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PubMed1987

A monoclonal antibody, GR7A4, reacting with the T10 antigen.

The monoclonal antibody GR7A4 was produced against a human lymphoblastic leukemia (ALL-B). Biochemical characterization of GR7A4 was carried out with Raji cells in SDS-PAGE studies. GR7A4 precipitated a 43 kd molecule. The tissue distribution and molecular weight were similar to the T10 antigen. Modulation and capping of GR7A4 antigen reduced its binding ability to cells with either GR7A4 or OKT10. However, the cell surface distribution pattern observed was somewhat different from other similar monoclonal antibodies. Thus GR7A4 reacted greatly with pre-B-cell lines, Burkitt cell lines, EBV cell lines and activated PHA, ConA and PWM lymphocytes, however reactivity with leukemic cells was very limited. The kinetics of appearance of GR7A4 antigen on PWM blasts show that this molecule seems to represent an intermediate stage in lymphocytic activation. The differences in comparison with other similar MAbs are discussed and correlated with the peculiar discontinous pattern of appearance of this antigen.

Antibodies, Monoclonal↗

PubMed1995

ATL cells recognize self class II HLA antigens: implication to leukemogenesis.

Adult T cell leukemia (ATL) cells show the decreased expression of T cell receptor (TCR)/CD3 complex on their surfaces in vivo. It is well known that excess amounts of antigen modulate TCR/CD3 complex on antigen-specific T lymphocytes. We hypothesized that antigen receptor of ATL cells was down-regulated with some antigenic stimulation in vivo, which might play an important role in leukemogenesis. In order to test this possibility, we studied whether the fresh ATL cells from three cases would respond to autologous and allogeneic lymphoid cell lines. In two of three cases, ATL cells could proliferate in the presence of autologous cell lines. In one case, this proliferation could be completely inhibited by anti-CD3 and anti-human leukocyte antigen (HLA)-DQ monoclonal antibodies, indicating that ATL cells recognized self HLA-DQ. In another case, the proliferation was suppressed by anti-CD3 and HLA-DR antibodies. These findings showed that ATL cells of some cases were derived from autoreactive T lymphocytes and such stimulation via TCR/CD3 complex plays an important role in the leukemogenesis of ATL in vivo.

Autoantigens↗

PubMed1983

Interaction of Ia antigen-bearing polymorphonuclear leukocytes and murine splenocytes.

Polymorphonuclear leukocytes (PMN) were induced in the peritoneum of a Balb/c mouse by ip injection of Fusobacterium nucleatum (FN) (greater than 95% PMN). A subpopulation of PMN harvested bore Ia surface antigens and stimulated a mixed lymphocyte reaction (MLR) when cultured with C57B1/6J splenocytes. The reaction was blocked by a short prior incubation of PMN with anti-Ia antibody or PMN cell depletion by the same antibody plus complement. The Ia antigen-bearing PMN were capable of antigenic modulation since incubation of PMN for 24 h rendered the cells incapable of stimulating an MLR. The Ia antigen-bearing PMN produced a soluble material that enhanced the phytohemagglutinin (PHA) response of murine splenocytes and the active material was a product of live cells since the supernatants contained no detectable lactate dehydrogenase activity. The data suggest that murine PMN subpopulations, defined by surface Ia antigen, can modulate mitogenic responses by production of an enhancing factor(s).

Animals↗

PubMed1981

H-2 negative teratocarcinoma cells become H-2 positive when passaged in genetically resistant host mice.

The murine 402AX teratocarcinoma is an H-2 negative, nullipotent stem cell tumor of testicular origin. Previous studies have demonstrated that host strain resistance and susceptibility to this tumor are under the control of 2 genes, one of which is closely linked to the mouse major histocompatibility complex. Earlier studies determined the lack of antigenic modulation and the absence of H-2 antigens on 402AX cells passaged in vitro or in genetically susceptible hosts. The present studies demonstrate that when passaged in genetically resistant host mice [C57BL/10, B10.SM, and B10.129(6M)], the H-2 negative 402AX cells modulate to become positive for H-2b antigens, as detected by indirect immunofluorescence, microcytotoxicity, and quantitative absorption. Two to 4 days of in vivo growth in resistant hosts is necessary for H-2b antigens to be expressed. H-2 positive tumor cells removed from resistant hosts and placed in culture become H-2 antigen negative within 1 to 4 hr in vitro. H-2 antigen turn-on on the teratocarcinoma cells is specific for the H-2 haplotype of the tumor cell origin (129, H-2b); alien H-2 antigens are not expressed. The observation that only teratocarcinoma cells growing in genetically resistant hosts turn-on for H-2 antigens suggests that major histocompatibility antigens on target cells are required for an efficient host cell-mediated immune response against tumor cells.

Absorption↗

PubMed1991

Selective loss of pertussis toxin-sensitive G-proteins from the plasma membrane after antibody-induced internalization of T-cell surface molecules.

Antibody-induced antigenic modulation occurs after binding of antibodies to a variety of cell surface proteins. It is characterized by aggregation and subsequent loss of the molecules from the cell surface, usually by internalization. In this study we have investigated the effect of modulation of the T-cell antigen receptor complex (TCR) and the transferrin receptor (TFR) on the distribution of cholera toxin (CTx)- and pertussis toxin (PTx)-sensitive GTP binding proteins in human T-lymphocytes. Modulation of both the TCR and the TFR induced a selective shift of PTx-sensitive G-proteins from the plasma membrane to a high density membrane fraction enriched for lysosomal membranes. The distribution of CTx-sensitive G-proteins was unaffected. This shift was found in both the T-cell leukemia line Jurkat and in normal T-cells. The loss of PTx-sensitive G-proteins from the plasma membrane required approximately 15 h to be complete and was not inhibited by cycloheximide. It had no influence on T-cell triggering via anti-T-cell receptor antibodies and is unrelated to the inactivating effect of TCR-modulation on T-cell signalling. The loss of PTx-sensitive G-proteins was not accompanied by greater sensitivity to stimuli raising cAMP concentration. These results show that PTx-sensitive G-proteins can be selectively depleted from the plasma membrane by antibody treatment of T-cells.

Adenosine Diphosphate Ribose↗

PubMed2001

Donor-derived soluble MHC antigens plus low-dose cyclosporine induce transplantation unresponsiveness independent of the thymus by down-regulating T cell-mediated alloresponses in a rat transplantation model.

BACKGROUND: In vitro, soluble MHC (sMHC) antigens modulate and induce apoptosis in alloreactive and antigen-specific T cells, demonstrating their potency to regulate T cell-mediated immune responses. However, their efficacy to regulate immunological responses in vivo remains unclear. Here, we report that repetitive intraperitoneal injection of recombinant Lewis rat-derived MHC class I antigens in Dark Agouti (DA) rats modulates alloreactivity. METHODS: RT1.A1 (Lewis derived) genes were cloned into mammalian expression vectors, and RT1.Aa (DA derived) genes were used to transfect a rat myeloma cell line. RT1.A1 molecules were injected intraperitoneally in DA recipients that subsequently underwent transplantation with Lewis-derived cardiac allografts. RESULTS: Soluble class I antigens were secreted by the transfected cells and were shown to be heterodimeric, peptide-loaded, and conformationally folded. Injection of donor-derived soluble MHC significantly reduced the ability of recipient animals to mount a cytotoxic T-cell response to donor-derived tissue. More interestingly, this treatment significantly prolonged donor-graft survival and allowed 60% of treated animals to develop graft tolerance (>120 days), when donor sMHC were combined with a single subtherapeutic dosage of cyclosporine. Thymectomy of recipient animals before transplantation did not interfere with induction of peripheral tolerance. CONCLUSIONS: Donor-derived sMHC are potential tolerogens for down-regulating the cytotoxic T-cell response of animals that undergo transplantation. Thus, these data provide for the first time a rationale for the application of directly injected sMHC in vivo to down-regulate immunological responses and aid the induction of graft tolerance.

Animals↗

PubMed1991

Differential modulation of surface antigens on human macrophages by IFN-gamma and GM-CSF: effect on susceptibility to LAK lysis.

We have previously reported that cultured human monocytes are lysed by autologous lymphokine-activated killer (LAK) cells in vitro and that treatment of monocytes with interferon-gamma (IFN-gamma) decreased their sensitivity to lysis. Conversely, incubation of monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly enhanced their susceptibility to LAK-mediated cytotoxicity. To determine if certain antigens were differentially modulated on macrophages by IFN-gamma and GM-CSF, cytokine-treated and untreated monocytes were analyzed for the expression of a variety of cell surface markers by flow cytometry. Cytotoxicity assays were performed to assess the ability of antibodies to each of these markers to block LAK lysis of macrophage target cells. While several of the surface structures were differentially modulated by cytokine treatment, it was found that only monoclonal antibodies to the adhesion proteins CD11a and CD18 were capable of blocking lysis of either cytokine-treated or untreated target macrophages.

Antibodies, Monoclonal↗

PubMed1987

Biochemical studies on a cell surface determinant involved in T-cell proliferation.

Previous studies have shown that a monoclonal antibody (TH5.2) recognizes a cell-surface determinant which is involved in the proliferative capability of T cells. The work reported here demonstrates that the T-cell-surface antigen recognized by TH5.2 is a glycoprotein of 55,000 to 60,000 molecular weight. The molecule shows a single molecular weight species upon reduction and denaturation, and it contains only a few percent of tunicamycin-sensitive carbohydrate structures. As shown in sequential immunoprecipitation studies, the TH5.2 antigen is on a molecule distinct from the interleukin-2 (Tac) receptor and the T4 molecule. Cell-surface antigenic modulation experiments indicate that the TH5.2 antigen does not comodulate with, and therefore is distinct from, the T3, T4, T8, and Leu-5 T-cell antigens.

Antibodies, Monoclonal↗

PubMed1983

Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis.

In an analysis of pooled data, we have found that cytotoxic-suppressor T cells outnumber the helper-inducer subset and also the population of cells bearing the pan-T cell marker in specimens of CNS from patients dying with MS (Booss et al. 1983). In the present study of individual data, we have reviewed the case histories to determine if these findings were consistent in various clinical settings. Variables examined included disease duration, tempo of evolution, immunosuppressive therapy, and other potentially immunomodulating features such as tumours. The predominance of the cytotoxic-suppressor subset was not found to be altered by any of these variables. We also present an individual data analysis of cases dying without known CNS disease and of cases with chronic non-inflammatory CNS disease. We found that the low but consistently observed number of T cells was apparently unrelated to the age of the individual or the site of the CNS sampled. Analysis of selected perivascular infiltrates showed, in contrast to the CNS parenchyma, that the pan-T cells and each of the subsets were approximately equal in proportion. Consideration of this observation and of the cytotoxic-suppressor subset preponderance in the parenchyma is compatible with the possibility of antigenic modulation of the T cell differentiation antigens. Finally, the potential contribution of perivascular infiltrates to the CSF pleocytosis is considered.

Aged↗

PubMed1975

Transformation of primate and rodent cells by temperature-sensitive mutants of SV40.

Cells of mouse, hamster, human and monkey origin were transformed by wild-type SV40 and by temperature-sensitive mutants defective in gene A. The mutant-transformed cells appear to be temperature sensitive for maintenance of transformation. Evidence of reversion of the transformed phenotype of nonpermissive temperatures was obtained in experiments which assayed saturation density, colony formation, and uptake of 2-deoxy-D-glucose. In addition, S antigen modulated in shift experiments while T antigen did not. Based on these results, a model is presented for the mechanism of transformation by SV40.

Antigens, Viral↗

PubMed2000

TGF-(beta)1 maintains hematopoietic immaturity by a reversible negative control of cell cycle and induces CD34 antigen up-modulation.

Somatic stem cells are largely quiescent in spite of their considerable proliferative potential. Transforming growth factor-(beta)1 (TGF-(beta)1) appears to be a good candidate for controlling this quiescence. Indeed, various mutations in the TGF-beta signalling pathway are responsible for neoplasic proliferation of primitive stem/progenitor cells in human tissues of various origins. In hemopoietic single cell culture assays, blocking autocrine and endogeneous TGF-(beta)1 triggers the cell cycling of high proliferative potential undifferenciated stem/progenitor cells. However, it has never been demonstrated whether TGF-(beta)1 has an apoptotic effect or a differentiating effect on these primitive cells, as already described for more mature cells. Using single cell experiments both in liquid or semi-solid culture assays and dye tracking experiments by flow cytometry, we demonstrate that low, physiological concentrations of TGF-(beta)1, which specifically maintain primitive human hemopoietic stem/progenitor cells in quiescence, have a reversible effect and do not induce apoptosis. We moreover demonstrate that these low concentrations prevent the rapid loss of the mucin-like protein CD34, a most common marker of immature hematopoietic stem/progenitor cells, which is progressively lost during differentiation. TGF-(beta)1 not only up-modulated the CD34 antigen before S phase entry but also maintained a high level of CD34 expression on cells which had escaped cell cycle inhibition, suggesting that proliferation inhibition and differentiation control by TGF-(beta)1 may be independent. These data provide additional evidence that TGF-(beta)1 acts as a key physiological factor ensuring the maintenance of a stem cell reserve.

Antigens, CD34↗

PubMed1987

[In vivo use of OKT3 monoclonal antibodies in recipients of renal allografts].

The OKT3 monoclonal antibody, that is specific for all mature human T lymphocytes represents a potent immunosuppressant when injected in vivo. The OKT3 antibody has been administered to more than 500 renal allograft recipients either to treat or prevent acute rejection episodes. OKT3 exerts its immunosuppressive effect by inducing rapid and important T cell depletion following the first injection. Then, OKT3 mediates the antigenic modulation of its T cell target antigen a phenomenon that is also related to the immunosuppressive effect exerted by the monoclonal antibody. The principal side effect observed following OKT3 administration, particularly if the antibody is injected alone, is the xenosensitisation against the foreign protein. Essentially, two sorts of anti-OKT3 antibodies are produced that respectively recognize the isotypic and the idiotypic determinants of the antibody molecule. The different strategies that may be envisaged to overcome this important side effect, that may totally neutralize the therapeutic effectiveness of OKT3 are discussed in detail.

Antibodies, Monoclonal↗

PubMed1987

[Monoclonal antibodies: therapeutic possibilities and limitations].

Monoclonal antibodies offer a unique possibility for specific recognition of a particular cell type. They can, in principle, be used for immunotherapy, for instance to destroy tumour cells, or to induce immunosuppression by eliminating T lymphocytes. The Fc moiety is essential for the biological effects of the antibody. The interaction of the Fc moiety with natural effector mechanisms (like complement, and Fc receptor positive cells of the monocytic-phagocytic system) is strongly dependent on the subclass and origin (species) of the antibody, and may be a limiting factor for its in vivo use. Furthermore, the binding of a monoclonal antibody may induce antigenic modulation (the selective removal of the antigen from the cell surface) thus making the cell resistant to antibody-mediated elimination. Another phenomenon affecting the therapeutic efficacy of a monoclonal antibody, is the antibody response evoked by the administration of the heterologous immunoglobulin.

Animals↗

PubMed1975

Detection of a TL(+) murine leukemia cell line that resists the cytotoxic effects of guinea pig complement and specific antiserum.

RADA-1 cells [H-2a thy-1b; thymus-leukemia (TL) 1, 2, 3], a radiation-induced murine leukemia cell line maintained by serial transfer in histocompatible recipients, resisted lysis by guinea pig complement (GPC) and TL 1, 3; TL 2; or TL 1, 2, 3 antiserum. The cells expressed TL antigenic specificities as determined by indirect fluorescent antibody methods, the direct isolation of TL antigens from the cells, and the capacity of the cells to reduce known titers of TL antisera. GPC was consumed to the same extent during the reaction of resistant cells and TL antisera as occurred in the reaction of sensitive cells (killed under similar conditions) and TL antisera. RADA-1 cells were not nonspecifically resistant to complement (C)-mediated lysis; they were killed in the presence of H-2a antiserum and GPC. The TL antisera contained antibodies for TL determinants. They stimulated the C-mediated lysis of ASL-1 cells (TL 1, 2, 3) and thymocytes from strain A mice (TL 1, 2, 3). The TL antigens of resistant RADA-1 cells underwent antigenic modulation, the reversible disappearance of TL antigens from the cells stimulated by specific antiserum. After the cells were treated with neuraminidase, they became susceptible to the cytotoxic effects of aliquots of the same TL antisera and GPC used previously.

Animals↗

PubMed1977

Detection of thymus leukemia antigens on the surface membranes of murine leukemia cells resistant to thymus leukemia antibodies and guinea pig complement.

The thymus leukemia (TL) antigens of ASL-1 murine leukemia reversibly disappeared from the membranes of cells exposed to TL antisera; the cells acquired resistance to fresh TL antiserum and complement (antigenic modulation). Three independent methods, however, indicated that the acquisition of complement resistance preceded the complete disappearance of TL antigens from the cell surface. Modulated cells reduced known titers of TL antisera by absorption; they stained positively in immunofluorescence studies involving TL antibodies and fluorescence-labeled rabbit anti-mouse immunoglobulin. TL antigens labeled previously with 125I were recovered by immunoprecipitation from cellular extracts prepared with nonionic detergent. Continued exposure of the cells to TL antiserum led to virtually complete disappearance of the antigens. Similar results were obtained for RADA-1 cells, another murine leukemia that forms TL antigens, although in this instance the cells were resistant to the cytolytic effects of TL antisera and guinea pig complement (GPC) without prior exposure to TL antibodies. The density of TL antigens remaining on the surface of different TL(+) cell types failed to correlate with resistance to TL antibodies and GPC. Cells from F, hybrids of TL(+) and TL(-) mouse strains formed TL antigens and were susceptible to TL antibodies and GPC even though the density of TL antigens formed by the susceptible cells was less than the density of TL antigens formed by modulated cells. Stable somatic hybrids of RADA-1 cells and TL(-) cells formed TL antigens at lower density than did RADA-1 cells and lysed in the presence of aliquots of the TL antisera and GPC used in previous tests.

Animals↗

PubMed1991

Potentiation of growth suppression and modulation of the antigenic phenotype in human melanoma cells by the combination of recombinant human fibroblast and immune interferons.

Administration of interferon as a single therapeutic regimen in cancer patients with various neoplasias has had only limited efficacy in ameliorating the negative clinical course of their disease. In the present study, we have evaluated the effect of recombinant human fibroblast (IFN beta) and immune (IFN gamma) interferon, alone and in combination, on growth, differentiation and the expression of class I and II histocompatibility locus antigens (HLA) and melanoma-associated antigens on the human melanoma cell line H0-1. The effect of combinations of interferons on the antigenic profile of human melanoma cells displaying different organ colonization and spontaneous metastatic potential in athymic nude mice was also determined. H0-1 cells were more sensitive to the antiproliferative activity of IFN beta than to IFN gamma and the combination of interferons resulted in a potentiation of growth suppression. The antiproliferative effect of both interferons was greater in later-passage than in earlier-passage H0-1 cells, possibly reflecting alterations in the evolving tumor cell population as a result of long-term in vitro propagation and/or the selective outgrowth of cells with an increased growth rate. The enhanced growth suppression observed in H0-1 cells treated with the combination of IFN beta plus IFN gamma was not associated with a significant increase in the level of melanin, a marker of melanoma differentiation, above that observed with either interferon used alone. IFN beta and IFN gamma differentially modulated the expression of class I and II HLA and melanoma-associated antigens in H0-1 cells and a series of melanoma cells with different organ colonization and metastatic potential, including MeWo, MeM 50-10, MeM 50-17, 3S5 and 70W. No consistent potentiation or antagonism in the expression of any specific antigen was observed in any of the melanoma cell lines exposed to the combination of interferons. The present study demonstrates that the combination of IFN beta plus IFN gamma can potentiate growth suppression in H0-1 human melanoma cells and that this effect is not associated with an increase in differentiation or a potentiation in antigenic modulation. In addition, no direct correlation between the expression of any specific antigen or its modulation by IFN beta or IFN gamma, alone or in combination, and organ colonization and metastatic potential in nude mice was observed in the different melanoma cell lines.

Animals↗

PubMedDate not supplied

Regulation of class II MHC gene expression by interferons: insights into the mechanism of action of interferon (review).

Modulation of class I and II MHC antigen expression by interferons has been the focus of considerable attention because the regulation of these molecules serves as a useful model system to study factors exerting transcriptional control of gene expression and because of the relevance of these molecules to expression of the neoplastic phenotype. While our knowledge of the molecular mechanisms regulating the ability of interferon to mediate enhancement of MHC genes has increased, this information is primarily based on studies employing established cell lines, and it remains to be determined whether similar controls are also exerted in short term cultured cell lines. In this short review, we have discussed the structural organization of the 5' flanking regions of the MHC genes, with special emphasis on class II genes, and the implications of these data for the transcriptional regulation of these and of other interferon inducible genes. Present evidence indicates the existence of at least four conserved upstream sequences which are shared by interferon responsive genes and which appear to be involved in the transcriptional control of these genes. The pattern of metabolic requirements for IFN-alpha and IFN-beta versus IFN-gamma upregulation of the class I and II MHC genes suggests that the regulation of gene expression by IFN-gamma requires unique regulatory molecules, i.e. newly synthesized proteins, which are not required by IFN-alpha and IFN-beta treated cells. These putative mediators of gene expression are likely to be shared by many of the biochemical induction pathways involved in the regulation of genes which exhibit interferon responsive sequences. However, in addition to common regulatory signals, other specific pathways and possibly additional regulatory sequences, are also required to account for locus--or subunit-specific patterns of antigenic modulation. Future studies are required, including those employing short term tumor cell cultures, to precisely define the molecular details of gene regulation of class I and II MHC genes, as well as other interferon--responsive--genes, by interferons. These investigations will not only prove valuable on a fundamental scientific level, but they will also be crucial for the more effective application of interferons in clinical oncology.

Gene Expression Regulation↗

PubMed1983

Failure of regulation of Tac antigen/TCGF receptor on adult T-cell leukemia cells by anti-Tac monoclonal antibody.

Anti-Tac monoclonal antibody, which blocks the membrane binding and action of human T-cell growth factor (TCGF), is strongly proposed to recognize TCGF receptor. We have demonstrated that anti-Tac antibody reacted with leukemic cells from patients with adult T-cell leukemia (ATL) and reacted with T-cell lines established from ATL cells. Although antigenic modulation, or down-regulation, of Tac antigen on activated normal T cells was induced by anti-Tac antibody, the expression of Tac antigen on ATL cells or T-cell lines was not affected when examined by the fluorescence-activated cell sorter (FACS) and the radioassay using 125I-staphylococcal protein A. These results indicate that regulation of Tac antigen-TCGF receptor is different between normal and malignant T cells, suggesting that failure of down-regulation of Tac antigen on leukemic cells by anti-Tac antibody may play an important role in the malignant proliferation of ATL cells.

Animals↗