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Results for “Antigenic Modulation”

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PubMed1996

Mechanisms of immunosuppression induced by antithymocyte globulins and OKT3.

OKT3 monoclonal antibody and polyclonal antithymocyte or antilymphocyte globulins are among the most potent immunosuppressive agents which have been used in organ transplantation for many years. Both induce a rapid and profound lymphocytopenia classically attributed to several mechanisms, such as complement-dependent cytolysis, cell-mediated antibody-dependent cytolysis, as well as opsonization and subsequent phagocytosis by macrophages. However, the relative contribution of these three Fc-dependent mechanisms in vivo is difficult to ascertain and may be less important than previously thought. In addition OKT3 induces T-cell receptor modulation in vivo and modulated T cells no longer interact with antigen-presenting cells. Modulation of the T-cell receptor complex has not been documented for antithymocyte and antilymphocyte globulins as yet. The monoclonal antibody OKT3, which is directed against the epsilon chain of the CD3 molecule on the T-cell surface, but also antithymocyte and antilymphocyte globulins, which contain antibodies directed against CD3 and other functional molecules on the surface of T and B cells, generate various transduction signals to the target cells which can affect their functions in different ways. Recent in vitro studies suggest that these antibodies interfere with activation signals. Indeed, antithymocyte and antilymphocyte globulins, at low concentrations, inhibit T-cell activation induced by alloantigens, whereas they induce polyclonal T-cell activation at higher concentrations. Mitogenic antibodies can trigger an activation-induced cell death phenomenon as documented with anti-CD3 antibodies. Anti-CD3 antibodies can also induce a state of specific unresponsiveness (clonal anergy) which may contribute to their long-lasting immunosuppressive effect. One may hypothesize from in vitro data that in spite of their nonspecific immunosuppressive effects which may result in severe iatrogenic immunodeficiency, antilymphocyte antibodies may also act on stimulated alloreactive T-cell clones and therefore contribute to donor-specific graft adaptation.

Antibodies↗

PubMed2003

Drug- and cell-mediated antitumor cytotoxicities modulate cross-presentation of tumor antigens by myeloid dendritic cells.

The way a tumor cell dies is believed to influence both its engulfment by dendritic cells (DC) and access of the relevant antigen(s) to the cross-presentation pathway. Here we have studied the effect of lymphokine activated killer (LAK) cells, gamma-radiation and the antimetabolite drug 5-fluorouracil (5-FU) on tumor uptake by HLA-matched DC, and DC presentation of tumor antigens to autologous T lymphocytes. LAK cells and radiation were the best inducers of apoptotic death (Annexin-V+/propidium iodide-) on the gastric cell line KATO III and a primary gastric carcinoma, respectively. The highest rate of tumor uptake by monocyte-derived, granulocyte macrophage colony stimulating factor/interleukin (IL)-4-driven DC was associated with 5-FU, followed by radiation. These treatments also induced high levels of heat shock protein (hsp70). In contrast, only DC that had been taken up 5-FU- or LAK-treated tumors up-modulated IL-12 and presented tumor-associated antigens with increased efficiency, as shown by class I MHC-restricted interferon-gamma release and cytotoxic responses by autologous lymphocytes. Together, these data indicate that apoptotic death induced by anti-cancer therapies can induce distinct patterns of class I MHC cross-presentation of gastric carcinoma-associated antigens to cytotoxic T lymphocyte precursors.

Antigen Presentation↗

PubMed2005

Death or survival: membrane ceramide controls the fate and activation of antigen-specific T-cells depending on signal strength and duration.

Sphingomyelinase (SMase)-mediated release of ceramide in the plasma membrane of T-lymphocytes induced by different stimuli such as ligation of Fas/CD95, irradiation, stress, inflammation or anticancer drugs primarily involves mitochondrial apoptosis signaling, but under specific conditions non-apoptotic Fas-signaling was also reported. Here we investigated, using a quantitative simulation model with exogenous C2-ceramide (and SMase), the dependence of activation and fate of T-cells on the strength and duration of ceramide accumulation. A murine, influenza virus hemagglutinin-specific T-helper cell (IP12-7) alone or together with interacting antigen presenting B-cells (APC) was used. C2-ceramide induced apoptosis of TH cells above a 'threshold' stimulus (>25 microM in 'strength' or >30 min in duration), while below the threshold C2-ceramide was non-apoptotic, as confirmed by early and late apoptotic markers (PS-translocation, mitochondrial depolarization, caspase-3 activation, DNA-fragmentation). The modest ceramide stimuli strongly suppressed the calcium response and inhibited several downstream signal events (e.g. ERK1/2-, JNK-phosphorylation, CD69 expression or IL-2 production) in TH cells during both anti-CD3 induced and APC-triggered activation. Ceramide moderately affected the Ca2+ -release from internal stores upon antigen-specific engagement of TCR in immunological synapses, while the influx phase was remarkably reduced in both amplitude and rate, suggesting that the major target(s) of ceramide-effects are membrane-proximal. Ceramide inhibited Kv1.3 potassium channels, store operated Ca2+ -entry (SOC) and depolarized the plasma membrane to which contribution of spontaneously formed ceramide channels is possible. The impaired function of these transporters may be coupled to the quantitative, membrane raft-remodeling effect of ceramide and responsible, in a concerted action, for the suppressed activation. Our results suggest that non-apoptotic Fas stimuli, received from previously activated, FasL+ interacting lymphocytes in the lymph nodes, may negatively regulate subsequent antigen-specific T-cell activation and thus modulate the antigen-specific T-cell response.

Animals↗

PubMed1991

Modulating effects on CD25 and CD71 antigen expression by lectin-stimulated T lymphocytes in the elderly.

During the last few years, several observations outline that the impaired T lymphocyte proliferative capacity in the elderly is due to a reduced interleukin 2 (IL-2) release. To further investigate the activation process during lectin stimulation, aged peripheral blood mononuclear cells (PBMC) were stimulated with phytohemagglutinin (PHA) and assessed for CD25 (IL-2 receptor) and CD71 (transferrin receptor) expression at different intervals of time. Our results provided evidence for a significant decline of both structure induction, above all in the later phase of culture. Indomethacin (INDO) treatment gave rise to an enhancement of CD71 antigen expression only, while prostaglandin E2 (PGE2) supplementation to culture media further decreased either CD25 or CD71 receptor induction. Interferon (IFN)-alpha and IFN-gamma treatment failed to modulate the frequency of CD25+ and/or CD71+ cells. Finally, the expression of CD71 receptor was increased by deferoxamine supplementation, this suggesting a partial involvement of iron overload in the depressed function. Although further studies are required to evaluate at a molecular level the decreased antigen expression, these findings indicate that several mechanism are involved in the elderly-related decline of T lymphocyte activation structures during lectin stimulation.

Aged↗

PubMed1991

Opposing effects of protein tyrosine kinase inhibitors on the monoclonal antibody induced internalization of CD3 and CD4 antigens.

We have previously demonstrated that the monoclonal antibody (mAb)-induced modulation of CD3 and CD4 antigens from the surface of human peripheral blood lymphocytes is not dependent from protein kinase C activity (Thuillier et al., Eur. J. Immunol. 1990. 20:1197). In the present report we study the effect of genistein and of herbimycin A, two potent inhibitors of protein tyrosine kinases (PTK), on the mAb-induced modulation of CD3 and CD4 surface antigens. Both genistein and herbimycin inhibited the mAb-induced internalization of CD3 and, in contrast, facilitated that of CD4 antigen. These results indicate that the mAb-induced modulation of CD3 is essentially dependent on the PTK pathway, whereas PTK appear to negatively regulate the mAb-induced modulation of CD4.

Antibodies, Monoclonal↗

PubMed2000

Effects of SSM (specific substance maruyama) on HBe antigen-positive chronic hepatitis B -clinical efficacy and modulation of cytokines.

Twenty-three patients with HBe antigen-positive chronic hepatitis B were treated with capitalite first letters Maruyama (SSM). HBe antigen turned negative in 15 patients. The levels of various cytokines in pre- and post-treatment frozen serum samples from six patients whose HBe antigen turned negative and from five whose HBe antigen did not were examined. Reduction of serum interleukin (IL) -10 level to below 20 pg/ml was observed after SSM treatment in four of the six patients whose HBe antigen turned negative. SSM was found to stimulate the production of interferon (IFN) -gamma in peripheral blood cells from two healthy volunteers. This stimulatory effect was confirmed in 12 out of 24 healthy volunteers. SSM augmented the production of IFN-gamma in eight out of 10 patients with chronic hepatitis B and nine of 10 with hepatitis C. These results demonstrate for the first time that SSM stimulates the production of IFN-gamma in human peripheral blood cells and also suggest that treatment of HBe antigen-positive chronic hepatitis B patients with SSM leads to the clearance of HBe antigen and normalization of serum aspartate aminotransferase levels through inhibition of IL-10 and stimulation of IFN-gamma.

Adult↗

PubMed2000

Blood group antigen expression in the rat colon II. Modulation by dietary ethanol consumption.

In the accompanying article, we established that in the rat distal colon expression of H, B, and Le(b) blood group antigens by goblet cells is phenotypically fetal in nature. Because of the cocarcinogenic property of ethanol, the present study examined the effects of dietary ethanol consumption, fasting, and withdrawal on the expression of these antigens in the adult rat colon. To that effect, male adult Sprague-Dawley rats were pair-fed ethanol-containing or control Lieber-DeCarli liquid diets for 3 weeks. The effects of ethanol withdrawal were studied in rats fed the ethanol-containing diet for 3 weeks followed by the control diet for 1, 3, and 6 days. In rats fed the control diet, no antigen expression in the distal colon was observed, as expected. Ethanol feeding for 3 weeks resulted in a striking reappearance of H, B, and Le(b) antigens in goblet cells of the distal colon. In colonic crypts, a lower-to-upper crypt gradient of increasing numbers of positive goblet cells was present, suggesting that the induction of antigen expression paralleled the differentiation of goblet cells. After an overnight fast, the number of positive cells was significantly decreased. Withdrawal of ethanol for 1 day further decreased the number of positive goblet cells. The decrease was reflected by a downward shift in the number of positive cells per crypt column, which was more striking in the lower and mid-crypt segments than in the upper segment, suggesting that antigen expression was more labile in immature differentiating goblet cells than in mature ones. No antigen staining of goblet cells was detected after 3 and 6 days of ethanol withdrawal. Hence, expression of H, B, and Le(b) antigens by goblet cells of the distal colon can be modulated by ethanol consumption. Expression in the distal colon of A and Le(a) antigens, which did not exhibit a fetal phenotype, was not affected by ethanol feeding. In conclusion, because of the oncofetal phenotype of H, B, and Le(b) antigens, their reappearance in the distal colon may serve as a cytochemical marker for early recognition of epithelial changes of the colon in ethanol-related cocarcinogenesis before more overt manifestations of neoplasia.

Alcohol Drinking↗

PubMed1989

Immunoelectron microscopy studies on the modulation of common acute lymphoblastic leukemia antigen (CALLA) on NALM-6 cells: delineation of intracellular transport.

Even though much is known about the presence of the common acute lymphoblastic leukemia antigen (CALLA) with respect to its distribution in hematopoietic and non-hematopoietic tissues, its functional role in lymphoid cells is as yet unknown. Given the fact that CALLA is completely modulated on the surface of lymphoid cells, we have employed pre-embedding immunogold techniques at electron-microscopical level and demonstrated that J5 monoclonal antibody (MoAb)-mediated modulation of CALLA expression on the lymphoblastic cell line NALM-6 is a specific, rapid process, closely resembling receptor-mediated endocytosis. Furthermore, it was found that CALLA was internalized through plasmalemmal pits and cytoplasmic vesicles and processed intracellularly in multivesicular bodies and secondary lysosomes. In contrast, HLA-DR antigen remained at the cell surface upon contact with specific MoAb. These data suggest that CALLA might be a receptor for a hitherto unknown signal molecule.

Antigens, Differentiation↗

PubMed1998

CD22 negatively and positively regulates signal transduction through the B lymphocyte antigen receptor.

The CD22 cell-surface adhesion molecule is capable of modulating B lymphocyte antigen receptor (BCR)-mediated signals, as well as the generation of BCR-independent signals. Within the cytoplasmic domain of CD22 are motifs that are structurally homologous to known activation and inhibitory motifs. These motifs demonstrate physiologic significance via associations with known effector proteins that likely mediate their corresponding inhibitory and activation roles. Furthermore, the targeted deletion of CD22 in mice results in phenotypic changes and alterations in BCR-mediated signal transduction that are consistent with both positive and negative roles for CD22 in B cell development and activation.

Animals↗

PubMed1990

Interleukin-1 alpha inhibits the effects of gamma-interferon and tumor necrosis factor alpha on the expression of the major histocompatibility antigens by the rat endothelium.

Modulation of the major histocompatibility (MHC) antigen expression on rat endothelial cells by a mixture of cytokines has been examined. Experiments were performed employing both enzyme-linked immunoassay (ELISA) and fluorescence-activated cell-sorting (FACS) techniques and recombinant cytokines: interleukin-1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF alpha), and gamma-interferon (tau IFN). The results obtained show that TNF alpha enhances the effect of tau IFN on the expression of class I and II MHC antigens. IL-1 alpha did not affect tau IFN-induced class I expression but did inhibit tau IFN-induced class II expression. Finally, TNF alpha-induced class I MHC expression was inhibited strongly by IL-1 alpha. Pretreatment of endothelium with tau IFN did not potentiate the effects of IL-1 alpha or TNF alpha on the endothelial MHC antigen expression. These results suggest a possible anti-inflammatory role of IL-1 alpha via down-regulation of MHC antigen expression by the endothelium.

Animals↗

PubMed1989

Elevation of 3'5' cyclic adenosine monophosphate alters CD3 and CD25 antigens expression in activated T lymphocytes.

Modulation of CD3 molecules and expression of receptors for IL-2 (CD25) are pivotal events of lymphocyte activation and proliferation. Knowing the inhibitory effect of cAMP elevating agents on T lymphocyte activation, we investigated the effect of cholera toxin (CT) and dibutyryl cyclic AMP (dbcAMP) on the modulation of the CD3/Ti complex and on the appearance of the CD25 antigen on PHA-activated human lymphocytes. Cytofluorometry analysis of indirectly anti-CD3 labelled cells showed that CT accelerated the disappearance of CD3 molecules and slowed their reappearance. CT or dbcAMP inhibited the expression of CD25 antigen. In both cases, not only the relative number of CD3+ or CD25+ cells decreased, but the number of CD3 or CD25 antigens per cell as well. Exogenous rIL-2 did not reverse the inhibition of IL-2R expression by CT, showing that this effect is independent of the inhibition of IL-2 production already demonstrated. We conclude that augmenting cAMP levels might affect early steps of activation such as antigen receptor modulation, but do affect more profoundly late IL-2 dependent steps especially the autocrine IL-2 pathway of IL-2 receptor upregulation and the production of IL-2.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2001

Toxoplasma gondii and MHC-restricted antigen presentation: on degradation, transport and modulation.

Resistance against Toxoplasma gondii, an obligate intracellular protozoan parasite surrounded by a parasitophorous vacuolar membrane, is mediated by the cellular arm of the immune system, namely CD8+ and CD4+ T cells. Thus, priming and activation of these cells by presentation of antigenic peptides in the context of major histocompatibility complex class I and class II molecules have to take place. This is despite the fact that the vacuolar membrane avoids fusion with the endocytic compartment and acts like a molecular sieve, restricting passive diffusion of larger molecules. This raises several cell biological and immunological questions which will be discussed in this review in the context of our current knowledge about major histocompatibility complex-restricted antigen presentation in other systems: (1) By which pathways are parasite-derived antigens presented to T cells? (2) Has the parasite evolved mechanisms to interfere with major histocompatibility complex-restricted antigen presentation in order to avoid immune recognition? (3) To what extent and by which mechanism is antigenic material, originating from the parasite, able to pass through the vacuolar membrane into the cytosol of the infected cell and is it then accessible to the antigen presentation machinery of the infected cell? (4) What are the actual antigen-presenting cells which prime specific T cells in lymphoid organs? An understanding of these mechanisms will not only provide new insights into the pathogenesis of Toxoplasma gondii and possibly other intravacuolar parasites, but will also improve vaccination strategies.

Animals↗

PubMed1991

Analysis of phenotypic and functional changes during ganglioside-induced inhibition of human T cell proliferation.

Glycosphingolipids added to the cell culture medium can be incorporated into the plasma membrane and interfere with the growth of certain cell types. In the past years, previous reports have shown that gangliosides, a class of glycosphingolipids bearing sialic acid can inhibit antigen or mitogen induced T cell proliferative responses in vitro. We report here that the inhibition of PHA induced proliferation by the trisialoganglioside GT1b was not reversed by addition of exogenous IL-1, IL-2, TPA and calcium ionophore. Furthermore, GT1b did not affect IL-2 production by activated T cells. In addition, GT1b ganglioside could also decrease strongly the expression of the T cell antigens CD3, CD2, CD4, CD8 and the alpha/beta T cell receptor antigenic complex whereas it did not affect HLA-class I antigens. By contrast, GT1b modulated only partially membrane expression of activation antigens such as CD25 (Tac) and transferrin receptor and increased the expression of HLA-class II antigens. Moreover CD25 messenger RNA induction was not affected by GT1b treatment of PHA-stimulated T cells. Our results demonstrate that gangliosides, in spite of their anti-proliferative capacity and their modulation effect on T cell antigen membrane expression, do not prevent the progression of T cells into early stages of the activation process.

Antigens, CD↗

PubMed2001

CD28 and CTLA4 coordinately regulate airway inflammatory cell recruitment and T-helper cell differentiation after inhaled allergen.

Airway inflammation after inhaled allergen exposure requires the recruitment, activation, and differentiation of antigen-specific T cells into T helper (Th) 2 effector cells. These processes are regulated not only by antigen engagement of the T-cell receptor, but also by specific accessory molecules on the surface of the T cell. We examined how the balance of signals derived through the CD28 and cytotoxic T-lymphocyte antigen (CTLA) 4 receptors modulate the outcome of inhaled antigen exposure in a murine model of allergic airway inflammation. Mice deficient in CD28 have defective Th2 cell development and failed to develop inflammation after sensitization and inhaled challenge with ovalbumin. Prevention of B7-CTLA4 interactions in CD28-deficient mice restored lymphocyte but not eosinophil recruitment to the airway. Analysis of cytokine gene expression revealed that T cells from CD28-deficient mice failed to differentiate into Th2 cells in either the presence or absence of B7-dependent signals, and therefore did not recruit eosinophils to the airway. Thus, the processes of T-cell recruitment to the airway and T-cell differentiation have distinct requirements for signals mediated through the CD28 and CTLA4 receptors, demonstrating that these receptors are important regulatory components in the development of allergic airway inflammation.

Abatacept↗

PubMed1994

Modulation and intracellular transport of CD20 and CD21 antigens induced by B1 and B2 monoclonal antibodies in RAJI and JOK-1 cells--an immunofluorescence and immunoelectron microscopy study.

By fluorescence microscopy (FM), flow cytometry (FCM) and immunoelectron microscopy (IEM) we have shown that B1 and B2 monoclonal antibodies (MoAbs) were able to induce modulation of CD20 and CD21 in RAJI and JOK-1 cell lines. Redistribution and internalization of both antigens (Ags) after binding with MoAbs was readily demonstrated by FM, and by IEM CD20 and CD21 were found to be processed by the pathway of receptor-mediated endocytosis. The rate of intracellular transport varied: CD21 > CD20 and RAJI > JOK-1. Approximately 65 and 55% of CD20 and 60 and 45% of CD21 were cleared from the surface of RAJI and JOK-1 cells, respectively (FCM and IEM). These values, however, clearly exceeded those corresponding to internalization (11, 9, 24 and 16%) indicating shedding of Ag-MoAb complexes. No evidence of recycling was found. The present data support the hypothesis that the kinetics of modulation vary from one Ag to another and probably also reflect the stage of differentiation of the malignant B-cells. The results are discussed in the context of the possible usefulness of B1 and B2 MoAbs in the therapy of B-cell malignancies.

Antibodies, Monoclonal↗

PubMed1987

Lateral mobility of class I histocompatibility antigens in B lymphoblastoid cell membranes: modulation by cross-linking and effect of cell density.

We have studied the lateral mobility of class 1 major histocompatibility complex (MHC) proteins in the membranes of human Epstein-Barr virus-transformed B cells using fluorescence photobleaching recovery. Class I MHC antigens were labeled with either W6/32 monoclonal antibody or its Fab fragment directly conjugated to fluorescein isothiocyanate. The diffusion coefficient of class I antigens labeled with Fab fragments of W6/32 was identical to that of a lipid analogue, fluorescein phosphatidylethanolamine, and was 10-fold greater than that of antigens labeled with intact W6/32. Furthermore, antigens labeled with Fab fragments but not with intact W6/32 had fractional mobilities identical to that of the lipid probe. The lateral mobility of class I antigens was dependent on the time of incubation with fluorescent antibody and on the presence of antibody microaggregates. Finally, class I MHC proteins labeled with intact W6/32 but not with Fab fragments were immobilized in the membranes of most cells grown in suspension at high cell density. These results suggest that, in the unperturbed state, class I MHC antigens diffuse as rapidly as membrane lipid, i.e., without cytoskeletal constraint. Cross-linking with bivalent ligand and growth to high cell density may trigger membrane events leading to slowing and immobilization of these proteins.

Antibodies, Monoclonal↗

PubMed1999

Onchocerciasis modulates the immune response to mycobacterial antigens.

Chronic helminth infection induces a type-2 cellular immune response. In contrast to this, mycobacterial infections commonly induce a type-1 immune response which is considered protective. Type-2 responses and diminished type-1 responses to mycobacteria have been previously correlated with active infection states such as pulmonary tuberculosis and lepromatous leprosy. The present study examines the immune responses of children exposed to both the helminth parasite Onchocerca volvulus and the mycobacterial infections, Mycobacterium tuberculosis and M. leprae. Proliferation of peripheral blood mononuclear cells (PBMC) and production of IL-4 in response to both helminth and mycobacterial antigen (PPD) decreased dramatically with increasing microfilarial (MF) density. Although interferon-gamma (IFN-gamma) production strongly correlated with cellular proliferation, it was surprisingly not related to MF density for either antigen. IL-4 production in response to helminth antigen and PPD increased with ascending children's age. IFN-gamma and cellular proliferation to PPD were not related to age, but in response to helminth antigen were significantly higher in children of age 9-12 years than children of either the younger age group (5-8 years) or the older group (13-16 years). Thus, there was a MF density-related down-regulation of cellular responsiveness and age-related skewing toward type 2 which was paralleled in response to both the helminth antigen and PPD. This parasite-induced immunomodulation of the response to mycobacteria correlates with a previous report of doubled incidence of lepromatous leprosy in onchocerciasis hyperendemic regions. Moreover, this demonstration that helminth infection in humans can modulate the immune response to a concurrent infection or immunological challenge is of critical importance to future vaccination strategies.

Adolescent↗

PubMed1999

Viral effects on antigen processing.

Viruses have evolved numerous mechanisms that modulate MHC-mediated antigen presentation, which in turn protect infected cells from T-lymphocyte-mediated immunosurveillance. Recent studies of previously identified viral immunomodulatory proteins reveal the allelic specificity of these proteins, their ability to function in xenogeneic systems and the difficulty in translating in vitro data to in vivo models; moreover, new mechanisms of viral modulation of MHC expression have emerged.

Animals↗