bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional discrepancies between tumor necrosis factor and lymphotoxin α explained by trimer stability and distinct receptor interactions
Authors: Schuchmann Marcus , Hess Sigrun , Bufler Philip , Brakebusch Cord , Wallach David , Porter Alan , Riethmüller Gert , Engelmann Hartmut 
Published: March 2007

AbstractTumor necrosis factor (TNF) and lymphotoxin α (LTα) are closely related cytokines which bind with nearly identical affinities to the same pair of cell surface receptors, p55 and p75TNFR. Therefore it is assumed that TNF and LTα are redundant cytokines. This study, however, demonstrates that TNF and LTα differ significantly with regard to their mitogenic and cytotoxic potentials. LTα's superior mitogenic effect could be explained by its formation of a more stable trimer. In contrast to the TNF trimer, which disintegrated under physiological conditions into biologically inactive monomers, the LTα trimer remained stable for several days. Accordingly, LTα more effectively induced fibroblast growth which demands long‐term presence of the cytokine. TNF's superior cytotoxicity, which requires only short‐term impact of the cytokine, could be attributed to a distinct interaction with the human p55TNFR. This was demonstrated in NIH 3T3 cells transfected with the human p55TNFR, where cytotoxicity is mediated exclusively by the transfected receptor. Although the p55TNFR had virtually identical affinities for TNF and LTα, as defined by Scatchard analysis, it nevertheless discriminated between binding of each cytokine and showed a 200‐fold enhanced cytotoxicity mediated by TNF.
Plasma cell tumors decrease CD23 mRNA expression in vivo in murine splenic B cells
Authors: Ruzek Melanie C. , Mathur Ambika 
Published: March 2007

AbstractCD23, the low‐affinity Fc receptor for IgE, is constitutively expressed on mature, naive B cells, but is lost following B cell activation. We and others have shown that CD23 expression on B cells decreases in mice bearing plasma cell tumors. In contrast to these findings, we find that IgE‐secreting tumors do not cause a loss of CD23 expression on host splenic B cells. Decreased expression of CD23 on B cells induced by plasma cell tumors requires direct contact between tumor cells and B cells; and other host cells are not involved. The loss of surface CD23 expression is associated with a decrease in steady‐state CD23 mRNA levels in B cells from plasma cell tumor‐bearing mice. Interestingly, loss of CD23 mRNA is observed even in B cells from mice with IgE‐secreting tumors, where we find surface CD23 protein expression to be similar to that of normal mice. The maintenance of surface CD23 expression on B cells in mice with IgE‐secreting tumors is dependent solely on the presence of IgE, and is not a tumorspecific effect. Therefore, we conclude that in vivo, IgE secreted by plasma cell tumors can result in the maintenance of normal levels of surface CD23 expression by a post‐transcriptional mechanism, even when the tumor induces a down‐regulation of CD23 mRNA levels.
Immunosuppression by Fc region‐mismatched anti‐T cell antibody treatment
Authors: Thierfelder Stefan , Mocikat Ralph , Mysliwietz Josef , Lindhofer Horst , Kremmer Elisabeth 
Published: March 2007

AbstractFormation of anti‐antibodies (anti‐Ab) is known to counteract immunotherapy with anti‐T cell antibodies. Our previously described immunological approach prevented anti‐Ab with the consequence of prolonged survival of fully mismatched skin grafts in C57BL/6 mice. These mice were treated with a single priming injection of a monoclonal anti‐T cell Ab followed by repeated injections of anti‐T cell mAb differing in species origin from the priming mAb. We now show prolonged tolerance to discordant xenogeneic, to bispecific, and even to polyclonal Ab, and demonstrate that the underlying immunosuppressive principle is due to a difference in heavy chain constant region between first and second antibodies, independent of whether or not they share the same idiotype. To examine this phenomenon, a panel of mAb was generated which share the same mouse anti‐Thy‐1.2 idiotype, but carry a human IgG1(T23), IgG3(T212C8), or mouse IgG2a(MmT1) constant heavy chain region. We found that sequential injection of MmT1 and T23 according to the above treatment schedule induced huIgG1 isotype‐specific tolerance to T23, which was similar to that seen when using a primary mAb (MmT5) that was, instead, fully mismatched with T23 in both idiotype and constant region. Thus, differences of idiotype between primary and booster Ab were inconsequential for their ability to inhibit anti‐Ab formation. This novel form of induced specific tolerance to anti‐T cell Ig survived graft rejection and was still evident 230 days after termination of the T cell depletion protocol. Taken together, these results demonstrate that rechallenge with Fc region‐mismatched Ab opens an immunological window that allows for induction of tolerance to immunogenic anti‐T cell Ab and prolonged immunosuppression.
Interleukin‐12 increases interleukin‐4 production by established human ThO and Th2‐like T cell clones
Authors: Jeannin Pascale , Delneste Yves , Life Paul , Gauchat Jean‐François , Kaiserlian Dominique , Bonnefoy Jean‐Yves 
Published: March 2007

AbstractInterleukin (IL)‐12 is a potent inducer of cell‐mediated immunity: it favors the generation of interferon (IFN)‐γ‐producing T cells, increases IFN‐γ production by T cells and natural killer cells and prevents the generation of a Th2 response in murine in vivo models. Nevertheless, the effects of IL‐12 on an established Th2 response remain poorly documented. In the present paper, we analyzed the effect of IL‐12 on the profile of lymphokines produced by established IL‐4‐producing Th0 and Th2‐like human T cell clones (TCC) and by polyclonal T cells. We found that IL‐12 (i) enhances, as previously reported, IFN‐γ production by Th0 TCC and, to a smaller extent, by Th2‐like TCC, (ii) increases the proliferation of Th0 and Th2‐like TCC and (iii) unexpectedly, synergizes with T cell receptor‐associated or nonspecific stimuli in increasing IL‐4 production by these TCC. Thus, IL‐12 potentiates the production of IFN‐γ and also of IL‐4 by established IL‐4‐producing TCC. Although IL‐12 has been widely reported to induce a Th1 response and to prevent the development of a Th2 response in vivo, IL‐12 may on the contrary potentiate an established Th2 response in humans.
Regulation of cell surface APO‐1/Fas (CD95) ligand expression by metalloproteases
Authors: Mariani Sara M. , Matiba Bernd , Bäumler Caroline , Krammer Peter H. 
Published: March 2007

AbstractAPO‐1/Fas (CD95) ligand (APO‐1L) induces apoptosis in sensitive target cells. Activation‐induced T cell death and Ca2+‐independent cytotoxicity in perforin knockout mice are mediated by APO‐1L. To define whether APO‐1L is expressed on the surface of activated T cells and to investigate the mechanisms leading to the release of a soluble form, we developed rabbit anti‐APO‐1L antibodies (Ab). The purified rabbit Ab detected the mature forms of the human and mouse APO‐1L of approximately 42 and 40kDa. In addition, the Ab recognized the non‐glycosylated form of APO‐1L of approximately 32‐33 kDa. In activated human T cells, the soluble form of APO‐1L was detectable with a moleculas mass of 26 kDa. Immunofluorescence of three human T lymphoblastoid cell lines showed that activation of these cells by phorbol 12‐myristate 13‐acetate/ionomycin induced a significant increase in cell surface APO‐1L only in the presence of metalloprotease inhibitors. Zn2+, but not Ca2+, prevented the increase in surface APO‐1L observed in the presence of 1,10‐phenanthroline. Blocking of other classes of proteases (serine‐ and acid‐proteases, chymotrypsin) had no effect. Increased expression of surface APO‐1L by metalloprotease inhibitors was not dependent on T cell activation, as the metalloprotease inhibitors also modulated the low level of constitutive APO‐1L expression. These results suggest that cell surface expression of human APO‐1L is regulated by Zn2+‐dependent metalloproteases. Cleavage of surface APO‐1L may act as a regulatory mechanism to prevent accumulation of the membrane‐bound form and may cause systemic effects of the APO‐1L.
Experimental gene therapy of cancer using tumor cells engineered to secrete interleukin‐13
Authors: Lebel‐Binay Sophie , Laguerre Brigitte , Quintin‐Colonna Françoise , Conjeaud Hélène , Magazin Marilyn , Miloux Brigitte , Pecceu Florence , Caput Daniel , Ferrara Pascual , Fradelizi Didier 
Published: March 2007

AbstractCytokines locally delivered to the site of a tumor boost both specific and nonspecific host anti‐tumor defenses. Interleukin (IL)‐13 is a recently described cytokine produced by mouse type 2 helper T lymphocytes. The aim of this study was to evaluate the inhibition of tumor growth induced by IL‐13 delivered locally within or around transplanted tumor cells in mice. We observed that local administration of IL‐13 at the site of transplanted tumor cells in vivo had potent inhibitory effects on growth of both immunogenic (P815 mastocytoma, H‐2d) or nonimmunogenic (3LL lung carcinoma, H‐2b) tumor cells. Mice injected with transfected P815 cells secreting large amounts of IL‐13 rejected the P815 tumor and developed systemic specific anti‐tumor immunity leading to long‐lasting specific anti‐tumor protection. Less efficient anti‐tumoral effects were obtained with the nonimmunogenic 3LL tumor model when local administration of IL‐13 was achieved by co‐inoculating xenogeneic chinese hamster ovary (CHO) IL‐13 cells. Several local injections of CHO IL‐13 cells were needed to obtain rejection of 3LL tumors and no induction of long‐lasting anti‐3LL memory was obtained. Several studies were performed to elucidate the IL‐13 anti‐tumoral effects. Experiments with nude mice indicated that IL‐13 can also stimulate nonspecific anti‐tumor defenses. The histological examination of P815 IL‐13 cells undergoing rejection showed monocytic cells and neutrophils infiltrating the tumor. Studies indicated that IL‐13 administered in vitro did not directly stimulate the cytotoxicity of peritoneal macrophages and natural killer cells. However, experiments with Boyden chemotaxis chambers indicated that IL‐13 was chemotactic for macrophages. Finally, preliminary experiments in vitro suggest that IL‐13 improved antigenic presentation of P815 membranes. Thus, anti‐tumor effects of IL‐13 in vivo most probably result from pleiotropic effects including recruitment of nonspecific cells and improved stimulation of immune‐specific anti‐tumor effectors.
Follicular dendritic cells and the maintenance of IgE responses
Authors: Helm Shirley L. T. , Burton Gregory F. , Szakal Andras K. , Tew John G. 
Published: March 2007

AbstractAntigen (Ag) is retained for long periods of time in secondary lymphoid tissues in the form of immune complexes on follicular dendritic cells (FDC). Ag retained on FDC is thought to play a role in maintaining antibody (Ab) responses in vivo. A model for study of Ab production induced by retained Ag in vitro is the spontaneous Ab response. In this response, specific Ab production is induced spontaneously (no exogenous Ag needed) in cultures derived from secondary lymphoid tissues containing persisting Ag. Specific IgG is spontaneously induced and we reasoned that FDC may also play a role in the maintenance of specific IgE responses. To test this hypothesis, we monitored spontaneous antiovalbmin (OVA) IgE production in cultures of lymph node (LN) fragments from OVA‐immunized mice. In addition, highly enriched preparations of OVA bearing FDC were added to OVA‐specific memory cells in an attempt to stimulate OVA‐specific IgE production. Months after secondary immunization, anti‐OVA IgE responses were spontaneously induced when fragments from draining LN were placed into culture. Furthermore, FDC bearing OVA from draining LN induced anti‐OVA IgE production when incubated with spleen cells from OVA‐immune mice whereas identical cultures with FDC bearing environmental Ag from non‐draining LN of the OVA immune animals did not. The anti‐OVA IgE responses were elicited only in cultures containing OVA‐immune memory cells indicating that specific memory cells were critical for these anti‐OVA IgE responses. Removal of FDC from cultures with an FDC‐specific mAb dramatically decreased anti‐OVA IgE production. These studies demonstrate that FDC can induce specific memory T and B cells to produce IgE and help support the concept that FDC‐associated antigen may be involved in the long‐term maintenance of specific IgE responses.
Reciprocal homologous recombination in or near antibody VDJ genes
Authors: Umar Asad , Gearhart Patricia J. 
Published: March 2007

AbstractTo determine if rearranged heavy chain variable (VDJ) genes can recombine with each other by crossing over of DNA strands, we constructed a transgene that contained a promoter, VDJ gene, reporter gene to detect crossover events, intron enhancer, matrix attachment region, and constant gene for IgM (Cμ). Following immunization of transgenic mice, hybrid molecules were isolated from B cell DNA which contained the transgene recombined with the endogenous IgH locus. Reciprocal products of crossovers were detected by plasmid rescue and PCR amplification, and they were sequenced. Recombination occurred somewhere within 147 bp of homology that contained the JH4 gene segment and 3′ flanking DNA. The recombined transgenes had a 20‐fold increase in mutation in the VDJ region compared to nonrecombined transgenes, which indicates that DNA sequences 3′ of the Cμ gene in the endogenous IgH locus are necessary for full activity of the mutator mechanism. The recovery of recombinants between VDJ transgenes and endogenous VDJ genes raises the possibility that reciprocal recombination may somatically diversify rearranged genes between maternal and paternal alleles.
Monoclonal nonspecific suppressor factor β inhibits interleukin‐4 secretion by a type‐2 helper T cell clone
Authors: Nakamura Morihiko , Xavier Ricardo M. , Tanigawa Yoshinori 
Published: March 2007

AbstractMonoclonal nonspecific suppressor factor (MNSF) is a lymphokine product of a murine T cell hybridoma that inhibits the generation of lipopolysaccharide‐induced immunoglobulin secreting cells in an antigen‐nonspecific manner. Most recently, a cDNA clone encoding MNSFβ, a subunit of MNSF, was isolated and sequenced (Nakamura et al., Proc. Natl. Acad. Sci. USA 1995. 92: 3463). The MNSFβ cDNA encodes a 14.5‐kDa ubiquitin‐like protein showing several MNSF activities. We have previously observed that hybridoma‐derived native MNSF can inhibit interleukin (IL)‐4 secretion by bone marrow‐derived mast cells. Therefore, we studied whether MNSFβ is also able to inhibit IL‐4 secretion by the type‐2 helper T cell clone D10. G4.1. MNSFβ inhibited both the IL‐4 secretion and the proliferation of concanavalin A‐activated D10 cells, although neither effect was complete.
CD40‐mediated lymphotoxin α expression in human B cells is tyrosine kinase dependent
Authors: Worm Margitta , Geha Raif S. 
Published: March 2007

AbstractThe cytokine lymphotoxin (LT)α is known to play a role in B cell activation. As the engagement of the B cell antigen CD40 is known to lead to B cell proliferation and differentiation, we studied LTα expression in human B cells after CD40 ligation. We demonstrate that anti‐CD40 monoclonal antibody (mAb) induces strong LTα mRNA and surface expression in human tonsil B cells. Induction of LTα mRNA and surface expression by CD40 ligation is inhibited by the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein in a dose‐dependent manner. The protein kinase C (PKC)‐specific inhibitors sphingosine and bisindolylmaleimide caused negligible inhibition of anti‐CD40‐induced LTα mRNA and surface expression. No inhibition is observed with the protein kinase (PKA) inhibitors H89 and HA1004. Cross‐linking of the transmembrane phosphatase CD45 to CD40 by using goat‐anti‐mouse F(ab')2 fragments strongly inhibits CD40‐mediated LTα expression in human B cells, confirming the role of PTK activation in CD40‐mediated induction of LTα expression. Inhibitors of the serine/threonine protein phosphatases PP1 and PP2A, okadaic acid and calyculin induce LTα mRNA expression. In contrast, cyclosporin A, an inhibitor of the serine/threonine phosphatase calcineurin has no effect on anti‐CD40‐induced LTα expression. These results suggest that induction of LTα expression in B cells following engagement of CD40 involves activation of protein tyrosine kinases.
Differential effects of interleukin‐10 on the expression of HLA class II and CD1 molecules induced by granulocyte/macrophage colony‐stimulating factor/interleukin‐4
Authors: Thomssen Henrike , Kahan Melvyn , Londei Marco 
Published: March 2007

AbstractInterleukin (IL)‐10 down‐regulates HLA class II molecules, whether constitutively expressed or up‐regulated by interferon‐γ or IL‐4 on monocytes but not on B lymphocytes. In this study we show that IL‐10 does not inhibit HLA class II expression induced by the combination granulocyte/macrophage colony‐stimulating factor and IL‐4 on monocytes, although it simultaneously abrogates the expression of CD1 molecules induced by the same combination of cytokines. CD1 molecules can act as element of genetic restriction for CD4− CD8− T lymphocytes, and the suppression of CD1 expression by IL‐10 abolished antigen presentation to CD1‐restricted CD4− CD8− T cell receptor‐positive T cells. Although HLA class II expression was not down‐regulated by IL‐10, the antigen specific proliferative response of CD4+ T cells was nevertheless decreased. This was not caused by down‐regulation of known co‐stimulatory molecules such as B7.1, B7.2 and ICAM‐1. IL‐10 decreased the antigen specific proliferative response further by directly influencing the T lymphocytes. Our results indicate that IL‐10 exerts some of its immunoregulatory functions by differential modulation of antigen presenting molecules, induced by the same combination of cytokines.
Peptide‐specific activation of cytolytic CD4+ T lymphocytes against tumor cells bearing mutated epitopes of K‐ras p21
Authors: Abrams Scott I. , Dobrzanski Mark J. , Wells Donald T. , Stanziale Stephen F. , Zaremba Sam , Masuelle Laura , Kantor Judith A. , Schlom Jeffrey 
Published: March 2007

AbstractAlterations in the ras p21 protein have been associated with both rodent and human neoplasia. Thus, mutated ras p21 proteins may bear unique antigenic epitopes for immune recognition, such as by T cells, which have been implicated in host antitumor activity. Synthetic peptides that mimic segments of mutated ras p21 have been reported to be immunogenic in mice in vivo, although detailed functional analyses remains undefined. Here, in a murine model, we explored and characterized distinct effector properties of host‐derived T lymphocytes reactive to mutated ras peptides, which was consistent with the CD4+ T helper type 1 (Th1) subset. BALB/c mice (H‐2d) were immunized with a purified peptide, 13 amino acids in length, containing the substitution of Gly (G12) to Val (V12) at position 12, which is commonly found in human carcinomas. An αβ T cell receptor‐positive, CD3+, CD4+, CD8− T cell line was established, which expressed peptide‐specific proliferation. Cytokine assays revealed the production of interleukin‐2, interferon‐γ, tumor necrosis factor and granulocytemacrophage colony‐stimulating factor. Moreover, antigen‐specific cytotoxicity was demonstrable against: (1) Iad‐bearing A20 tumor cells incubated with exogenously bound V12 peptide; and (2) A20 tumor cells transduced with the K‐ras p21 oncogene encoding the corresponding point mutation. CD4+‐mediated cytotoxicity was major histocompatibility complex (MHC) class II‐restricted, as revealed by the absence of lysis against MHC class II− P815 targets, inhibition of A20 lysis with anti‐Iad monoclonal antibodies, and induction of lysis against L cell targets transfected with EαAβd. Independent isolation of a second CD4+ V12 line revealed a very similar cytolytic and MHC class II‐restricted profile. Overall, these data demonstrated that peptide immunization produced a CD4+ Th1 response that specifically recognized tumor cells expressing endogenous activated K‐ras epitopes, which may have implications for the development of peptide‐based active immunotherapies.
Quantitation of endogenous mouse mammary tumor virus superantigen expression by lymphocyte subsets
Authors: Waanders Gary A. , Lees Rosemary K. , Held Werner , MacDonald H. Robson 
Published: March 2007

AbstractSuperantigens (SAg) encoded by endogenous mouse mammary tumor viruses (Mtv) interact with the Vβ domain of the T cell receptor (TcR‐Vβ). Presentation of Mtv SAg can lead to stimulation and/or deletion of the reactive T cells, but little is known about the quantitative aspects of SAg presentation. Although monoclonal antibodies have been raised against Mtv SAg, they have not been useful in quantitating SAg protein, which is present in very low amounts in normal cells. Alternative attempts to quantitate Mtv SAg mRNA expression are complicated by the fact that Mtv transcription occurs from multiple loci and in different overlapping reading frames. In this report we describe a novel competitive polymerase chain reaction assay which allows the locus‐specific quantitation of SAg expression at the mRNA level in lymphocyte subsets from mouse strains with multiple endogenous Mtv loci. In B cells as well as T cells (CD4+ or CD8+), Mtv‐6 SAg is expressed at the highest levels, followed by Mtv‐7 SAg and (to a much lesser extent) Mtv‐8,9. Consistent with functional Mtv‐7 SAg presentation studies, we find that Mtv‐7 SAg expression is higher in B cells than in CD8+ T cells and very low in the CD4+ subset. The overall hierarchy in Mtv SAg expression (i.e. Mtv‐6 > Mtv‐7 > Mtv 8,9) was also observed for mRNA isolated from neonatal thymus. Furthermore, the kinetics of intrathymic deletion of the corresponding TcR‐Vβ domains during ontogeny correlated with the levels of Mtv SAg expression. Collectively our data suggest that T cell responses to Mtv SAg are largely controlled by SAg expression levels on presenting cells.
Transplantation tolerance induced by antigen pretreatment and depleting anti‐CD4 antibody depends on CD4+ T cell regulation during the induction phase of the response
Authors: Bushell Andrew , Morris Peter J. , Wood Kathryn J. 
Published: March 2007

AbstractAdult mice pretreated with donor‐specific transfusion and depleting anti‐CD4 antibody 28 days before transplant accept fully allogeneic heart grafts and become specifically tolerant without further treatment. The induction of tolerance in this model is not simply a function of CD4+ T cell ablation, but appears to depend on residual CD4+ T cells which escape depletion and engage donor alloantigen during a transient period of antibody blockade. To test the hypothesis that these CD4+ T cells might be responsible for regulating immune responses toward the graft, mice were reconstituted with naive recipient leukocytes at various times after pretreatment. Reconstitution either shortly after pretreatment or shortly after transplant had little effect on graft survival. However, when pretreated mice were given an additional dose of depleting anti‐CD4 antibody at the time of transplant to target putative regulatory cells, naive leukocytes were able to cause acute graft rejection. These data suggest that in clinical transplantation specific T cell regulation might develop following pretreatment with antigen and non‐depleting anti‐CD4 antibodies. Such an approach could provide donor‐specific unresponsiveness prior to transplant without the risks associated with sustained CD4+ T cell depletion.