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PubMed1988

Establishment of human mesothelioma cell lines (MS-1, -2) and production of a monoclonal antibody (anti-MS) with diagnostic and therapeutic potential.

We have established and characterized two mesothelioma cell lines, MS-1 and MS-2, in four attempts at long-term culture of these cells. Both MS-1 and MS-2 cells consistently express cytokeratin and vimentin, and both have long, slender microvilli. The cells that grew indefinitely (MS-1, MS-2) had a higher DNA index and a higher nucleus:cytoplasm ratio than did those cells that failed to grow (MS-3, MS-4). All mesothelioma cells, both in short- and in long-term culture, responded to phorbol ester induction by displaying morphological differentiation, such as an increase in the number of microvilli. The distribution of vimentin and cytokeratin in the cells, however, remained the same regardless of the growth pattern or the phorbol-ester treatment of the cells. We have used MS-1 cells to produce a monoclonal antibody (anti-MS) that reacts with mesothelioma cells, but rarely with reactive or normal mesothelial cells or with cells of normal tissues. The antibody does not induce the modulation of antigen, and it causes no direct or complement-mediated cytotoxicity of MS-1 or MS-2 cells. If a toxin or an isotope conjugate of the antibody is used, it may be valuable in the near future to test it for use in immunoimaging or immunotherapy.

Antibodies, Monoclonal↗
PubMed1989

Modulation of major histocompatibility complex antigens and inhibition of proliferative activity of YAC lymphoma cells by a natural killer lysis resistance-inducing factor (NK-LRIF).

Concanavalin-A-activated rat spleen cells secrete a natural killer lysis resistance-inducing factor (NK-LRIF) distinct from interleukin-2 and interferon, which induces resistance to NK-cell-mediated lysis in YAC tumor cells. In order for NK-LRIF to have an effect on YAC cells, several hours of incubation is required. When NK-LRIF-treated YAC cells are washed and cultured in the absence of NK-LRIF, normal NK susceptibility is regained. YAC cells treated with NK-LRIF show a significant decrease in the rate of proliferation as judged by changes in cell numbers and rate of thymidine incorporation. Cell cycle studies indicate that the proportion of G0/G1 phase cells increases in YAC preparations treated with NK-LRIF. Major histocompatibility complex (MHC) class I antigen expression is markedly enhanced on YAC cells incubated with NK-LRIF but the expression of MHC class II antigens and Thy-1 antigen remains unchanged. No effect of NK-LRIF treatment on the capacity of YAC cells to bind effector spleen cells could be demonstrated.

Animals↗
PubMed1986

Phagocytosis of Plasmodium chabaudi: modulation by immune serum and antigen in vitro.

The phagocytosis of free Plasmodium chabaudi parasite by resident peritoneal macrophages of mouse was studied in an in vitro system. The effect of antimalarial antiserum (HIS) was assessed by preincubation of parasite macrophages and both parasite and macrophages with HIS prior to use in phagocytic assays. Highest phagocytic index was obtained with HIS pretreated parasites. The two activities viz. opsonic (parasite dependent) and cytophilic (macrophage dependent) were noted to operate independent of each other. The phagocytosis promoting activity was found to be complement dependent. The receptor site for binding of HIS opsonized but not medium opsonized parasite on the surface of macrophages was blocked by pretreatment of these cells with HIS-soluble antigen combination.

Animals↗
PubMed1988

Expression of 67,000 MW calcimedin and its binding protein in resident and thioglycolate-elicited macrophages.

Calcimedins are newly recognized calcium-dependent hydrophobic-binding proteins. The 67,000 MW calcimedin exhibits calcium-dependent specific binding to a 60,000 MW intracellular acceptor protein (60,000 MW). Macrophages possessed 30,000 MW and 67,000 MW calcimedins and 60,000 MW acceptor protein, identified by immunofluorescence and confirmed by SDS-PAGE and Western immunoblots. Compared with low levels in resident macrophages, thioglycolate-elicited inflammatory macrophages showed large increases in the levels of 67,000 MW calcimedin and 60,000 MW acceptor protein, especially at cell-limiting membranes. Levels of calmodulin and 30,000 MW calcimedin appeared similar in both populations. Trypsinization removed most 67,000 MW calcimedin and some 60,000 MW acceptor-protein staining. The calcimedins appear to represent novel macrophage-differentiation antigens. Their modulation suggests that they may play a role in the inflammatory response.

Animals↗
PubMed1986

T cell-activating protein on murine lymphocytes.

A functional T cell surface molecule, T cell-activating protein (TAP), has been identified on murine lymphocytes. TAP is a protein with an apparent molecular mass of 10-12 kilodaltons (kDa) nonreduced, 16-17 kDa reduced. Cross-linking of TAP can result in profound activation of T lymphocytes to produce lymphokines and to enter the cell cycle. Furthermore, antibody binding to TAP can modulate antigen-driven T cell stimulation. Current data suggest that TAP is physically distinct from the T cell receptor complex. On unstimulated lymphocytes, TAP is expressed on T cells and defines heterogeneity within the major T cell subsets. Its profile of expression is rapidly altered on cell activation. Ontologically, it is first detected in the thymus, where it is found on both the most immature and the most mature cell subsets, and it is functional on both. Together, these TAP+ cells constitute a small fraction of thymocytes. TAP expression, however, defines the immunocompetent compartment of the thymus, and thus could be involved in functional maturation. Finally, the gene controlling TAP expression has been mapped, and is tightly linked to a locus of hematopoietic antigens (Ly-6). TAP is molecularly distinct from these antigens. Furthermore, all of these proteins show a markedly distinct developmental regulation in their cell surface expression.

Animals↗
PubMed1986

Transient modulation and internalization of T4 antigen induced by phorbol esters.

Phorbol esters are known to alter the expression of surface antigens and receptors on a variety of mammalian cell types. On T lymphoblastoid cell lines and peripheral blood T cells, phorbol esters have been shown to selectively reduce the expression of the T4 antigen. To more fully characterize this process, we have examined the metabolic requirements for this phorbol ester effect, and have evaluated the relationship between phorbol ester-induced T4 loss and the expression of receptors for phorbol-12,13-dibutyrate (PDB) on purified peripheral blood T4 cells. We observed that the loss of T4 on peripheral blood lymphocytes (PBL) occurred at PDB concentrations at which 10 to 15% of phorbol ester binding sites were occupied. The loss of T4 was inhibited at 4 degrees C, and by azide, methylamine, and sodium fluoride, but not by inhibitors of DNA synthesis. When cells were exposed to phorbol esters for greater than 2 days, the T4 antigen was again expressed on the cell surface despite the continued presence of phorbol esters. Cells which had recovered T4 were resistant to the effects of freshly added PDB on this antigen, and this resistance correlated with a 55% reduction in phorbol ester binding sites. Studies on fixed PBL T4 cells and MOLT-4 cells by immunofluorescence microscopy demonstrated that the decreased expression of T4 from the cell surface correlated with a bright clustering of T4 within the cytoplasm, indicating that PDB had induced an internalization of this antigen. These observations demonstrate that the binding of phorbol esters to specific receptors on lymphocytes initiates metabolically dependent events which result in the internalization of the T4 antigen. These findings may be relevant to mechanisms by which T4 functions as a signal-transducing molecule in vivo.

Adult↗
PubMed1986

Monoclonal antibodies to the CD5 antigen can provide the necessary second signal for activation of isolated resting T cells by solid-phase-bound OKT3.

Activation of human peripheral blood T cells by the anti-CD3 antibody OKT3 has been shown to require not only cross-linking of CD3 molecules with multimeric binding of the Fc part of OKT3 to a solid support, but also a second accessory cell-provided signal. Accordingly, measurement of T cell activation in cultures of highly enriched T cells with solid-phase-bound OKT3 can be used to investigate whether other agents can replace accessory cells. In this study we examined the capacity of anti-CD5 monoclonal antibodies to provide the additional activation signal. Resting T cells were prepared by isolating E rosette-positive cells, by removing OKM1(+) and HLA-DR(+) cells by panning, and by subsequent treatment of the cells with L-leucine methyl ester to kill remaining monocytes. These T cells were unresponsive to phytohemagglutinin (PHA) or to solid-phase-bound OKT3. However, when cultured in the presence of an anti-CD5 monoclonal antibody (anti-Leu-1, OKT1, or anti-T1), a proliferative response to solid-phase-bound OKT3 (but not to soluble OKT3 or to PHA) was observed. Anti-CD5 had no functional effect by itself, but in association with solid-phase-bound OKT3 it enhanced IL 2 receptor expression and IL 2 production and it initiated T cell proliferation. T cell proliferation under these conditions could be inhibited by an IL 2 receptor blocking antibody anti-Tac, thus confirming that anti-CD5 provides the second signal for an IL 2-dependent pathway of T cell proliferation. Preincubation of T cells with anti-Leu-1 or OKT1 resulted in complete loss of CD5 antigenicity, and such CD5 modulation was sufficient to induce a proliferative response to solid-phase-bound OKT3. It is concluded that in T cell activation by solid-phase-bound OKT3 the necessary additional signal can be provided by modulation of the CD5 antigen with an anti-CD5 antibody. CD5 therefore appears to be a positive signal receptor on the T cell membrane, whose physiologic ligand still has to be determined.

Antibodies, Monoclonal↗
PubMed1988

Recombinant human IFN-gamma, but not IFN-alpha or IFN-beta, enhances MHC- and non-MHC-encoded glycoproteins by a protein synthesis-dependent mechanism.

Despite quantitative as well as qualitative differences, all three types of IFN (IFN-alpha, IFN-beta, and IFN-gamma) modulate the synthesis as well as the expression of class I and class II histocompatibility Ag and a melanoma-associated Ag located in the plasma membrane as well as the cytoplasm of human melanoma cells. By employing inhibitors of RNA and protein synthesis it was demonstrated that IFN-alpha and -beta increase the expression of histocompatibility products and this tumor-associated Ag by a process not requiring new protein synthesis. In contrast, IFN-gamma does require de novo protein synthesis for its modulatory activity. Thus, it appears that IFN might trigger various adaptive functions in different cell lineages by inducing at least two separate sets of responses specific for either IFN-alpha and -beta or IFN-gamma. Because the induction requirements for (2'-5')-oligoadenylate synthetase as well as for the development of a cellular antiviral state by different IFN also display a similar protein synthesis dependence pattern, the present results suggest that a similar set of cellular mediators may be involved in the modulation of antigenic expression by IFN-gamma in human melanoma cells.

Antigens, Neoplasm↗
PubMed1987

Immunomodulation by cancer chemotherapeutic agents.

Cytotoxic agents may specifically interfere with the different components of cellular and humoral immunity, and consequently modulate the responses in opposite directions, by not only inducing impairment but also augmenting some immune functions. They may also modulate tumor antigenic expression, leading to increased immunogenicity. Glucocorticoids at sufficiently high concentrations can inhibit virtually any function of lymphocytes, NK cells, monocytes and macrophages. Azathioprine and other antimetabolites, such as 6-mercaptopurine, methotrexate and cytarabine, have a similar generalized immunosuppressive activity and may be used therapeutically for this purpose in the clinic. Cyclophosphamide exerts an immunosuppressive or an immunostimulating effect when given at high or low doses, respectively. The marked Cy-induced inhibition of T suppressor lymphocytes, the predominant immune cell population in cancer patients favoring tumor growth, may have important therapeutic significance. DX enhances proliferation of lymphocytes in the presence of mitogens, but may inhibit antibody production; it also increases the tumoricidal activity of monocytes and macrophages and does not alter substantially NK cytolytic activity. A detailed study of drug effects on the tumor and host immune system may contribute to their more rational use in cancer chemotherapy with regard to toxicity and efficacy.

Adjuvants, Immunologic↗
PubMed1983

Changes in cell-surface expression of MHC and Thy-1.2 determinants following treatment with lipid modulating agents.

Treatment of normal mouse spleen cells with lipid fluidity modulators changes the expression of cell-surface H-2 determinants. BALB/c spleen cells treated for 1 to 2 hr with cholesteryl hemisuccinate (CHS) displayed reduced levels of all tested H-2 determinants (H-2L, H-2K, and H-2D) as evaluated by flow microfluorometry and increased membrane lipid packing density as determined by 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence polarization. In contrast, decreasing membrane lipid packing density by phosphatidylcholine treatment decreased DPH fluorescence polarization and increased the expression of MHC determinants. The effects were selective in that expression of Thy-1.2 determinants was decreased by the latter treatment and not increased by CHS. The results are discussed in terms of passive modulation of antigenic expression.

Animals↗
PubMed1984

Modulation of class I HLA antigens on HL-60 promyelocytic leukemia cells by serum-free medium: re-induction by gamma-IFN and 1,25-dihydroxyvitamin D3 (calcitriol).

During studies on the effect of different nutrient media on the growth and differentiation of the HL-60 promyelocytic leukemia cell line, we found that the density of the class I HLA antigens is profoundly decreased on cells cultured in a serum-free medium. The ability of recombinant DNA-derived interferons (IFN) and a number of myeloid differentiating agents to induce re-expression of class I HLA antigens and beta-2-m was therefore studied. All three classes (alpha, beta, and gamma) of IFN were capable of re-inducing HLA and beta-2-m, although gamma-IFN was more potent. Of a variety of chemical differentiating agents, only 1,25-dihydroxyvitamin D3 (calcitriol) was found to induce HLA class I antigens. These results suggest that HLA and beta-2-m are not necessarily constitutive cell surface proteins, but instead that their expression is highly inducible.

Antibodies, Monoclonal↗
PubMed1981

Plasma membrane microviscosity of Lewis lung carcinoma cells derived from local growth and pulmonary metastases.

Significant differences in plasma membrane microviscosity between 3LL Lewis lung carcinoma cells, grown at the site of their original inoculation (1-3LL), and the pulmonary metastatic cells of this tumor (m-3LL) were detected by a recent improvement of the fluorescence polarization technique, especially designed for cells in suspension. Membrane microviscosity was also found to depend on the site of the growth and the stage of tumor development. The results show that lung metastases are lower in membrane microviscosity compared to 1-3LL and that, within the latter, cells grown in the muscle are characterized by higher microviscosity than those grown under the skin or in the footpad. Within one transplantation period, 3LL tumor cells tend to acquire membrane microviscosity values typical of the anatomical location of tumor growth. Tumors at advanced stages were generally found to be more rigid than young ones, where tumor size (volume) rather than its age seemed to determine the membrane microviscosity. These differences are discussed in terms of both the causes and the biological, as well as immunological, implications in relation to the newly proposed hypothesis of passive modulation of antigenic expression.

Animals↗
PubMed1981

Interaction between Plasmodium chabaudi and C57Bl mice with particular reference to the immune response.

The parasitaemia consequent upon infection of normal, T cell-deprived, or nude mice with a strain of Plasmodium chabaudi was studied. In normal mice three waves of parasitaemia of successively diminishing magnitude were observed, the infected animals becoming aparasitaemic within 45 days. In most T cell-deprived and nude mice a sustained cyclicity of parasitaemia was observed. Slight evidence was adduced of increase in virulence of the parasite with increasing time of infection in deprived mice. No positive evidence could be obtained for modulation of antigenicity of the parasite although this is suspected to be present. The results seem to be in conflict with the notion that the transient diminishing cyclicity of parasitaemia observed in normal mice is due to suppression of the parasite by the host. In the absence of what could be regarded as part of the host defence mechanism the cyclicity far from disappearing was exaggerated and prolonged.

Animals↗
PubMed1995

The DNA binding activity of wild type p53 is modulated by blocking its various antigenic epitopes.

Interaction of wild type p53 with specific DNA target sequences, which is dictated by several structural domains, can be modified by blocking the different antigenic epitopes of the protein. Comparison of p53 protein expressed by recombinant bacteria (wtp53-Bac) to that produced in an eukaryotic system by a vaccinia expression vector (wtp53-Vac), indicated that only the later exhibited spontaneous DNA-binding activity. Furthermore, DNA-binding patterns of these wild type p53 proteins were affected differently by their interactions with monoclonal anti-p53 antibodies recognizing individual antigenic epitopes of the molecule. While the vaccinia derived p53 that spontaneously bound DNA is supershifted by the N'-terminal specific antibodies PAb-248, the bacterial derived p53 protein that retains this antigenic epitope but does not bind DNA spontaneously, is not affected. The C'-terminal specific PAb-421 antibodies accelerated binding of the bacterial p53 protein and modified the pattern of the interaction of the vaccinia derived p53 DNA. DNA-binding patterns generated by PAb-421 and PAb-248, suggest that either interaction of wild type p53 is dependent on modification of the p53 protein or that it interacts with cellular factors which their activity can be mimicked by PAb-421. Saturation of both types of wild type p53 with several anti-p53 monoclonal antibodies directed against the wild type p53 specific epitope that maps to the N'-terminal border of the DNA-binding region, blocked specific DNA-binding. The fact that most p53 mutants have lost the wild type p53 conformation specific epitope coupled with the observation that blocking of this site by binding specific antibodies, prevents the interaction of wild type p53 with DNA, suggests that maintaining the correct structural conformation of this site is central for DNA-binding activity. The wild type specific epitope which maps to the N'-terminal border of the DNA-binding region is neighboring the first beta-strand detected by the recent crystallographic analysis.

Animals↗
PubMedDate not supplied

[Present and future therapeutic strategies in rheumatoid arthritis].

The triad of inflammation, immunoproliferation and synovial hyperplasia is recognized in the pathogenesis of rheumatoid arthritis, however, the sequence of events remains as highly controversial as ever. The "RA pyramid" was established on the assumption that inflammation is at the top with the destructive processes as sequelae. The moderate successes achieved by conservative therapy with regard to long-term outcome cast doubt on this hypothesis. Inhibitors of prostaglandin synthesis have not been and are not disease modifying. Do substances which influence the endothelial adhesion molecules or leucocyte adhesion receptors (leumedines) promise to be more successful? Do the empirically developed disease modifying antirheumatic drugs (Gold parenteral, MTX) have to be administered earlier? Unfortunately, there is a need for a differential diagnosis which is prognostically valid with regard to the dynamics and aggressiveness of rheumatoid arthritis. Moreover, a pharmacological basis for optimally founded combination strategies is also lacking. Presently, the emphasis of research is directed at the regulation of dysfunctional immune systems. Immunosuppressives (cyclosporin A), cytokine antagonists, receptor antagonists and soluble cytokine receptors (IL-1, IL-6, TNF-alpha), antibodies against lymphocyte subgroups (CD4, CD7) or against cytokines and their receptors are part of the arsenal for the medium term. Too little is still known about the role of protective cytokines (TGF-beta, IL-4, gamma-INF). Currently, however, it is prognosticated that these targeted therapies will only succeed in RA subgroups or only in intelligent combinations. More attractive alternative are strategic therapy modalities which intervene very early in the pathological process, such as the modulation of antigen presentation (MHC blocking peptides, T-cell receptor antagonists, T-cell vaccination) or the induction of tolerance against autoantigens through the oral administration of antigens (collagen II, HSP's, OM-8980). If the center of the pathological process, however, is found in the synovial proliferation of tumor-like cell clusters, then there are only a few years at the beginning of the disease when there is a real chance to impede destruction. In this case, aggressive induction therapy can be the only key to success. In the future, specifically active cytostatics (inhibitors of angiogenesis) will have to be developed and clinical trials conducted on adjuvant therapies with substances which strengthen bone and cartilage, making them more resistant to aggressive cell clusters (bisphosphonates, calcitonins, metalloproteinase- or collagenase-inhibitors).

Adjuvants, Immunologic↗
PubMed1994

The rationale for immunotherapy in HIV-1 infection.

Human immunodeficiency virus type 1 (HIV-1) infection causes progressive and ultimately profound immunosuppression. Initially, however, infection is associated with vigorous virus-specific immune responses, including both neutralizing antibodies and cytotoxic T lymphocytes (CTLs). Although the host immune response is ultimately unable to eliminate the virus, experimental data suggest that these immune responses help to inhibit virus replication during the prolonged asymptomatic phase of illness. A number of mechanisms have been proposed to contribute to viral persistence in infected persons, among them direct immunosuppressive effects of the virus; defects in antigen presentation; down-modulation of human leukocyte antigens (HLA); clonal deletion of existing immune responses; sequence variation leading to immune escape; and decreased T-helper cell function. The rationale supporting the use of vaccine therapy in HIV-1 infection is based on the hypothesis that viral persistence is due to an inadequate immune response generated by natural infection and that the immune system can be induced to generate more effective immunoregulatory responses by vaccination. Potential mechanisms by which this might occur include enhanced clearance of circulating virus, enhanced recognition of virus variants, enhanced presentation of viral antigens to the immune system, and increased regional T-cell help. A number of protocols evaluating vaccine therapy in HIV-1 infection are presently under way, the results of which should facilitate rational decisions regarding the use of this approach in HIV-1-infected persons.

AIDS Vaccines↗
PubMed1993

Modulation by MHC class I antigens of the biology of melanoma cells. Non-immunological mechanisms.

Many human as well as experimental tumours, including melanoma, express reduced levels of major histocompatibility complex (MHC) Class I antigens. Decreased MHC Class I antigen expression may be selected during neoplastic progression because it allows tumour cells to escape killing by cytotoxic T lymphocytes. Furthermore, the regulatory role of MHC Class I antigens in the proliferation of T cells suggests that abnormalities in MHC Class I antigen expression may play a role in the disordered proliferation of malignant cells and in their metastatic potential by non-immunological mechanisms. This paper reviews some of the available evidence supporting the concept of non-immune functions of MHC Class I antigens in the biology of malignant cells, with emphasis on experimental models for metastatic melanoma.

Animals↗