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PubMed1989

Modulation of the antigenicity of amylase in cervical glandular atypia, adenocarcinoma in situ and invasive adenocarcinoma.

Using a polyclonal anti-salivary alpha-amylase antibody and a biotin-avidin-peroxidase detection system immunoreactive amylase was detected in 39/40 cases of invasive cervical adenocarcinoma, 6/7 cases of adenocarcinoma in situ, 6/6 cases of high-grade cervical glandular atypia and 12/14 cases of low-grade cervical glandular atypia. Expression was seen in only 2/18 normal endocervices and this was weak and patchy. In contrast, strong amylase activity was demonstrated in 18/18 normal endocervices using a starch film assay on frozen sections. It is proposed that antigenic modulation of amylase occurs during endocervical neoplastic transformation.

Adenocarcinoma↗
PubMed2002

Stability of the B cell antigen receptor modulates its signaling and antigen-targeting functions.

The binding of antigens to the B cell antigen receptor (BCR) results in the initiation of signaling cascades and the internalization of the antigens for processing and presentation. Recent studies indicate that antigen binding destabilizes the BCR as a mechanism to down-regulate B cell responses. Two point mutations in the transmembrane domain of murine membrane IgM (mIgM) (YS to VV) weaken the interaction of mIgM with Igalpha/Igbeta heterodimer, resulting in a destabilized BCR. Using muYS/VV BCR, effects of the destabilized BCR on the functions of an endogenous wild-type mIgG(2a) BCR were analyzed. The muYS/VV BCR is defective in signaling and does not target antigens to late endocytic compartments for processing and presentation. Coligation of the muYS/VV BCR with the endogenous BCR interferes with antigen-targeting functions of the endogenous BCR. Thus, the destabilized BCR has a dominant effect, down-regulating the function of stable wild-type BCR. The ability of the destabilized BCR to influence the stable BCR may play an important role in turning off B cell responses for antigen-driven anergy and tolerance.

Amino Acid Sequence↗
PubMed1979

Redistribution and modulation of Gross murine leukemia virus antigens induced by specific antibodies.

Gross murine leukemia virus (G-MuLV)-induced rat leukemia cells in tissue culture replicate G-MuLV, express strong virus-associated membrane antigenicity, and are consistently killed by specific antibodies and complement in cytotoxicity tests. To explore the effect of specific antibodies, rat anti-G-MuLV antisera were added to the cultures of leukemia cells for variable periods of time. Redistribution of virus particles as well as of membrane virus antigens in the form of polar patches and caps was observed by electron microscopy, indirect immunofluorescence, and immunoelectron microscopy. Substantial decreases in cytotoxicity indexes accompanied these changes. The antigen modulation induced by anti-G-MuLV antibodies in vitro paralleled similar changes obtained in vivo by transplanttion of leukemia cells in rats with high anti-G-MuLV antibody titers. The importance of antigen modulation in this system resides in its direct relationship with the malignant potential of the leukemia cells.

AKR murine leukemia virus↗
PubMed1980

Modulation of thymus-leukemia antigens on mouse leukemia cells induced by IgG, but not IgM, antibody.

Exposure of mouse leukemia cells bearing thymus-leukemia (TL) surface antigens to whole TL alloantiserum has previously been shown to desensitize the cells to subsequent lysis by guinea pig complement (C) and fresh antiserum (antigenic modulation) and to correlate with the ability of cells to escape immune destruction in mice immunized against TL antigens. Tested in vitro, IgG of TL.1,2,3,5 antiserum modulated RADA1 leukemia cells (TL.1,2,3,5) completely within 2 hours at 37 degrees C when fully sensitizing amounts were used, with normal mouse serum as a source of C3. Similar results were obtained with IgG1, IgG2a, and IgG2b fractions of TL antiserum. An IgG2a monoclonal TL.3 antibody also completely modulated TL.3 antigens and partially modulated all antigens detected with TL.1,2,3,5 antiserum. IgM anti-TL.1,2,3,5 failed to modulate RADA1 cells even after 6 hours in vitro when fully sensitizing amounts of antibody were used. An IgM monoclonal TL antibody also failed to induce modulation. Modulation did occur on cells incubated with fully sensitizing amounts of IgG and IgM TL.1,2,3,5 antibody simultaneously, and nearly all cell-bound immunoglobulins were IgG. In mice passively immunized with IgG TL antibody, RADA1 cells modulated completely within 24 hours, whereas no modulation occurred during 4 days in mice immunized with IgM antibody. However, in both instances, tumor cells grew actively, which indicated that tumor escape did not depend on achievement of a modulated state.

Animals↗
PubMed1995

Modulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants.

Bound antibodies can modulate antigen processing but it is not clear to what extent this affects antigen presentation. Here we show that presentation of T cell determinants in tetanus toxin can be either enhanced or suppressed as a direct consequence of antibody modulation of antigen processing in human B lymphoblastoid cells. Remarkably, a single bound antibody or its Fab fragment can simultaneously enhance the presentation of one T cell determinant by more than 10-fold while strongly suppressing the presentation of a different T cell determinant. Biochemical analysis demonstrates that both the suppressed and boosted determinants fall within an extended domain of antigen stabilized or "footprinted" by this antibody during proteolysis. These results demonstrate that bound antibodies can modulate the capture of peptides by class II major histocompatibility complex (MHC), thus manipulating the T cell response towards or away from particular determinants. Altered processing of protein-protein complexes leading to enhanced loading of class II MHC and substantially lowered threshold for T cell activation suggests a novel mechanism that might reveal "cryptic" self determinants.

Amino Acid Sequence↗
PubMed1994

Exposure of monocytes to heat shock does not increase class II expression but modulates antigen-dependent T cell responses.

Expression of heat shock (HS) proteins (HSP) increases after exposure to elevated temperatures or other types of injury, such as oxidative injury. Because of their function as 'molecular chaperones', HSP are suggested to participate in antigen processing and presentation. We have previously reported that HS modulates antigen presentation in a human EBV-transformed B cell line. Here we investigated the effects of HS on MHC class II expression and on antigen processing and presentation by human monocytes. Monocytes were isolated from peripheral blood of normal human volunteers, purified by adherence, then exposed to temperatures ranging from 37 to 45 degrees C for 20 min, allowed to recover for 2 h at 37 degrees C and used for immunofluorescence or as antigen presenting cells in autologous and heterologous lymphocyte proliferation assays. No increase in class II expression was detected as assessed by flow cytometry. Monocytes (3 x 10(4)) and lymphocytes (1 x 10(5)) were co-cultured for 5 days in the presence of several antigens [diphtheria toxoid, tetanus toxoid or purified peptide derivative (PPD)] and labeled with 1 microCi [3H]thymidine for 16 h. Pre-exposure to HS (44 degrees C) significantly (P < 0.001) increased T cell responses to diphtheria toxoid, whereas the effect on the responses to other antigens (tetanus toxoid or PPD) were not significant. HS did not increase heterologous T cell responses nor T cell proliferation induced by the non-processed superantigens such as staphylococcal enterotoxin B. The effect of HS was inhibited by actinomycin B and thus appeared dependent upon HSP synthesis. HSP-mediated increases in antigen processing may potentiate the ongoing immune response at inflammatory sites.

Antigen Presentation↗
PubMed1991

Suppression in murine experimental autoimmune thyroiditis: in vivo inhibition of CD4+ T cell-mediated resistance by a nondepleting rat CD4 monoclonal antibody.

Genetically susceptible mice become resistant to experimental autoimmune thyroiditis (EAT) induction with mouse thyroglobulin (MTg) and lipopolysaccharide after pretreatment with deaggregated MTg (dMTg). Recent work showed this suppression to be mediated by CD4+ suppressor T cells (Ts). To study Ts action in vivo, we used a rat IgG2a monoclonal antibody (mAb), YTS 177.9, which modulates CD4 antigen in vivo without depleting CD4+ cells. Initial studies showed that after two 1-mg doses of mAb 7 days apart, extensive CD4 antigen modulation of peripheral blood leukocytes occurred within 4 days. Mice given CD4 mAb 24 hr before dMTg (2 doses, 7 days apart) were resistant to EAT induction when immunized with MTg and LPS 20 days later. Also, anti-rat IgG2a titers were reduced following challenge with heat-aggregated rat IgG2a compared to controls. Subsequent analysis of serum in CD4 mAb-treated animals revealed that mAb was present in the circulation for 14 days. Moreover, mice given CD4 mAb and dMTg, then challenged after only 10 days, when CD4 mAb was still circulating, developed a significantly higher incidence of thyroid damage than controls. These findings suggest that modulation of CD4 antigen does not interfere with Ts activation, but the presence of CD4 mAb, at the time of autoantigenic challenge, can interfere with tolerance to EAT induction. Thus, the direct relationship between the presence of CD4 mAb and inhibition of EAT suppression implicates a role for CD4 molecules in the mediation of suppression.

Animals↗
PubMed2000

Modulation of antigenicity of mycelial antigens during developmental cycle of Karnal bunt (Tilletia indica) of wheat.

Indirect enzyme linked immunosorbent assays (ELISA) were developed using polyclonal antibodies against soluble cytoplasmic (SCA) and insoluble cell wall antigens (ICWA) for monitoring modulation of mycelial antigens during growth cycle of T. indica. With SCA, continuous decrease in ELISA reactivity was observed in maturing fungus cultures, suggesting that SCA were expressed predominantly during early vegetative phase and their decreasing role was apparent as the fungus matures possibly towards sporogenous mycelium. In case of ICWA, the reaction profile showed an increase up to exponential phase of growth probably due to increase in the cell division and branching of mycelium. But later, ICWA antibody reactivity was decreased which may be due to conversion of mycelial phase to sporogenous phase, a quiescent stage of growth. Characterization of changes in antigenic configuration during developmental cycle of Tilletia indica by these antibodies could prove to be useful in identification of developmentally related and virulence marker(s).

Antigens, Fungal↗
PubMed1984

Enhancing effects of monocytes on modulation of a lymphocyte membrane antigen.

Redistribution, or modulation, of some cell surface antigens occurs in the presence of specific antibody. The phenomenon of antigenic modulation may therefore affect the use of antibodies as therapeutic agents. This study was undertaken to investigate modulation of the 65,000 dalton T65 antigen, present on normal and malignant T cells and some malignant B cells, which is recognized by the monoclonal antibody T101. To induce cell surface antigenic modulation, normal or leukemic lymphoid cells were cultured in the presence of monoclonal antibody T101 for 3-hr periods. Removal of monocytes from mononuclear cell preparations resulted in significantly lower degrees of T65 antigenic modulation. The degree of antigenic modulation could be increased by adding monocytes back to monocyte-depleted lymphocyte suspensions. Furthermore, maximal modulation occurred in the presence of monocytes at T101 concentrations that were 3 logs lower than in the absence of monocytes. The enhancing effect of monocytes was dependent on the Fc portion of the T101 antibody molecule, and presumably was mediated by cross-linking of antigen-antibody complexes on the surface membrane of the modulating cell by Fc receptors present on monocytes. Further experiments performed to examine the characteristics of this enhancement of antigenic modulation by monocytes indicated that autologous as well as allogeneic monocytes were effective, indicating that the enhancing phenomenon was not dependent upon recognition of major histocompatibility antigens. Viable monocytes were required, but pretreatment of monocytes with sodium azide to inhibit energy production, or indomethacin to inhibit prostaglandin synthesis had no effect on this phenomenon. Polymorphonuclear leukocytes did not mediate similar enhancement, although monocytic and myeloid cell lines U937, THP-1, and HL-60 did. Spent culture medium from modulated cultures and preparations containing IL 1 activity did not enhance modulation of the T65 surface antigen on lymphocytes, suggesting that direct contact between lymphocytes and monocytes is required to mediate the effect. The finding that leukemic cells from patients with CLL undergo modulation of the T65 antigen to a much lower degree in vitro than observed in vivo, and that this difference can be overcome by the addition of monocytes, suggests that monocytes or the reticuloendothelial system may augment antigenic modulation in vivo.

Antibodies, Monoclonal↗
PubMed1985

Modulation of expression of mouse macrophage surface antigens by monoclonal antibodies.

Mouse macrophages from peritoneal cavity were exposed to monoclonal antibodies (MAbs) directed against cell surface antigens and the effect on antigen expression was investigated. The two Mabs used, 3A33 and 3A35, were produced by cell fusion between a mouse plasmacytoma and rat lymphocytes immunized against mouse macrophages. The binding of the MAbs to cell surface was measured by immunofluorescence and flow cytometry or by a radioimmunological technique. When injected i.p. the MAbs diminished the expression of the corresponding antigens but did not alter it when added to cultures of adherent macrophages. Antigenic modulation, however, could be produced in vitro either by inhibiting macrophage adherence during incubation with MAbs or by using a second antibody layer. MAb 3A33 (IgG2a) was more effective than 3A35 (IgM) in provoking modulation. The appearance of re-synthesized antigens on cell surface was not affected by macrophage adherence. The modulated antigens were found to internalize into cytoplasmic vacuoles.

Animals↗
PubMed1996

[Internalization of tumor associated antigen on human lung adenocarcinoma cell line SPC-A-1 by McAb LC-1].

Antigenic modulation of tumor cells is a kind of immunophenomenon that the antigenicity of tumor cell surface antigen could be lessened, weakened or completely lost. It is a potential route for tumor cells to escape the immunosurveillance and immunoattack of the host. One of the means to cause the antigenic modulation is by means of the antibody. In present research, gold labeled monoclonal antibody LC-1, which is raised against human lung cancer in our lab, as a molecular tracer to study the internalization and the subsequent fate of the membrane tumor associated antigen-LC-1 complex on the SPC-A-1 cell surface has been used. We found that this complex was internalized via the receptor-mediated endocytic pathway and concentrated in the multivesicular bodies and transported to lysosomes for proteolysis in the end. Strikingly, we noted that LC-1 had induced the autophagocytosis of ribosomes in SPC-A-1 cells in the median time it induced the internalization of the cell surface antigen cause by internalization and the restoration after antigenic modulation were also analyzed by the fluorescence activated cell sorter (FACS).

Adenocarcinoma↗
PubMed1994

Modulation of associated ovarian carcinoma antigens by 5 cytokines used as single agents or in combination.

Optimization of intraperitoneal radioimmunotherapy of ovarian cancer depends on increasing the antigenic expression of tumor cells. For this purpose, we studied the effect of 5 cytokines (IFN-alpha, IFN-beta, IFN-gamma, TNF-alpha and TGF-beta), used as single agents or in combination, on 4 ovarian cancer cell lines which present different antigenic profiles with the monoclonal antibodies (MAbs) tested (OC125, OVTL-3, MOv 18 and MOv 19). Analyses were performed by flow cytometry and the Scatchard technique in order to study antigenic modulation. The effect on proliferation was determined by cell counting. Expression of O3 antigen, recognized by the OVTL3 MAb, was increased up to 2.5 times after IFNs and TNF-alpha (used as single agent) on the 2 lines presenting low basal expression (SHIN-3 and IGROVI). The expression of CA125 antigen and the antigens recognized by MOv 18 and MOv 19 MAbs was not increased by any of the cytokines tested. The combination IFN-gamma+TNF-alpha was synergistic on cytotoxicity and enhanced O3 expression, providing 10 times as many sites per cell on the SHIN-3 line. For 3 other associations (IFN-alpha+IFN-gamma, IFN-beta+IFN-gamma and IFN-alpha+TNF-alpha), there was an additive effect on O3 expression and on cell cytotoxicity.

Antigens, Neoplasm↗
PubMed1995

Modulation of antigen processing and presentation by covalently linked complement C3b fragment.

Ligands such as complement fragments (C3, C4), IgG or alpha 2-macroglobulin, which bind antigen (Ag) before their uptake by antigen-presenting cells (APC), are likely to modulate the different steps of Ag processing and presentation. These ligands contribute to internalization and endosomal targeting of Ag; they also influence its processing and, consequently, the binding of resulting peptides to major histocompatibility complex (MHC) class II molecules before presentation to T cells. Complement protein C3 contains, like other members of the alpha 2-macroglobulin family, an intrachain thiolester bond. Conformational alteration or limited proteolysis of C3 into C3b leads to breaking of the thiolester with transient capacity of the revealed carbonyl group to esterify hydroxyl groups of Ag. Ester-linked complexes including tetanus toxin (TT) and C3b were prepared to analyse the influence of bound C3b on TT processing and presentation by APC. Covalent binding of C3b to TT resulted in increased and prolonged stimulation of specific T-cell proliferation. This effect was observed with non-specific B cells, as well as with a TT-specific B-cell clone, as APC. On the other hand, SDS-PAGE analysis of proteolysates of TT or C3b-TT, obtained with endosome/lysosome-enriched subcellular fractions prepared from human Epstein-Barr virus (EBV)-transformed B cells, indicated a delay of TT proteolysis when TT was associated to C3b. Treatment of APC with protease inhibitors, before and during exposure of the cells to Ag, resulted in differences in the inhibition of TT and C3b-TT proteolysis. Using purified cathepsins B and D, we demonstrated that covalent binding of C3b to TT totally abolished TT proteolysis by cathepsin D, while proteolysis by cathepsin B was preserved. This finding and the absence of cathepsin B in endosomes may explain a delay in TT processing when it is associated to C3b. Confirming these data, presentation by formaldehyde-fixed cells of C3b-TT proteolysates showed higher stimulation of specific T-cell clones than formaldehyde-fixed TT proteolysates.

Antigen Presentation↗
PubMed1990

Phototoxic liposomes coupled to an antibody that alone cannot modulate its cell-surface antigen kill selected target cells.

Molecules such as antibodies that bind to cell surfaces can be used to deliver cytotoxic drugs to selected cells. To be effective the drug must usually be taken into the cells by endocytosis. In this study a T-cell line (CCRF-CEM) was effectively killed by liposomes carrying a photosensitizer and bearing the antibody OKT4 (anti-CD4). The unconjugated antibody does not induce antigenic modulation in the target cells, an indication of the absence of endocytosis, and would therefore not normally have been selected as an agent for drug delivery. It cannot, however, be concluded with certainty that the conjugates act at the cell surface and several alternative explanations of their efficacy are offered.

Animals↗
PubMedDate not supplied

Attack on neoplastic cell membranes by therapeutic antibody.

Mouse monoclonal antibody is not well fitted to destroying tumour cell targets. Complement and cellular effectors are inefficiently recruited, the cells can undergo antigenic modulation, antigen-negative mutants can arise, and the tumour-bearing subject can amount an immune response against the therapeutic antibody. This paper describes the preparation of two chimeric antibody derivatives designed to cirvumvent some of these problems. The first derivative is FabFc, prepared by linking Fab' gamma from monoclonal antibody to Fc gamma from human IgG. The bismaleimide linking agent forms a thioether bond with an SH group released by reduction of SS bonds in the hinge of each constituent. The second derivative is bisFabFc, formed by a bismaleimide in this case joining two FabFc molecules via a free SH in the Fc hinge of each. As regards antibody activity against target cells bisFabFc can be univalent (one active, one inactive Fab arm), bivalent, or bispecific (with each Fab arm directed against a different cell surface antigen). Its juxtaposed dual Fc regions are designed to promote cooperative binding of effectors. Some preliminary characterization in vitro has employed antibodies of anti-idiotypic specificity directed against guinea-pig L2C leukaemic B lymphocytes. The parent mouse IgG1 antibody failed to invoke complement cytotoxicity or antibody-dependent cellular cytotoxicity, while the chimeric derivatives yielded good killing in both systems. In complement lysis bivalent bicFabFc outperformed univalent, which in turn outperformed the FabFc monomer.

Animals↗
PubMed2005

A new automated fourth-generation HIV screening assay with sensitive antigen detection module and high specificity.

New screening enzyme immunoassays, which permit the simultaneous detection of HIV antigens reduce the diagnostic window period between the time of immunodeficiency virus (HIV) infection and seroconversion. The VIDAS HIV DUO Ultra is an enzyme-linked fluorescent assay (ELFA) for the screening of HIV infection. It is performed with the fully automated VIDAS or mini-VIDAS instruments, which are so-called walk away systems. The detection limit is 3 pg of HIV-1 p24 Ag/mL serum. HIV antibody is detected with the same sensitivity as stand-alone third-generation antibody tests. The total incubation time is about 2 h. Results are calculated, interpreted, and printed by the VIDAS instrument. Usually, fourth-generation assays demand a special algorithm for the analysis of reactive samples. For the anti-HIV part of the assay, confirmation of reactivity should be done with an assay that lacks the p24-antigen detection module and when reactivity persists subsequently by immunoblot. For the p24-antigen part, confirmation of reactivity should be analyzed in an assay that lacks the anti-HIV detection part.

Antibody Specificity↗
PubMed1994

Mechanism involved in the systemic suppression of antigen-presenting cell function by UV irradiation. Keratinocyte-derived IL-10 modulates antigen-presenting cell function of splenic adherent cells.

Exposure to UV radiation suppresses tumor rejection and delayed-in-time hypersensitivity reactions and depresses splenic APC function. Because almost all of the UV radiation is absorbed in the upper layers of the skin, it appears unlikely the direct irradiation of APC can account for the impaired ability of splenic adherent cells to present Ag after total-body UV exposure. Because UV-irradiated keratinocytes release IL-10, and in light of the well-documented effects of IL-10 on Ag presentation, we tested the hypothesis that keratinocyte-derived IL-10 is responsible for the systemic impairment of APC function following UV exposure. Injecting supernatants from UV-irradiated keratinocytes suppressed the ability of splenic adherent cells to present Ag. Treating the supernatants with anti-IL-10 mAb neutralized the suppressive effect. Similarly, when splenic adherent cells were isolated from mice exposed to UV radiation, APC function was suppressed. Injecting the UV-irradiated animals with anti-IL-10 restored APC function. In addition, spleen cells from UV-irradiated mice did not efficiently present Ag to Th1 clones, and injecting anti-IL-10 after UV exposure restored APC function. The reverse was observed when spleen cells from UV-irradiated mice were used to present Ag to Th2 clones; in which case, UV exposure enhances APC function, and anti-IL-10 reverses this effect. These findings suggest that UV-induced, keratinocyte-derived IL-10 can modulate splenic APC function.

Animals↗
PubMed1981

H-2 antigen expression on teratocarcinoma cells passaged in genetically resistant mice is regulated by lymphoid cells.

Previous studies have demonstrated that resistance and susceptibility to the 402AX testicular teratocarcinoma are under genetic control in the mouse. Under normal culture conditions or when passaged in genetically susceptible hosts, the nullipotent 402AX cells do not express H-2 antigens. However, when passaged in genetically resistant animals, the tumor cells become strongly positive for H-2 antigens in the absence of other indications of differentiation. These studies suggested that H-2 antigen modulation on teratocarcinoma cells is mandatory for an effective host cell-mediated immune response against this tumor. The present studies further examine the role of H-2 antigen modulation on teratocarcinoma cells and determine which host cell populations are mediating H-2 modulation on the tumor cells. Reconstitution of lethally irradiated susceptible hosts with resistant bone marrow extends the mean survival time of the host but does not confer complete resistance. Teratocarcinoma cells passaged in such reconstituted hosts do not express H-2 antigens. Two lines of evidence suggest that H-2 antigen modulation is mediated by lymphoid cells: (i) sublethal irradiation of genetically resistant hosts inhibits H-2 antigen modulation on teratocarcinoma cells passaged in vivo and (ii) immunological priming can overcome the loss of H-2 modulation that is normally associated with aging in genetically resistant hosts. Genetically susceptible mice can be fully reconstituted for tumor rejection and H-2 antigen expression on teratocarcinoma cells by reconstitution with genetically resistant bone marrow plus lymphoid cells from tumor-primed resistant hosts. These results: (i) imply the necessity for H-2 antigens on tumor cells for an effective host cell-mediated immune response against the tumor, and (ii) indicate that host lymphoid cells regulate H-2 antigen expression on tumor cells passaged in vivo.

Animals↗