclonal antibody. VSV8 peptides substituted with pBM1/TCR contact residues (N6 and T7) retained low affinity characteristics and among pBM1 peptides substituted with residues Q6 and/or G7 present in VSV8, only pBM1(G7) was recognized, albeit with characteristics akin to those of VSV8. Despite the difference in KD values and the faster dissociation rate of multimeric VSV8/H‐2Kb as compared to pBM1/H‐2Kb complexes, similar TCR occupancy could be achieved with both multimers either at 4 or 37°C. Only TCR engagement with pBM1/H‐2Kb, however, resulted in early (Ca2+ flux) and late(CD69 expression) activation events in naive BM3.3TCR CD8 T cells. CD8 coreceptor, essential for binding of the weak agonists, was dispensable for binding of pBM1/H‐2Kb multimers and their induction of signaling in naive T cells. Hence, high number of TCR and coreceptor engagement by weak agonists fail to substitute for strong agonist TCR engagement that can be coreceptor‐independent and involve a limited number of TCR.
Essential role for TLR4 and MyD88 in the development of chronic intestinal nematode infection
Authors: Helmby Helena , Grencis Richard K.
Published: October 2003

Expulsion of the gastrointestinal nematode Trichuris muris is mediated by a T helper 2 type response involving IL‐4 and IL‐13. Here we show that Th1 response‐associated susceptibilityis dependent on activation signals mediated by MyD88 and Toll‐like receptor 4 (TLR4). TLR4‐ and MyD88‐deficient mice are highly resistant to chronic T. muris infection and develop strong antigen‐specific Th2 responses in mucosa‐associated lymphoid tissues. Hence, TLR4 and MyD88 are involved not only in the development of pro‐inflammatory responses against bacterial pathogens but are also crucially involved in responses against multicellular organisms such as helminths. These results provide the first demonstration of the critical role of TLR4 and MyD88 in bridging the innate and acquired immune response during gastrointestinal nematode infection.
Endothelial expression of PD‐L1 and PD‐L2 down‐regulates CD8+ T cell activation and cytolysis
Authors: Rodig Nancy , Ryan Timothy , Allen Jessica A. , Pang Hong , Grabie Nir , Chernova Tatyana , Greenfield Edward A. , Liang Spencer C. , Sharpe Arlene H. , Lichtman Andrew H. , Freeman Gordon J.
Published: October 2003

Interactions between CD8+ T cells and endothelial cells are important in both protective and pathologic immune responses. Endothelial cells regulate the recruitment of CD8+ Tcells into tissues, and the activation of CD8+ T cells by antigen presentation and costimulatory signals. PD‐L1 and PD‐L2 are recently described B7‐family molecules which bind to PD‐1 on activated lymphocytes and down‐regulate T cell activation. We found that PD‐L1 is expressed on interferon‐γ stimulated cultured human and mouse endothelial cells, while PD‐L2 was found on stimulated human but not mouse endothelial cells. Expression was further up‐regulated by TNF‐α. Antibody blockade of endothelial cell PD‐L1 and PD‐L2 enhanced endothelial cell costimulation of PHA‐activated human CD8+ T cells. Antibody blockade of mouse endothelial cell PD‐L1 enhanced both IFN‐γ secretion and cytolytic activity of CD8+ T cells in response to endothelial cellantigen presentation. These results show that IFN‐γ activated endothelial cells can inhibit T cell activation via expression of the immunoinhibitory PD‐L1 and PD‐L2 molecules. Endothelial expression of PD‐ligands would allow activation and extravasation of T cells without excessive vessel damage. Our findings highlight a potentially important pathway by which endothelial cells down‐regulate CD8+ T cell‐mediated immune responses.
Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4+ T cell responses
Authors: Schjetne Karoline W. , Gundersen Hans T. , Iversen Jens‐Gustav , Thompson Keith M. , Bogen Bjarne
Published: October 2003

Here, we have investigated if targeting of T cell epitopes to chemokine receptors results in improved CD4+ T cell responses. Mouse monoclonal antibodies (mAb) with κL chains were targeted to various chemokine receptors expressed on human monocytes or immature dendritic cells (DC), and proliferation of cloned human, DR4‐restricted CD4+ T cells specific for mouse Cκ40–48 was measured. When using monocytes as antigen‐presenting cells, mAb specific for CCR1, CCR2, CCR5, and CXCR4 were 100–10,000‐fold more efficient at inducing T cell proliferationwhen compared to isotype‐matched control mAb on a per molecule basis. Targeting of immature DC was less effective and was only seen with anti‐CCR1 and anti‐CXCR4 mAb. Anti‐chemokine receptors mAb required to be processed by the conventional endosomal MHC class II presentation pathway. The mAb did not induce signaling through the chemokine receptors as they failed to induce mobilization of cytosolic Ca2+ and actin polymerization. They also failed to induce APC maturation. The results strongly suggest that chemokine receptors channel antigen into the endocytic pathway for presentation on MHC class II molecules. Targeting T cell epitopes to chemokine receptors by recombinant antibody should be a useful vaccine strategy for the induction of strong CD4+ T cell responses.
Bacterial DNA activates human neutrophils by a CpG‐independent pathway
Authors: Trevani Analía S. , Chorny Alejo , Salamone Gabriela , Vermeulen Mónica , Gamberale Romina , Schettini Jorge , Raiden Silvina , Geffner Jorge
Published: October 2003

Bacterial DNA stimulates macrophages, monocytes, B lymphocytes, NK cells, and dendritic cells in a CpG‐dependent manner. In this work we demonstrate that bacterial DNA, but not mammalian DNA, induces human neutrophil activation as assessed by L‐selectin shedding, CD11b upregulation, and stimulation of cellular shape change, IL‐8 secretion, and cell migration. Induction of these responsesis not dependent on the presence of unmethylated CpG motifs, as neutrophil stimulatory properties were neither modified by CpG‐methylation of bacterial DNA nor reproduced by oligonucleotides bearing CpG motifs. We found that human neutrophils express Toll‐like receptor (TLR) 9 mRNA. However, as expected for a CpG‐independent mechanism, activation does not involve a TLR9‐dependent signaling pathway; neutrophil stimulation was not prevented by immobilization of bacterial DNA or by wortmannin or chloroquine, two agents that inhibit TLR9 signaling. Of note, both single‐stranded and double‐stranded DNA were able to induce activation, suggesting that neutrophils might be activated by bacterial DNA at inflammatory foci even in the absence of conditions required to induce DNA denaturation. Our findings provide the first evidence that neutrophils might be alerted to the presence of invading bacteria through recognition of its DNA via a novel mechanism not involving CpG motifs.
Control of inflammatory diseases by pathogens: lipids and the immune system
Authors: van der Kleij Desiree , Yazdanbakhsh Maria
Published: October 2003

Inflammatory diseases such as asthma and diabetes are rising in industrialized countries and the modern lifestyle that is associated with lower exposure to microbes has been held responsible for the increasing prevalence of these diseases. Several studies have shown an inverse association between pathogen‐exposure and allergy or autoimmunity. The mechanisms behind such protective effectshave been investigated at the epidemiological, cellular and molecular level and have provided data on the ability of lipids either derived directly from pathogens or up‐regulated as a result of an infection to down‐regulate immune responses and thereby control inflammatory diseases. In this mini‐review, recent findings and new concepts relating to the immunosuppressive effects of endogenous lipids and those encountered upon exposure to bacteria, protozoa and particularly helminths are discussed. The overview focuses on the modulation of interactions between the antigen‐presenting compartment and T cells to start an anti‐inflammatory "program" with potential to regulate disease processes.
CD30 ligation differentially affects CXCR4‐dependent HIV‐1 replication and soluble CD30 secretion in non‐Hodgkin cell lines and in γ δ T lymphocytes
Authors: Biswas Priscilla , Mantelli Barbara , Delfanti Fanny , Ferrarini Marina , Poli Guido , Lazzarin Adriano
Published: October 2003

We studied whether signaling through CD30, a member of the TNF receptor family, affected acute infection with HIV‐1, encompassing its entire replicative cycle. Several non‐Hodgkin cell lines, targets of CXCR4‐dependent (X4) HIV‐1 infection, were positive for CD30 expression. CD30 ligation induced up‐regulation of viral replication only in certain CD30+ cell lines. Enhancement ofX4 virus replication by CD30 engagement inversely correlated with both CD30 surface density and constitutive NF‐κB activation. Conversely, expression of CD30, but not of other members of the TNF receptor family, was proportional to constitutive NF‐κB binding. Concomitantly, secretion of soluble (s) CD30 increased in all cell lines by CD30 ligation. sCD30 release was enhanced by engagement of CD30 alone and, to a greater extent, by co‐engagement of CD3 also in primary γ δ T lymphocytes, along with complementary modulations of their surface CD30 expression. sCD30‐containing supernatant specifically inhibited HIV‐1 expression induced by CD30 engagement in chronically infected ACH‐2 T cells; thus sCD30 may act as a negative feed‐back molecule. In conclusion, we have delineated novel features of CD30 biology and underline the peculiar link of CD30 expression to constitutive NF‐κB activation which is pivotal to both HIV replication and cell survival.
LIGHT, a new TNF superfamily member, is essential for memory T helper cell‐mediated activation of dendritic cells
Authors: Morel Yannis , Truneh Alemseged , Costello Régis T , Olive Daniel
Published: October 2003

LIGHT is a recently identified member of the TNF superfamily that is up‐regulated on activated T cells and can cooperate with CD40L to condition DC for the priming of CTL. In this report, we show that an intracellular pool of LIGHT is found selectively in some CD45RA–CD27+CD4+ "central" memory T cells and to a greater extent in some CD45RA–CD27–CD4+ effector memory T cells. LIGHT, like CD40L, is rapidly up‐regulated on memory CD4+ T cells upon activation. Unlike CD40L, LIGHT up‐regulation on naive T cells is delayed. Stmulation of DC with each subset of memory T cells in the presence of superantigen revealed that CD40L and LIGHT are required for optimal secretion of IL‐12. Moreover, effector memory T cells, which can interact with DC in peripheral tissues, contribute to CCR7 induction on DC. LIGHT and CD40L can also regulate IL‐12 production by CCR7+ DC capable of migration to lymph nodes. These data suggest that both LIGHT and CD40L may be involved in the maintenance or reactivation of secondary Th1 responses.
Probabilistic approach for active control based on structural energy
Authors: Min Kyung‐Won , Hwang Jae‐Seung , Lee Sang‐Hyun , Chung Lan
Published: October 2003

This paper presents an active control algorithm using the probability density function of structural energy. It is assumed that structural energy under excitation has a Rayleigh probability distribution. This assumption is based on the fact that the Rayleigh distribution satisfies the condition that the structural energy is always positive and the occurrence probability of minimum energy is zero. The magnitude of the control force is determined by the probability that the structural energy exceeds the specified target critical energy, and the sign of the control force is determined by the Lyapunov controller design method. The proposed control algorithm shows much reduction of peak responses under seismic excitation compared with the LQR controller, and it can consider the control force limit in the controller design. Also, the chattering problem which sometimes occurs in the Lyapunov controller can be avoided. Copyright © 2003 John Wiley & Sons, Ltd.
A yield displacement distribution‐based approach for strength assignment to lateral force‐resisting elements having strength dependent stiffness
Authors: Tso W. K. , Myslimaj B.
Published: October 2003

Recent studies have shown that for many lateral force‐resisting elements (LFRE) stiffness is dependent on strength, and as a result strength assignment to these elements would affect both the strength and stiffness distributions in a structure. Consequently, stiffness distribution cannot be considered known prior to strength assignment. This paper presents a yield displacement distribution‐based strength assignment strategy that does not require the knowledge of stiffness distribution prior to strength assignment. It is shown that structural systems with their center of rigidity (CR) and center of strength (CV) located on the opposite sides of the center of mass (CM) will have small torsional responses under seismic excitation. Copyright © 2003 John Wiley Sons, Ltd.
Experimental study of the semi‐active control of building structures using the shaking table
Authors: Sun Qing , Zhang Ling , Zhou Jinxiong , Shi Qingxuan
Published: October 2003

A magnetorheological (MR) damper has been manufactured and tested and a non‐linear model is discussed. The parameters for the model are identified from an identification set of experimental data; these parameters are then used to reconstruct the force vs. displacement and the force vs. velocity hysteresis cycles of the MR damper for the hysteretic model. Then experiments are conducted on a three‐storey frame model using impact excitation, which identifies dynamic parameters of the model equipped with and without the MR damper. Natural frequencies, damping ratios and mode shapes, as well as structural properties, such as the mass, stiffness and damping matrices, are obtained. A semi‐active control method such as a variable structure controller is studied. Based on the ‘reaching law’ method, a feedback controller is presented. In order to evaluate the efficiency of the control system and the effect of earthquake ground motions, both numerical analysis and shaking table tests of the model, with and without the MR damper, have been carried out under three different ground motions: El Centro 1940, Taft 1952, and Ninghe 1976 (Tangshan Earthquake in Chinese). It is found from both the numerical analysis and the shaking table tests that the maximum accelerations and relative displacements for all floors are significantly reduced with the MR damper. A reasonable agreement between the results obtained from the numerical analysis and those from the shaking table tests is also observed. On the other hand, tests conducted at different earthquake excitations and various excitation levels demonstrate the ability of the MR damper to surpass the performance of a comparable passive system in a variety of situations. Copyright © 2003 John Wiley & Sons, Ltd.
Tracking rapidly changing dynamical systems using a non‐parametric statistical method based on wavelets
Authors: Ching Jianye , Glaser Steven D.
Published: October 2003

A non‐parametric statistical method of tracking rapidly changing dynamical systems is introduced. The method implements the non‐linear wavelet thresholding estimator to estimate the evolutionary transfer function of the system. The consistency and optimality of the resulting estimate of our method on rapidly changing systems are stated, while no linear estimator can achieve the same optimality. Two examples of real data are studied using this non‐parametric method, including two vertical seismic array case studies and a series of seismic slope experiments. The analysis results are consistent with previous research for the vertical seismic array data. Moreover, our estimate is superior to those from previous research in the sense that our estimate is neither over‐smoothed nor under‐smoothed. The ana‐ lysis results are also consistent with the experimental observations for the seismic slope experimental data. Copyright © 2003 John Wiley & Sons, Ltd.
Effects of reinforcement slippage on the non‐linear response under cyclic loadings of RC frame structures
Authors: Limkatanyu Suchart , Spacone Enrico
Published: October 2003

This paper discusses the importance of including the bond‐slip effects in assessing the response under cyclic loads of reinforced concrete frames. The discussion is based on analyses performed using numerical models which are simple, computationally efficient and capable of representing the salient features of reinforced concrete frames under both static and dynamic loads. The numerical models comprise a displacement‐based, reinforced concrete frame element with bond‐slip and a rigid beam column joint element with bond‐slip. Two applications illustrate the model accuracy and show the importance of including bond‐slip. The first application considers a reinforced concrete beam‐column subassemblage experimentally tested under cyclic loads. The second application considers the shaking table test of a two‐story one‐bay reinforced concrete frame In both cases the analytical results correlate well with the experimental results in terms of strength, displacement demands and hysteretic energy dissipation. Furthermore, the paper shows how the analyses that include bond‐slip yield a better correlation with the experimental results with respect to the analyses that assume a perfect bond. Copyright © 2003 John Wiley & Sons, Ltd.
Ground motion scaling methods for different site conditions and structure characteristics
Authors: Kurama Y. C. , Farrow K. T.
Published: October 2003

Non‐linear dynamic time‐history analyses conducted as part of a performance‐based seismic design approach often require that the ground motion records are scaled to a specified level of seismic intensity. Recent research has demonstrated that certain ground motion scaling methods can introduce a large scatter in the estimated seismic demands. The resulting demand estimates may be biased, leading to designs with significant uncertainty and unknown margins of safety, unless a relatively large ensemble of ground motion records is used. This paper investigates the effectiveness of seven ground motion scaling methods in reducing the scatter in estimated peak lateral displacement demands. Non‐linear single‐degree‐of‐freedom systems and non‐linear multi‐degree‐of‐freedom systems are considered with different site conditions (site soil profile and epicentral distance) and structural characteristics (yield strength, period, and hysteretic behavior). It is shown that scaling methods that work well for ground motions representative of stiff soil and far‐field conditions lose their effectiveness for soft soil and near‐field conditions for a wide range of structural characteristics. Copyright © 2003 John Wiley & Sons, Ltd.
Numerical modelling of the pressure wave propagation in the arterial flow
Authors: Pontrelli Giuseppe , Rossoni Enrico
Published: October 2003

A differential model of blood flow through an arterial vessel is presented. It consists of a one‐dimensional model describing the non‐linear fluid–wall interaction coupled with a simple lumped parameter model which accounts for outlet boundary conditions. The model includes a local stiffening of the vessel and the wave propagation of disturbances due to prosthetic implantations is also studied. The non‐linear problem is solved by a finite‐difference method on a staggered grid and some numerical simulations are analysed and discussed. Copyright © 2003 John Wiley & Sons, Ltd.
Auto‐regulation and blood flow in the cerebral circulation
Authors: David Tim , Brown Michael , Ferrandez A.
Published: October 2003

The application of computational fluid dynamics (CFD) to model biological flows is quite a recent one. This study presents a CFD model of the Circle of Willis developed to simulate the human cerebrovascular tree. Specifically, we aim to show firstly how the auto‐regulation mechanism can be modelled and secondly how smaller arteries, often not visible by non‐intrusive MR studies, can be detected by making use of the results obtained from the computer simulation. Results show the time‐varying mass flow in each of the efferent vessels and how collateral vessels are even used in naturally ‘balanced’ configurations. Copyright © 2003 John Wiley & Sons, Ltd.
Effects of blood models on flows through a stenosis
Authors: Neofytou Panagiotis , Drikakis Dimitris
Published: October 2003

The paper presents a numerical investigation of non‐Newtonian modelling effects on unsteady periodic flows in a two‐dimensional (2D) channel with a stenosis. The geometry and boundary conditions were chosen so as to reproduce the flow features that are observed in real haemodynamic conditions. Three different non‐Newtonian constitutive equations for modelling the shear characteristics of the blood namely the Casson, power‐law and Quemada models, are utilized. Similarly with previous studies based on Newtonian modelling, the present simulations show the formation of several vortices downstream of the stenosis, as well as substantial variations of the wall shear stress throughout the unsteady cycle. Additionally, it is shown that: (i) there are substantial differences between the results obtained by Newtonian and non‐Newtonian models, and (ii) the prediction of vortex formation, wall shear stress distribution and separation behind the stenosis is strongly dependent on the details of the non‐Newtonian model employed in the simulations. Copyright © 2003 John Wiley & Sons, Ltd.
The rapid and robust generation of efficient hybrid grids for rans simulations over complete aircraft
Authors: Shaw J. A. , Stokes S. , Lucking M. A.
Published: October 2003

A description is given of a method capable of automatically forming efficient, high‐quality hybrid meshes for viscous flow calculations over complete aircraft, given engineers' requirements on mesh density and first cell‐height. Mixed quadrilateral/triangular surface grids are constructed using the moving‐front approach, with point placement and connection optimized to ensure high‐quality, anisotropic panels are generated. The volume mesh is built in two stages. A near field mesh is formed using the advancing‐layer approach, significantly enhanced through the use of mesh enriching/collapsing techniques and layer‐intersection detection/front‐termination algorithms. The remainder of the domain is then covered by a cut‐cell Cartesian mesh of varying density that conforms to the outer‐surface of the near field mesh. Examples of meshes generated using the described methods are presented and the user‐input discussed. Copyright © 2003 John Wiley & Sons, Ltd.
Applications of patient‐specific CFD in medicine and life sciences
Authors: Löhner Rainald , Cebral Juan , Soto Orlando , Yim Peter , Burgess James E.
Published: October 2003

Recent advances in medical image segmentation, grid generation, flow solvers, realistic boundary conditions, fluid–structure interaction, data reduction and visualization arc reviewed with special emphasis on patient‐specific flow prediction. At the same time, present shortcomings in each one of these areas are identified. Several examples are given that show that this methodology is maturing rapidly, and may soon find widespread use in medicine. Copyright © 2003 John Wiley & Sons, Ltd.
Some challenges of realistic flow simulations by unstructured grid CFD
Authors: Nakahashi Kazuhiro , Ito Yasushi , Togashi Fumiya
Published: October 2003

This paper discusses the unstructured grid method to compute flows around geometrically complex bodies having relative motions. To enhance the capability to treat complex geometries, a surface triangulation method using the advancing front method coupled with geometric feature extraction technique is described. Stereolithography (STL) data are adopted as an interface between a CAD system and the surface grid generator. Moving bodies are treated by the overset unstructured grid method. The capability of the method is demonstrated for simulations of an airplane separation process from a rocket booster and a hornet in flight. In the hornet simulation, the detailed components such as antennas, legs and a sting are all included in the computational grid. The flapping wings are treated by the overset unstructured grid method where a grid around the wing is overlapped on a stationary grid around the body of a hornet and moves with time to simulate the flapping motion. Copyright © 2003 John Wiley & Sons, Ltd.
Unstructured Navier–Stokes grid generation at corners and ridges
Authors: Sharov Dmitri , Luo Hong , Baum Joseph D. , Löhner Rainald
Published: October 2003

Problems related to automatic generation of highly stretched unstructured grids suitable for 3‐D Reynolds‐averaged Navier–Stokes computations are addressed. Special attention is given to treatment of such geometrical irregularities as convex and concave ridges as well as corners where the ridges meet. The existing unstructured grid generation approaches may fail or produce poor quality meshes in such geometrical regions. The proposed solution is based on special meshing of non‐slip body surfaces resulting in smooth and robust volume meshing and high overall quality of generated grids. Several examples demonstrate the efficiency of the method for complex 3‐D geometries. Copyright © 2003 John Wiley Sons, Ltd.
The jump component of the volatility structure of interest rate futures markets: An international comparison
Authors: Chiarella Carl , Tô Thuy‐Duong
Published: October 2003

We propose a generalization of the Shirakawa (1991) model to capture the jump component in fixed‐income
markets. The model is formulated under the Heath, Jarrow, & Morton (1992) framework, and allows the presence
of a Wiener noise and a finite number of Poisson noises, each associated with a time deterministic volatility function. We derive the evolution of the
futures price and use this evolution to estimate the model parameters via the likelihood transformation technique of Duan (1994). We apply the method to the short‐term futures contracts traded on CME, SFE, LIFFE, and TIFFE, and find that
each market is characterized by very different behavior. © 2003 Wiley Periodicals, Inc. Jrl Fut Mark 23:1125–1158, 2003