bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin‐12 and B7.1 co‐stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors
Authors: Zitvogel Laurence , Robbins Paul D. , Storkus Walter J. , Clarke Martha R. , Maeurer Markus J. , Campbell Ronna L. , Davis C. Geoffrey , Tahara Hideaki , Schreiber Robert D. , Lotze Michael T. 
Published: March 2007

AbstractInterleukin‐12 (IL‐12) promotes specific and long‐lasting anti‐tumor immunity mediated by T cells in a variety of murine tumor models. IL‐12 also synergizes with B7.1 (CD80) co‐stimulation to induce proliferation and cytokine production by both human and murine T cells in vitro. We evaluated the combined antitumor efficacy of IL‐12 and B7.1 gene delivery in two apparently poorly immunogenic tumor models (TS/A and MCA207). In both of these models, expression of B7.1 and production of IL‐12 in the inoculum led to improved anti‐tumor immunity, with up to 80% long‐term tumor‐free animals (vs 0– 20% of mice remaining tumor free when inoculated with either B7.1‐ or IL‐12‐transfected tumors alone). Tumor‐free mice were capable of rejecting a subsequent rechallenge with the wild‐type tumor in 66% of the cases. Cooperativity was dependent upon the level of IL‐12 secreted by engineered cells. IL‐12 delivery required B7 expression of therapeutic effects to be observed in these models. Vaccines provided at a site distal to a control, non‐transfected tumor slowed (TS/A) or abrogated (MCA207) the progression of wild‐type tumors. The synergistic anti‐tumor effects associated with combined application of B7.1‐ and IL‐12‐transfected tumors were partially negated by systemic administration of the CD28‐B7.1/B7.2 antagonist CTLA4‐Ig or by inoculation with neutralizing antibodies directed against murine interferon‐γ or tumor necrosis factor‐α, two cytokines elicited in response to IL‐12 stimulation. These data support the potential clinical utility of combined gene therapy using IL‐12‐ and B7.1‐engineered autologous cells (tumor or fibroblasts) as a vaccine to elicit specific anti‐tumor immunity.
T cell recognition of Tn‐glycosylated peptide antigens
Authors: Jensen Teis , Galli‐Stampino Luisa , Mouritsen Søren , Frische Klaus , Peters Stefan , Meldal Morten , Werdelin Ole 
Published: March 2007

AbstractThe mouse hemoglobin‐derived decapeptide Hb (67–76), VITAFNEGLK, which binds well to Ek and is non‐immunogenic in CBA/J mice, was O‐glycosylated with the tumor‐associated carbohydrate Tn (α‐D‐N‐acetylgalactosamine, or α‐D‐GalNAc). Each of the ten positions in the peptide was substituted with serine or threonine having the Tn antigen attached. The complete set of Tn‐glycosylated peptides were then studied for binding to Ek and for immunogenicity in CBA/J mice. All of those glycopeptides which had the Tn attached to serine or threonine at a position in the peptide where, according to the crystal structure determinations, the amino acid side chain was oriented downwards into the binding site of the major histocompatibility complex (MHC) molecule, completely lost their capacity for binding to Ek. This was the case for the glycopeptides with Tn attacted at position 68 and 76, which are the major anchor residues and for those with Tn attached at position 71 and 73, which function as secondary anchor residues. Those glycopeptides which had Tn attached to serine or threonine at positions where the side chain pointed away from the binding site maintained their capacity for binding to Ek, except for those with Tn attached at position 70 and 74. Furthermore, some of the MHC‐binding glycopeptides were immunogenic. In particular, this was the case for the glycopeptide with Tn attached to the central position 72 in the decapeptide. From previous studies, this is known to be the dominant T cell receptor contact residue of Hb (67–76). The results suggest that T cells may be capable of recognizing epitopes which are partially defined by a small glycan group.
Human epidermal keratinocytes are induced to secrete interleukin‐6 and co‐stimulate T lymphocyte proliferation by a CD40‐dependent mechanism
Authors: Gaspari Anthony A. , Sempowski Gregory D. , Chess Patricia , Gish Julia , Phipps Richard P. 
Published: March 2007

AbstractAlthough the expression and function of CD40 on B lymphocytes has been well studied, the significance of CD40 on non‐lymphoid cells such as keratinocytes (KC) is not as well characterized. We demonstrate in this report that CD40 is expressed by virtually all human KC, and that it functions as an important signaling molecule. Flow cytometry of undifferentiated and terminally differentiated KC indicated that both cell types expressed CD40, as determined by binding to monoclonal antibodies and a recombinant CD40 ligand fusion protein; interferon‐γ (IFN‐γ) treatment of KC increased CD40 expression. Cultured KC also expressed 1.5‐kb CD40 transcripts. Activation of KC cell surface CD40 using the monoclonal antibody G28.5 resulted in the rapid generation of a 50‐kDa tyrosine phosphorylated polypeptide, as well as a dose‐dependent increase in the secretion of interleukin‐6, a cytokine that has been linked to KC proliferation. KC also co‐stimulated a significant T lymphocyte proliferative response to the mitogen phytohemagglutinin that was CD40 dependent. These data indicate that KC constitutively express a low level of functional CD40 and regulate their expression in response to IFN‐γ. These data support the concept that KC, via their expression of CD40, have the capacity to amplify inflammation in the skin by interacting with CD40 ligand‐bearing T cells.
Detection of primary direct and indirect human anti‐porcine T cell responses using a porcine dendritic cell population
Authors: Dorling Anthony , Lombardi Giovanna , Binns Richard , Lechler Robert I. 
Published: March 2007

AbstractThe pathways of human anti‐pig T cell xenorecognition have been investigated. Freshly isolated porcine alveolar lavage (AL) cells induced primary proliferative responses by human peripheral and cord blood mononuclear cells which were inhibited by anti‐HLA‐DR antibody (indirect xenorecognition). Following overnight culture, the AL cells acquired the capacity to stimulate proliferation by purified human T cells which was inhibited by anti‐SLA‐DR antibody (direct xenorecognition). The marked increase in immunogenicity in the porcine AL cells was accompanied by a phenotypic change consistent with dendritic cell maturation. Limiting dilution assays indicate that the total anti‐pig T cell response, in particular that mediated by indirect xenorecognition, is stronger than comparable alloresponses.
Contribution of interleukin‐3 to antigen‐induced Th2 cytokine production
Authors: Aoki Ichiro , Tanaka Shun‐Ichi , Ishii Norihisa , Minami Mutsuhiko , Klinman Dm 
Published: March 2007

AbstractShort‐term stimulation of mouse spleen cells in vitro with interleukin (IL)‐3 induces the secretion of the Th2 cytokines IL‐4 and IL‐6. Non‐B/non‐T cells were the target of this IL‐3 effect. However, during long‐term antigen‐dependent culture, T cells are the major source of IL‐4 and IL‐6. The addition of IL‐3 to such cultures also led to a significant increase in IL‐4 and IL‐6 production. This Th2 cytokine secretion was amplified by the addition of irradiated non‐B/non‐T cells at the initiation of culture, and was inhibited by anti‐IL‐4 antibodies. These findings suggest that IL‐3 induces the rapid release of IL‐4 and IL‐6 by non‐B/non‐T cells, thereby creating an immune milieu conducive to the development of antigen‐specific IL‐4 and IL‐6‐secreting Th2 cells.
Existence of a small population of IL‐2Rβhi TCRint cells in SCG and MRL‐lpr/lpr mice which produce normal Fas mRNA and Fas molecules from the lpr gene
Authors: Yamagiwa Satoshi , Kuwano Yuh , Hasegawa Katsuhiko , Sato Kazunari , Ohtsuka Kazuo , Iiai Tsuneo , Tomiyama Katsuhiro , Watanabe Hisami , Sugahara Satoshi , Seki Shuhji , Asakura Hitoshi , Abo Toru 
Published: March 2007

AbstractMice carrying the lpr gene, SCG and MRL‐lpr/lpr mice, were used to characterize the phenotype and lpr gene of abnormally proliferating T cells in these mice. A major population which expanded in these mice were T cells expressing intermediate (int) levels of T cell receptor (TCR) (and CD3) and the phenotype of interleukin‐2 receptor (IL‐2R)βlo α− (possibly abnormal TCRint cells). The levels of TCRhi cells of thymic origin (generated through the mainstream of T cell differentiation in the thymus) profoundly decreased after the onset of disease. However, a small population of normal TCRint cells (i.e. IL‐2Rβhi α−) were also found to exist in all tested organs. For example, the majority of abnormal IL‐2Rβlo TCRint cells were CD4−8− CD2−, while normal IL‐2Rβhi TCRint cells were a mixture of single‐positive cells (mainly CD8+), CD4−8− cells and CD2+ cells. Moreover, normal TCRint cells preferentially produced normal Fas mRNA and Fas molecules from the lpr gene. This phenomenon explains the leaky appearance of normal Fas mRNA and Fas molecules in mice carrying the lpr gene. It is suggested that a small population of IL‐2RβhiTCRint cells are resistant to the lpr genetic abnormality.
Selective suppression of endothelial cell activation by arachidonic acid
Authors: Stuhlmeier Karl M. , Tarn Chi , Csizmadia Vilmos , Bach Fritz H. 
Published: March 2007

AbstractEndothelial cell (EC) activation plays a key role in inflammation, thrombosis and organ rejection. Normally, EC are in a quiescent state in which their function is to prevent coagulation and thrombosis, and to participate in the regulation of leukocyte migration from the bloodstream into the tissue. Upon activation with cytokines or other stimuli, EC up‐regulate a number of genes, including E‐selectin (ELAM‐1), intercellular adhesion molecule (ICAM)‐1, vascular cell adhesion molecule (VCAM)‐1, interleukin (IL)‐1, IL‐8, tissue factor (TF), plasminogen activator inhibitor‐1 (PAI‐1), MCP‐1 (monocyte chemoattractant protein‐1) and endothelial cell inducible gene (ECI‐6). Arachidonic acid (AA) is produced by several cell types, including EC, and acts on various cells. We report here that AA inhibits the up‐regulation of some, but not all genes that are induced with EC activation in a dose‐dependent manner. AA suppresses TNF‐α, IL‐1α, LPS or PMA‐induced E‐selectin expression, as well as mRNA accumulation of E‐selectin, ICAM‐1 and IL‐8 stimulated by TNF‐α. The inhibition appears to be at the level of transcription. At the same time under the same conditions AA does not, repress mRNA accumulation for PAI‐1, ECI‐6, MCP‐1 and VCAM‐1. We suggest that the induced expression of AA with EC activation may result in a negative feedback loop regulating further activation.
Mouse γδ TCR+NK1.1+ thymocytes specifically produce interleukin‐4, are major histocompatibility complex class I independent, and are developmentally related to αβ TCR+NK1.1+ thymocytes
Authors: Vicari Alain P. , Mocci Simonetta , Openshaw Peter , O'Garra Anne , Zlotnik Albert 
Published: March 2007

AbstractMouse T cells co‐expressing an αβ T cell receptor (TCR) and the NK1.1 antigen have been shown to be major interleukin (IL)‐4‐producing cells and could therefore regulate cell‐mediated immune responses. We have identified a related subset of thymocytes co‐expressing a γδ TCR and NK1.1 which also produce IL‐4. Unlike αβ+NK1.1+ thymocytes, the selection of γδ+NK1.1+ thymocytes is not dependent upon β2‐microglobulin (β2m)‐associated class I molecule expression because these cells are present in β2m‐deficient mice. This suggests that γδ+NK1.1+ T cells may regulate immune responses to a different variety of antigens. However, the development of αβ+NK1.1+ and αβ+NK1.1+ thymocytes appears to be related. Analysis of different mutant mice lacking αβ+NK1.1+ thymocytes revealed a specific increase in γδ+NK1.1+ thymocyte production when the block in αβ+NK1.1+ thymocyte differentiation occurs after β TCR rearrangement.
Functional CD40 ligand expression on T lymphocytes in the absence of T cell receptor engagement: involvement in interleukin‐2‐induced interleukin‐12 and interferon‐γ production
Authors: Armant Myriam , Armitage Richard , Boiani Norman , Delespesse Guy , Sarfati Marika 
Published: March 2007

AbstractDespite the fact that the great majority of T cells at the site of an inflammatory response are not antigen specific, the mechanisms leading to activation and recruitment of these bystander T cells are poorly understood. We previously reported that soluble (s)CD23 potentiated the interleukin (IL)‐2‐induced interferon (IFN)‐γ production by T cells co‐cultured with autologous monocytes in the absence of T cell receptor (TCR) engagement. Our present data demonstrate that the IL‐2‐induced IFN‐γ secretion, in the presence but also in the absence of sCD23, is strictly IL‐12 dependent, inasmuch as anti‐IL‐12 antibody abrogated both responses. Most interestingly, anti‐CD40 ligand (CD40L) monoclonal antibody significantly inhibited IL‐2‐induced IL‐12 as well as IFN‐γ production. These results suggest that CD40L was expressed on T cells in the absence of TCR engagement. Indeed, purified unstimulated T cells readily expressed CD40L. IL‐2 and monocytes did not up‐regulate CD40L on resting T cells. It is proposed that low levels of CD40L expression on non‐antigen stimulated T cells are sufficient to signal through CD40 molecules on accessory cells and to induce IL‐12 secretion, which in turn can synergize with IL‐2 for the induction of IFN‐γ production, thus contributing to the inflammatory process.
Homocysteine modification of HLA antigens and its immunological consequences
Authors: Gao Xiao‐Ming , Wordsworth Paul , McMichael Andrew J. , Kyaw Myo M. , Seifert Martin , Rees David , Dougan Gordon 
Published: March 2007

AbstractHomocysteine‐treated cells can be specifically lysed by cytotoxic T lymphocytes (CTL) identifiable in patients with ankylosing spondylitis and reactive arthritis. Sensitization of target cells involves disulfide bonding and the interaction between homocysteine and HLA antigens occurs in a pre‐Golgi compartment in the cells. Salmonella‐infected B cells are also lysed by homocysteine‐specific CTL, suggesting that intracellular invading microorganisms may provide homocysteine which would gain access to the newly synthesized intracellular HLA molecules and modify them inside the cells. Two different mechanisms for homocysteine modification of HLA antigens are proposed: homocysteine could bind directly to the unpaired cysteine residues in HLA antigens, or it could bind indirectly to HLA antigens through cysteine‐containing peptides bound to them. Thus, HLA antigens containing unpaired cysteine residues (e.g. HLA B27) could be modified by homocysteine directly or indirectly, while HLA antigens without unpaired cysteine residues (e.g. HLA A68) could only be modified indirectly. The results are discussed in relation to the potential involvement of homocysteine‐specific CTL in ankylosing spondylitis and reactive arthritis, both of which are related to bacterial infections, associated with HLA B27, and considered to be autoimmune diseases.
T cell activation by concanavalin A in the presence of cyclosporin A: immunosuppressor withdrawal induces NFATp translocation and interleukin‐2 gene transcription
Authors: Bemer Véronique , Truffa‐Bachi Paolo 
Published: March 2007

AbstractCyclosporin A (CSA), an immunosuppressive agent used in organ transplantation and to treat some autoimmune diseases, blocks the Ca2+‐dependent steps involved in T cell receptor triggering leading to interleukin (IL)‐2 production. Considering that the early steps of T cell activation are insensitive to CSA, we asked whether the initial activation achieved in presence of this immunosuppressor could affect the capacity of the T cell to respond to a mitogenic restimulation. We found that T cells activated by concanavadin A (ConA) for 48 h in the presence of CSA retain the capacity to proliferate in response to ConA once the immunosuppressor is removed. These cells are able to transcribe anew the IL‐2 gene, without the requirement of new protein synthesis, and to up‐regulate the α chain of the IL‐2 receptor. Furthermore, we present the first direct evidence that the nuclear factor AP‐1 is present in the nucleus of the T cells primed for 48 h in presence of CSA and that withdrawal of the immunosuppressor leads to the translocation of NFATp from the cytoplasm to the nucleus.
Altered expression of host‐encoded complement regulators on human cytomegalovirus‐infected cells
Authors: Spiller O. Brad , Morgan B. Paul , Tufaro Frank , Devine Dana V. 
Published: March 2007

AbstractHuman cytomegalovirus (HCMV)‐infected cells persist in the presence of anti‐HCMV antibody, suggesting that HCMV has evolved mechanisms to evade host immune defenses. Insofar as no virus‐encoded complement inhibitors have been identified for HCMV, we hypothesized that HCMV infection may alter the expression of host‐encoded cell surface complement inhibitors. Herein, we report that cell surface expression of two complement regulator proteins, CD55 and CD46, which are members of the regulators of complement activation (RCA) gene cluster, increased up to eightfold following infection of fibroblasts or glioblastoma cells with HCMV, but not after infection with HSV‐1 or adenovirus. However, the cell surface expression of a third complement regulator, CD59, which is not a member of the RCA gene cluster, was not altered during HCMV infection. Functional studies using purified complement components demonstrated that up‐regulation of CD55 suppressed the activity of cell‐associated C3 convertases on HCMV‐infected cells. Furthermore, increased CD55 expression protected infected cells from complement‐mediated lysis, an effect which directly correlated with the length of HCMV infection. Increased expression of host‐encoded complement regulator proteins may provide protection of HCMV‐infected cells from the host immune response in vivo, through increasing the resistance of infected cells to complement‐mediated lysis and decreasing the deposition of C3‐derived products on the cell surface.
A tyrosine‐phosphorylated 110–120‐kDa protein associates with the C‐terminal SH2 domain of phosphotyrosine phosphatase‐1D in T cell receptor‐stimulated T cells
Authors: Frearson Julie A. , Yi Taolin , Alexander Denis R. 
Published: March 2007

AbstractThe role of cytosolic phosphotyrosine phosphatases (PTPase) in T cell receptor (TCR)‐mediated signaling was investigated. PTPase activity was detected in a purified immunocomplex comprising aggregated TCR from the cell surface of Jurkat T cells. Since TCR aggregation results in phosphorylation of critical immunoreceptor tyrosine‐based activation motifs (ITAM) in the TCR ζ chain, a doubly tyrosine‐phosphorylated synthetic peptide containing the membrane‐proximal ζ chain ITAM (ζp ITAM) was used to characterize TCR ζ‐associated PTPases. PTPase activity was detected in stable association with ζp ITAM and the SH2 domain‐containing PTPase PTP‐1D (Syp, SH‐PTP2) was identified in this complex. TCR stimulation resulted in increased total PTPase activity and PTP‐1D protein in ζp ITAM precipitates. TCR stimulation did not result in the tyrosine phosphorylation of PTP‐1D but caused the rapid and transient tyrosine phosphorylation of a 110–120‐kDa protein which associated selectively with the C‐terminal SH2 domain of PTP‐1D. This currently unidentified phosphotyrosine protein may be involved in localizing PTP‐1D to the TCR following receptor stimulation.
Detection of C5a receptors on human eosinophils and inhibition of eosinophil effector functions by anti‐C5a receptor (CD88) antibodies
Authors: Elsner Jörn , Oppermann Martin , Kapp Alexander 
Published: March 2007

AbstractEosinophils and complement activation are reported to play a crucial role in the pathogenesis of connective tissue diseases. Depositions of antigens and antigen‐antibody complexes lead to complement activation with the generation of anaphylatoxins, particularly C5a, which is thought to be responsible for the infiltration and activation of eosinophils in the tissue. Previous studies suggested that the eosinophil C5a receptor differs structurally from the receptor expressed on neutrophils. In this study, we investigated the expression and functional properties of C5a receptors on human eosinophils using the C5a receptor monoclonal antibody S5/1 (anti‐CD88 mAb). Flow cytometric analysis demonstrated that the anti‐CD88 mAb bound homogeneously on the surface of human eosinophils from nonatopic healthy donors. In addition, no subpopulations with respect to C5a receptor expression were identified in normodense or hypodense eosinophils of patients with hypereosinophilia. Pre‐incubation of eosinophils with anti‐CD88 specifically inhibited C5a‐induced intracellular calcium concentration transients. C5a‐induced chemotactic activity of eosinophils was significantly inhibited after pre‐incubation of cells with anti‐CD88 mAb in a dose‐dependent manner. Furthermore, anti‐CD88 mAb inhibited dose‐dependently the release of reactive oxygen species by eosinophils following stimulation with C5a. Thus, the human eosinophil C5a receptor is homogeneously expressed on normal eosinophils from healthy donors as well as on hypodense and normodense eosinophil subpopulations from patients with hypereosinophilia. Based on the inhibitory effect of the S5/1 mAb on C5a‐stimulated eosinophil effector functions, we conclude that a single C5a receptor type exists on human eosinophils. In addition, the inhibitory effect of the S5/1 mAb on C5a functions may enable a new experimental approach to the treatment of diseases that have been associated with C5a‐mediated activation.
Differential regulation of monocytic tumor necrosis factor‐α and interleukin‐10 expression
Authors: Meisel Christian , Vogt Katrin , Platzer Cornelia , Randow Felix , Liebenthal Christa , Volk Hans‐Dieter 
Published: March 2007

AbstractActivation of human monocytes by bacterial endotoxin (LPS) results in an initial burst of inflammatory cytokines like tumor necrosis factor (TNF)‐α which is followed by the secretion of anti‐inflammatory mediators like interleukin (IL)‐10. The signaling pathways in IL‐10 induction are unknown. Here, we show that the regulation of IL‐10 expression is more complex than that of TNF‐α. LPS‐induced TNF‐α and IL‐10 expression requires early activation of protein tyrosine kinases (PTK). Moreover, delayed addition of PTK inhibitors blocked IL‐10, but not TNF‐α, suggesting the impact of a late PTK activity. Two inducers of PTK activity are the downstream mediators of LPS activation, TNF‐α and cyclic adenosine monophosphate (cAMP). Both mediators synergistically up‐regulate IL‐10 expression. Downstream of PTK activation, they use distinct pathways. TNF‐α, but not cAMP‐induced IL‐10 gene expression was inhibited by pyrrolidine dithiocarbamate, suggesting the involvement of reactive oxygen species. Inhibition of protein kinase C (PKC) suppressed LPS‐induced TNF‐α and IL‐10 expression as well, but, unlike TNF‐α, direct activation of PKC by phorbol 12‐myristate 13‐acetate (PMA) did not induce IL‐10 expression. Furthermore, PKC is not involved in late events of IL‐10 activation, as delayed addition of PKC inhibitors did not suppress LPS‐induced IL‐10 expression and did not influence cAMP‐ or TNF‐α‐induced IL‐10. The modulation of IL‐10 expression by inflammatory mediators suggests a regulatory circuit of the inflammatory response.