bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody‐targeted superantigen therapy induces tumor‐infiltrating lymphocytes, excessive cytokine production, and apoptosis in human colon carcinoma
Authors: Litton Mark J. , Dohlsten Mikael , Lando Peter A. , Kalland Terje , Ohlsson Lennart , Andersson Jan , Andersson Ulf 
Published: March 2007

AbstractBacterial superantigens are the most potent known activators of human T lymphocytes. To engineer superantigens for immunotherapy of human colon carcinoma, the superantigen, staphylococcal enterotoxin A (SEA) was genetically fused to the Fab region of the colon carcinoma‐reactive monoclonal antibody C242. In the present study the effector mechanisms involved in the anti‐tumor response to C242 Fab‐SEA were characterized. Immunohistochemistry and computer‐aided image analysis were used in studies of cryopreserved tumor tissue to evaluate the phenotype of infiltrating cells and their cytokine profiles in response to therapy. Human T cells and monocytes were recruited to the tumor area and penetrated the entire tumor mass within hours after injection of C242 Fab‐SEA. The production of cytokines at the single‐cell level was found to be dominated by tumor necrosis factor (TNF)‐α, interleukin (IL)‐2, IL‐4, IL‐5, IL‐10, IL‐12, interferon (IFN)‐γ, granulocyte‐macrophage colony‐stimulating factor, and transforming growth factor‐β, whereas IL‐1‐α, IL‐1ra, IL‐1β, TNF‐β, IL‐3, IL‐6, and IL‐8 were undetectable. Most of the TNF‐α, IL‐2, IL‐12, and IFN‐γ were made by the infiltrating human leukocytes, while the colon carcinoma cells were induced to produce IL‐4, IL‐10, and TNF‐α. Up‐regulation of IFN‐γ receptors and TNF R p60 receptors was found, while the TNF R p80 receptor was absent. The cytokine production, T cell infiltration, and CD95 Fas receptor expression concomitantly occurred to induce programmed cell death in the tumor cells. This was followed by a strong reduction of the tumor mass that was seen within 24 h after C242 Fab‐SEA infusion. These findings demonstrate that antibody‐superantigen proteins efficiently recruit tumor‐infiltrating lymphocytes actively producing a variety of cytokines likely to be essential for the therapeutic effects observed in the model. Although the humanized SCID model has obvious limitations in its predictive value for treatment of human cancer, we believe that these results encourage clinical evaluation of antibody‐targeted superantigens.
T cell recognition of penicillin G: Structural features determining antigenic specificity
Authors: Padovan Elisabetta , Mauri‐Hellweg Daniela , Pichler Werner J. , Weltzien Hans Ulrich 
Published: March 2007

AbstractPenicillin G (Pen G) and other beta‐lactam antibiotics frequently induce allergic reactions constituting typical examples of human immune responses to haptens. In fact, penicillins represent a unique set of haptens with outstanding structural variability on the basis of an identical protein‐reactive beta‐lactam containing backbone. Although both cellular and humoral responses are involved in drug‐induced allergies, little is known about the T cell reactivity to penicillins. To understand which structural features determine antigenic specificity, we isolated a panel of MHC‐restricted, Pen G‐reactive T cell clones from different penicillin‐allergic patients and tested them for their capacity to proliferate in the presence of other penicillin derivatives. We found that the antigenic epitope consists of both the amide‐linked side chain, which is different in every member of the penicillin family, as well as the thiazolidine ring common to all penicillin derivatives. We also demonstrated the presence of two different types of penicillin‐specific T cells, one dependent, and the other independent of antigen processing by autologous antigen‐presenting cells. Our data strongly suggest that penicillins form part of the epitopes contacting the antigen receptors of T cells.
Characterization of cytokine production in murine Trypanosoma cruzi infection by in situ immunocytochemistry: Lack of association between susceptibility and type 2 cytokine production
Authors: Zhang Lei , Tarleton Rick L. 
Published: March 2007

AbstractCytokine production in the spleens of mice infected with the protozoan parasite Trypanosoma cruzi was analyzed in three models which differ in the outcome of the infection. Using immunocytochemical techniques to detect cytokine‐producing cells, the production of type 1 [interleukin‐2 (IL‐2) and interferon (IFN)‐γ], type 2 (IL‐4, IL‐5, IL‐10), inflammatory [tumor necrosis factor (TNF)‐α, IL‐1α, IL‐6] and regulatory (transforming growth factor‐β) cytokines were examined. With the exception of IL‐4 and IL‐5, cells producing all of the cytokines assayed were detected in both the resistant and susceptible models of T. cruzi infection. Cells producing IL‐4 and IL‐5 were not detected until later in infection in the resistant mice (>34 days), at about the time animals of the susceptible strain succumb to the infection. Mice of the susceptible model showed a slight delay in the appearance of cells producing the type 1 cytokines IL‐2 and IFN‐γ and an earlier appearance of TNF‐producing cells, in comparison to resistant mice. Cells producing IL‐2 or IL‐10 were transient in their appearance in the spleen while cells producing IL‐1, IL‐4, IL‐5, IL‐6, IFN‐γ, TNF, or TGF‐β were first detectable in either the acute or post‐acute stage of the infection and persisted up to 700 days post infection in two different resistant models of the infection. Cells producing IFN‐γ, TNF‐α and TGF‐β were particularly numerous even very late in the infection. Double‐staining techniques were used to show that the vast majority of the IFN‐γ‐producing cells in the spleen were CD4−, CD8− α/β TCR+ T cells. This study confirms the transience of IL‐2 production in the acute stage of T. cruzi infection and the persistent and simultaneous production of type 1 and type 2 cytokines during the late‐acute and chronic stages of the infection. Susceptibility or resistance to T. cruzi infection does not associate with a Th2 pattern of cytokine production in the three models examined in this study. The overlapping pattern of type 1 and type 2 cytokine‐producing cells in both the acute and chronic stages of T. cruzi infection demonstrates that longterm infections do not necessarily lead to a dominance of either type 1 or type 2 cytokine production.
Peripheral tolerance in T cell receptor‐transgenic mice: Evidence for T cell anergy
Authors: Falb Dean , Briner Thomas J. , Sunshine Geoffrey H. , Bourque Cheryl R. , Luqman Mohammad , Gefter Malcolm L. , Kamradt Thomas 
Published: March 2007

AbstractT cell tolerance can be induced in adult mice by injection of soluble antigenic peptide. The underlying mechanism has been difficult to establish in normal mice due to the low precursor frequency of T cells specific for any given antigen. Therefore, we examined peripheral tolerance in mice transgenic for a T cell receptor specific for a cytochrome c peptide bound to I‐Ek. Antigen‐specific hyporesponsiveness could be induced in the transgenic mice. We followed the transgene‐bearing T cells with a clonotypic monoclonal antibody and found similar numbers of clonotypic T cells in tolerized and control mice. To prevent de novo differentiation of T cells we analyzed thymectomized mice in which antigen‐specific hyporesponsiveness was induced. Our analysis of thymectomized transgenic mice showed that antigen‐specific T cell hyporesponsiveness following injection of peptide intravenously is not caused by gross elimination of T cells. These data provide evidence for the role of anergy in peripheral tolerance.
Tissue‐specific deoxyribonuclease I‐hypersensitive sites in the vicinity of the immunoglobulin Cλ cluster of man
Authors: Asenbauer Hildegard , Klobeck H.‐Gustav 
Published: March 2007

AbstractDuring B cell development, the onset of DNA rearrangements, expression, and somatic hypermutation of Ig genes are regulated through the complex interaction of cis‐acting elements with trans‐acting factors. Our aim is to identify DNA elements required during activation of the human Igδ light chain genes. Determination of deoxyribonuclease (DNase) I‐hypersensitive sites in complex regulated genes can lead to the identification of sequence elements which would have been overlooked by employing transient transfection protocols. We have therefore investigated the chromatin structure of human J‐Cλ genes and identified three DNase I‐hypersensitive sites (HSS‐1, −2, and −3) within an 8‐kb region downstream of the J‐Cλ7 gene. HSS‐2 and HSS‐3 are B cell specific. The DNase I‐hypersensitive sites are also present in X‐producing cell lines which have not rearranged the Igδ locus and produce germ‐line J‐Cλ transcripts. We conclude that in mature B cells, both x and λ loci are in an active structure regardless of the type of light chain they produce. This suggests that the chromatin structure of both loci is opened early in B cell development and that the active structure persists in mature B cells. The observed temporal order (first x, then δ) of activation can be explained by consecutive synthesis of the appropriate regulating factors and the tight regulation of the recombination machinery through the products of L chain gene rearrangements.
Major histocompatibility complex genes determine natural killer cell tolerance
Authors: Dorfman Jeffrey R. , Raulet David H. 
Published: March 2007

AbstractMurine natural killer (NK) cell subsets, as defined by expression of members of the Ly49 gene family, discriminate target cells expressing different major histocompatibility complex (MHC) class I alleles. For example, Ly49A+ NK cells lyse H‐2b but not H‐2d tumor target cells. The specificity arises because Dd on target cells binds to Ly49A, transducing an inhibitory signal into the Ly49A+ NK cells. The capacity of NK cells to discriminate allelic class I determinants raises a key issue: are NK cells self‐tolerant, and if so what are the mechanisms that lead to self‐tolerance? As previously reported, potentially autoaggressive Ly49A+ NK cells are not clonally deleted in H‐2b mice. However, IL‐2‐ cultured Ly49A+ effector cells from H‐2b mice exhibit reduced lysis of H‐2b (self) concanavalin A blast target cells, compared to Ly49A+ effector cells from H‐2d mice. Possible mechanisms accounting for this self‐tolerance are addressed in this report. Self‐tolerance was not due to anergy of the cells, because the Ly49A+ effector cells from both types of mice lysed β2‐microglobulin‐deficient target cells efficiently and equivalently. These results also suggest that tolerance results from inhibition mediated by β2m‐dependent H‐2b class I molecules. Significantly, blockade of Ly49A on Ly49A+ effector cells from H‐2b mice did not restore lysis of H‐2b target cells, suggesting that inhibition is not mediated through the Ly49A receptor. Additional experiments suggest that inhibition is also not mediated primarily through the Ly49C receptor. These results suggest that Ly49A+ effector cells from H‐2b mice, unlike those from H‐2d mice, express inhibitory receptors specific for H‐2b molecules that are distinct from Ly49A and Ly49C.
Analysis of major histocompatibility complex class I‐restricted hapten recognition by mutation of the V‐J joining of T cell receptor α chains
Authors: Von Bonin Arne , Plaga Sandra , Ruh Helga , Hebbelmann Sabine , Pflugfelder Ulrike , Martin Stefan , Weltzien Hans Ulrich 
Published: March 2007

AbstractHapten‐specific T cell responses are responsible for chemically induced immune disorders. However, the molecular details of hapten interactions with T cell receptors (TCR) are poorly understood. Recent studies of trinitrophenyl (TNP)‐specific responses revealed major histocompatibility complex‐associated TNP‐peptides as dominant epitopes for CD8+ and CD4+ T cells. The present study is based on the observation that two H‐2Kb/TNP‐specific CTL clones (II/7 and III/1), differing exclusively in two amino acids of their TCR α chains, also differed in their carrier specificities for various TNP‐peptides. The genes of the two α chains and the common β chain were cloned into expression vectors. Transfection of the TCR α chain of clone III/1 into a hybridoma of clone II/7 also transferred the fine specificity of clone III/1, indicating that the small α chain variations were indeed responsible for the different carrier specificities. Point mutations bridging the difference between the α chains of clones II/7 and III/1 and functional studies of the respective TCRαβ transfectants into a TCR‐negative hybridoma revealed an unexpected result: the two receptors did not represent examples of structural complementarity for different sets of hapten‐peptide conjugates; rather, they resembled two structures of principally similar specificity but of significantly different overall affinity. This was demonstrated more directly by comparing the fine specificities of III/1 transfectants expressing or not expressing the co‐receptor CD8: the CD8‐negative III/1 transfectant assumed a specificity pattern indistinguishable from that of a CD8‐expressing, II/7‐derived transfectant. Hence, comparable alterations of antigen recognition may be induced either by subtle TCR alterations or by removal of CD8, i.e. by the presence or absence of a non‐polymorphic adhesion molecule.
B cell‐B cell interaction through intercellular adhesion molecule‐1 and lymphocyte functional antigen‐1 regulates immunoglobulin E synthesis by B cells stimulated with interleukin‐4 and anti‐CD40 antibody
Authors: Katada Yoshinori , Tanaka Toshio , Ochi Hiroshi , Aitani Masakazu , Yokota Akira , Kikutani Hitoshi , Suemura Masaki , Kishimoto Tadamitsu 
Published: March 2007

AbstractIgE synthesis by purified human B cells is induced by two signals: a class switching factor, most commonly interleukin (IL)‐4, and the engagement of CD40, which is activated through its interaction with CD40 ligand (CD40L) expressed on activated T cells. Thus, the combination of IL‐4 and anti‐CD40 monoclonal antibody (mAb) has been shown to stimulate IgE production in vitro by highly purified B cells. In this T cell‐independent system, strong homotypic aggregation of B cells is observed prior to the production of IgE. Flow cytometric analysis and cell binding assays showed that the stimulation of purified B cells with anti‐CD40 mAb plus IL‐4 resulted in a striking increase of intercellular adhesion molecule (ICAM)‐1(CD54) expression, an induction of CD43 and an avidity change of lymphocyte functional antigen (LFA)‐1(CD11a/CD18), with little augmentation of CD 18 expression. Addition of anti‐ICAM‐1 mAb caused an inhibition of homotypic aggregation but augmented IgE synthesis by B cells stimulated with anti‐CD40 mAb and IL‐4, although it did not affect B cell proliferation or IL‐6 production by the B cells. Among the mAb against counter‐receptors for ICAM‐1 tested, anti‐CD11a mAb suppressed IgE synthesis, while anti‐CD18 mAb and anti‐CD43 mAb had little effect. The enhancing or inhibitory effect of anti‐ICAM‐1 mAb or anti‐CD11a mAb on IgE production was achieved by the increased or decreased expression of germline Cεe transcripts by B cells stimulated with anti‐CD40 mAb and IL‐4. These results indicate that B cell‐B cell interaction through ICAM‐1 and one of its counter receptors, LFA‐1, regulates IgE synthesis by modulating Cεe germ‐line transcription.
The β2 integrin Mac‐1 but not p150,95 associates with FcγRIIA
Authors: Annenkov Alexander , Ortlepp Susan , Hogg Nancy 
Published: March 2007

AbstractIn this study we have compared the ligand binding activity of the two closely related β2 integrins, Mac‐1 and p150,95, which are expressed separately as receptors permanently transfected into K562 cells. Mac‐1 has previously been shown to associate with FcγR, particularly FcγRIII, but K562 cells express only endogenous FcγRIIA. We have, therefore, taken advantage of this situation to examine a possible relationship between FcγRIIA with Mac‐1 and p150,95 in the absence of other FcγR. The main finding is that anti‐FcγRII mAb have a profound inhibitory effect on cell adhesion mediated by Mac‐1, but not on the adhesion mediated by p150,95. Thus, in spite of the fact that Mac‐1 and p150,95 bind to the same or at least a very similar selection of ligands, their association with other receptors on the cellular membrane, and therefore their mode of regulation may be different.
A tyrosinase nonapeptide presented by HLA‐B44 is recognized on a human melanoma by autologous cytolytic T lymphocytes
Authors: Brichard Vincent G. , Herman Jean , Van Pel Aline , Wildmann Claude , Gaugler Béatrice , Wölfel Thomas , Boon Thierry , Lethé Bernard 
Published: March 2007

AbstractThe human tyrosinase gene has been reported previously to code for two distinct antigens recognized on HLA‐A2 melanoma cells by autologous cytolytic T lymphocytes (CTL). By stimulating lymphocytes of melanoma patient MZ2 with a subclone of the tumor cell line of this patient, we obtained a CTL clone that lysed this subclone but did not lyse other subclones of the same melanoma cell line. The sensitive melanoma subclone was found to express a much higher level of tyrosinase than the others, suggesting that the antigen recognized by the CTL might be encoded by tyrosinase. Transfection of a tyrosinase cDNA demonstrated that the CTL clone indeed recognized a tyrosinase product presented by HLA‐B*4403. The relevant antigenic peptide corresponds to residues 192–200 of the tyrosinase protein. Lymphoblastoid cells of the B*4402 subtype were not recognized by the CTL following incubation with the peptide. Nevertheless, by stimulating in vitro lymphocytes of a healthy HLA‐B*4402 donor with autologous adherent cells pulsed with the same peptide, we obtained a CTL clone which recognized tumor cells expressing tyrosinase and HLA‐B*4402. As HLA‐B44 is expressed in 24% of Caucasians, the tyrosinase‐B44 antigen may constitute a useful target for specific immunotherapy of melanoma.
Prevention of murine lupus by an I‐E α chain transgene: Protective role of I‐E α chain‐derived peptides with a high affinity to I‐Ab molecules
Authors: Iwamoto Masahiro , Ibnou‐Zekri Nabila , Araki Kimi , Izui Shozo 
Published: March 2007

AbstractThe expression of a transgene encoding the I‐E α chain prevents a lupus‐like autoimmune syndrome in BXSB mice. However, it had not been elucidated whether the Eαd transgene‐mediated protective effect results from I‐E expression or from the generation of I‐E α chain‐derived peptides (Eα peptide) displaying high affinity for the I‐Ab molecule. To address this question, two different BXSB lines expressing the transgene at low or high levels were crossed with lupus‐prone MRL mice; this resulted in three types of (MRL × BXSB)F1 mice, differing in the expression levels of I‐E molecules and of Eα peptides presented by I‐Ab molecules. Comparative analysis of these three (MRL × BXSB)F1 mice as well as several BXSB transgenic lines showed that the Eαd transgene‐mediated protection paralleled the expression levels of Eα peptide presented by I‐Ab molecules, but not of I‐E molecules on B cells. In addition, use of transgenic and nontransgenic double bone marrow chimeras showed a selective activation of nontransgenic B cells during I‐Ab‐restricted T cell‐dependent immune responses, while both transgenic and nontransgenic B cells were comparably activated during T cell‐independent responses. These results favor a model of autoimmunity prevention based on competition for antigen presentation, in which excessive generation of Eα peptides prevents, because of their high affinity to the I‐A molecules, activation of potential autoreactive T and B cells.
Human natural killer cell inhibitory receptors bind to HLA class I molecules
Authors: Döhring Christian , Colonna Marco 
Published: March 2007

AbstractTo obtain direct evidence that human natural killer cell (NK) inhibitory receptors physically interact with polymorphic determinants of major histocompatibility complex class I molecules, a receptor termed NK‐associated transcript‐2 has been produced as a soluble fusion protein with the human IgG1 Fc portion. This soluble receptor binds specifically to HLA‐C alleles with serine 77 and asparagine 80 in cell adhesion assays.
Fas (CD95)/Fas ligand interactions regulate antigen‐specific, major histocompatibility complex‐restricted T/B cell proliferative responses
Authors: Ozdemirli Metin , El‐Khatib Maan , Foote Linda C. , Wang Julia K. M. , Marshak‐Rothstein Ann , Rothstein Thomas L. , Ju Shyr‐Te 
Published: March 2007

AbstractThe effect of Fas ligand (FasL) cytotoxicity on T/B collaboration was examined in vitro using cloned T helper 1 cells and antigen‐pulsed, activated B cells. We compared antigen‐pulsed B cells that had been activated through different membrane receptors (IgM, CD14 and CD40) for their ability to induce T cell proliferation and to respond to T cell help. We also used a Fas‐Ig fusion protein, an inhibitor of FasL‐mediated cytotoxicity, to determine the effect of FasL cytotoxicity on the T and B cell proliferative responses. The data show that the extent of both T and B cell proliferative responses correlate with the relative resistance of activated B cell populations to FasL cytotoxicity. Moreover, both T and B cell proliferation could be enhanced by Fas‐Ig. Our results demonstrate that FasL cytotoxicity is a negative regulatory mechanism for both T and B cell proliferative responses and that Fas‐Ig can be an immunopotentiating agent for both T and B cell immunity.
γδ T cells are secondary participants in acute graft‐versus‐host reactions initiated by CD4+ αβT cells
Authors: Tsuji Sachiyo , Char David , Bucy R. Pat , Simonsen Morten , Chen Chen‐Lo H. , Cooper Max D. 
Published: March 2007

AbstractTo examine the role of T cell subpopulations in an acute graft‐versus‐host (GVH) reaction, γδ T cells and αβ T cells expressing one of the two prototypic Vβ gene families were negatively isolated from adult blood samples and injected into allogeneic chick embryos. CD4+ αβ T cells expressing either Vβ1 or Vβ2 receptors were equally capable of inducing acute GVH reactions, consistent with the idea that αβ T cell alloreactivity is determined by CDR3 variability. By themselves, the γδ T cells were incapable of inducing GVH reactions. However, host γδ T cells were recruited into the donor αβ T cell‐initiated lesions, where they were activated and induced to proliferate. The data suggest that γβ T cells may play a secondary role in GVH reactions.
The phenotype and fate of the antibody‐forming cells of the splenic foci
Authors: Smith Kenneth G. C. , Hewitson Timothy D. , Nossal G. J. V. , Tarlinton David M. 
Published: March 2007

AbstractThe first product of the humoral response to antigen is low‐affinity antibody, produced by extrafollicular foci of antibody‐forming cells (AFC) in organs such as spleen and lymph node. These cells proliferate rapidly but then undergo an equally rapid decline, so that they are present in only small numbers 14 days after immunization. We have used 6‐parameter flow cytometry to isolate and examine the characteristics of (4‐hydroxy‐5‐nitrophenyl)acetyl‐specific AFC, looking in particular for those markers that might differentiate them from cells of the intrafollicular (germinal center) arm of the T‐dependent immune response. At day 7 of the primary response, most AFC were found to express surprisingly low levels of B220, high levels of syndecan, and retain significant levels of surface IgG1. We then used enzyme‐linked immunospot assays to demonstrate that the rapid decline of these cells was not likely to be due to migration to organs such as the bone marrow. Their decline could, however, be explained by apoptosis in situ, which was demonstrated immunohistologically by nick‐end labeling.