IgE in Reed-Sternberg cells.
Explore the source record for details and available documents.
Antigens, Differentiation, B-Lymphocyte↗
Biomedical subjects
S M Hsu
Publications and source records attributed to S M Hsu.
Thrombomodulin staining of mesothelioma cells.
Explore the source record for details and available documents.
Adenocarcinoma↗
Russell bodies consist of heterogenous glycoproteins in B-cell lymphoma cells.
The phenotypic expression of Russell bodies (RB) in the tumor cells of two patients with different types of B-cell lymphoma and of one patient with plasma cell myeloma were examined. In both B-cell lymphomas, the RBs reacted consistently with anti-Leu 8 and anti-immunoglobulin M. The RBs in one case also reacted with other monoclonal antibodies, including anti-CD5, CD19, CD22, and CD25. The membranes of most of the tumor cells containing RBs did not stain. In the myeloma, the RBs reacted only with anti-immunoglobulin, and the myeloma cells expressed no surface antigens associated with B lymphocytes. This finding suggests that RBs do not form in cells that can transport glycoproteins to the cell membrane, but rather occur as a result of defective transport or process of certain glycoproteins by plasmacytoid cells.
Antibodies, Monoclonal↗
Thrombomodulin expression in malignant pleural mesothelioma and pulmonary adenocarcinoma.
Thrombomodulin (TM) is a glycoprotein of molecular weight 75,000 kd that is normally present in restricted numbers of cells, including endothelial and mesothelial cells. In this study, the authors tested the possibility of using anti-TM to facilitate the diagnosis of mesothelioma. All of the 31 mesotheliomas and the two mesothelioma cell lines (MS-1 and MS-2) tested were stained positively with anti-TM. The specificity of anti-TM staining in mesothelioma cells was further confirmed by in situ hybridization of MS-1 cells with a TM-specific probe. The expression of TM in MS-1 cells was increased markedly when these cells were induced by 12-0-tetradecanyl phorbol 13-acetate (TPA) to differentiate. The expression of TM in mesothelioma cells, however, did not correlate with any particular phase of the cell cycle. In an attempt to differentiate pleural mesothelioma from pulmonary adenocarcinoma, the authors compared the expression of TM, carcinoembryonic antigen (CEA), and Leu M1 in these two types of tumors. Only four of 48 (8%) pulmonary adenocarcinomas were stained positively by antibodies to TM. Therefore, immunohistochemical staining with antibodies to TM yielded 100% sensitivity and 92% specificity for diagnosis of mesothelioma. All of the mesotheliomas stained negatively for CEA and Leu M1, except for one, which showed minimal focal positivity for Leu M1. In contrast, 79% and 60% of adenocarcinomas stained positively for CEA and Leu M1, respectively. These findings suggest that immunocytochemical staining with anti-TM should be added to the battery of tests to increase the diagnostic sensitivity and specificity for differentiating mesothelioma from pulmonary adenocarcinoma.
Adenocarcinoma↗
Functional heterogeneity and pathogenic significance of interleukin-6 in B-cell lymphomas.
A possible autocrine effect of interleukin-6 (IL-6) on the growth and differentiation of the tumor cells of 55 B-cell lymphomas was examined. Interleukin-6 was detected in a few types of B-cell lymphomas, including polymorphic immunocytoma (PI), small lymphocytic lymphoma (SLL), and immunoblastic lymphoma (IBL) with or without plasmacytoid differentiation. In PI and in IBL with plasmacytoid differentiation (IBL-P), IL-6 was detected only in immunoglobulin-containing plasmacytoid cells, and it was absent from most proliferating (Ki-67/PCNA-positive) lymphoma cells. In SLL, IL-6 was not observed in lymphoplasmacytoid cells; instead, IL-6 was observed in transformed (Ki-67/PCNA-positive) tumor cells in proliferation centers. The lymphoplasmacytoid cells in SLL exhibited a phenotype (IL-6/glutathione-S-transferase-pi [GST-pi]-negative), different from that of normal plasma cells (IL-6-negative/GST-pi-positive) and from the plasmacytoid cells (IL-6/GST-pi-positive) in PI and IBL-P. In IBL without obvious plasmacytoid differentiation, IL-6 was detected in most tumor cells that were highly proliferative (Ki-67/PCNA-positive). In this study, IL-6 was undetectable in most lymphomas related to follicular centers, in lymphoblastic lymphoma, in small noncleaved cell lymphomas of the Burkitt and non-Burkitt types, and in diffuse large cell lymphoma. This finding is compatible with a previous finding that IL-6 mRNA was absent from follicular center cells in reactive lymphoid tissues. The functions of IL-6 in these lymphomas may be quite diverse. It appears that IL-6, as an autocrine factor, is responsible for the plasmacytoid differentiation of lymphoma cells in IP and some IBL (IBL-P). The differentiation of lymphoplasmacytoid lymphoma cells in SLL, however, may not be mediated by an autocrine IL-6 mechanism. Interleukin-6 may provide a growth signal, rather than acting as a differentiation factor, for some IBL cells and for some transformed tumor cells in proliferation centers in SLL.
Cell Differentiation↗
Interleukin-4 may contribute to the abundant T-cell reaction and paucity of neoplastic B cells in T-cell-rich B-cell lymphomas.
T-cell-rich B-cell lymphomas (TCRBCLs) are diffuse lymphomas that contain a minority of large neoplastic B cells amidst a majority of non-neoplastic T cells and numerous histiocytes, an unusually pronounced reactive component not seen in most diffuse large B-cell lymphomas (DLBCLs). This reaction may be influenced by various cytokines secreted by lymphoma or reactive cells; therefore, expression of interleukin (IL)-1 beta, IL-2, IL-4, IL-6, and IL-9 was evaluated immunohistochemically on paraffin-embedded sections of 18 TCRBCLs and was compared with that of 15 DLBCLs containing a minority of reactive T cells and to that of seven reactive lymph nodes. Moderate to intense expression of IL-4 was detected in variable numbers of tumor cells and in numerous histiocytes in 16 TCRBCLs. In contrast, intense IL-4 expression in numerous histiocytes was observed in only one of 15 DLBCLs with few T cells. In four other DLBCLs and three reactive nodes, moderate to intense staining for IL-4 was noted only in rare large transformed cells or in occasional histiocytes. Except for one IL-1 beta positive and another IL-9 positive TCRBCL, there was no marking or weak staining only with other cytokine antibodies in the neoplastic and reactive cases studied. The expression of IL-4 in most TCRBCLs, but not in other DLBCLs or in reactive nodes, suggests that this cytokine is one factor involved in the pathobiology of the abundant T-cell reaction and, perhaps, contributes to the paucity of neoplastic B cells in TCRBCLs.
B-Lymphocytes↗
Interleukin-6, but not interleukin-4, is expressed by Reed-Sternberg cells in Hodgkin's disease with or without histologic features of Castleman's disease.
Hodgkin's disease (HD) is a neoplastic disease that is characterized by unbalanced and/or unregulated cytokine production. Information accumulated in our own and other laboratories indicates that the cytokines interleukin-1 (IL-1), IL-5, IL-9, tumor necrosis factor-alpha (TNF-alpha), granulocyte colony-stimulating factor (G-CSF), macrophage CSF (M-CSF), and transforming growth factor-beta (TGF-beta) are secreted by Hodgkin's and Reed-Sternberg (H-RS) cells. These and perhaps additional cytokines are likely to be responsible for the unique histopathologic and clinical alterations seen in patients with HD. In this study, we confirmed that IL-6 is produced by cultured H-RS cells as well as by H-RS cells in tissues. By using an enzyme-linked immunosorbent assay, we found that approximately 2 to 10 ng/ml of IL-6 was secreted by cultured H-RS cells (10(6) cells/ml). In tissues, we were able to immunolocalize IL-6 in the cytoplasm in 10 to 30% of H-RS cells by using rabbit polyclonal and mouse monoclonal anti-IL-6 antibodies. There was no correlation among the IL-6 staining intensity, number of H-RS cells stained, and the degree of plasma cell infiltration. However, in 3 of 17 cases studied, a large number (60%) of H-RS cells were positive for IL-6, and in these patients, abundant plasma cells were present. In one patient, the involved lymph node also showed histologic features similar to those of Castleman's disease. In this patient, we noted abundant IL-6 expression not only in H-RS cells, but also in most reactive histiocytes. The cultured H-RS cells did not express functional receptors for IL-6, and exogenously added IL-6 did not induce proliferation of these cells. We also conducted studies with specific anti-IL-4 antibodies, which did not show IL-4 production by H-RS cells in both cultures and tissues. In tissues, only rare IL-4 positive lymphoid cells or dendritic cells were identified. Thus, the study demonstrated that adequate amounts of IL-6 are required for an abundant plasma cell reaction, and that an additional source of IL-6 from histiocytes is essential for the formation of Castleman's disease-like changes in lymph nodes involved by HD. Furthermore, IL-4 is not likely to be responsible for the T-lymphocyte reaction in tissues, by a mechanism distinct from that in T-cell-rich B-cell lymphomas.
Aged↗
Correlation of c-fos/c-jun expression with histiocytic differentiation in Hodgkin's Reed-Sternberg cells. Examination in HDLM-1 subclones with spontaneous differentiation.
The c-fos proto-oncogene, which is the normal homolog of the transforming gene carried by murine osteogenic sarcoma viruses, interacts with the protein product of another proto-oncogene, c-jun, to form a heterodimer that can recognize and bind to a specific sequence of nucleotides in the DNA. The expression of c-fos and c-jun is linked to the proliferation of certain cells and the differentiation of others, including those of monomyelocyte lineage. The authors used two cultured Hodgkin's Reed-Sternberg (H-RS) cell lines, KM-H2 and HDLM-1, and their single-cell clones to study the correlation of c-fos/c-jun expression with cell differentiation in H-RS cells. Within 48 hours after induction with phorbol ester (TPA), both parent lines exhibited markedly increased expression of c-fos/c-jun. The expression returned to the preinduction level after 96 hours, however, and the cells retained their differentiated status. The transitory increase in c-fos/c-jun expression suggests that binding of these proteins to a specific promoter in the nucleus triggers a cascade of events that result in cell differentiation. Expression of these proteins may not be required for the cells to maintain their differentiation. The authors selected three groups of sublines of HDLM-1 cells based on their degree of spontaneous cytologic differentiation. The first group, without obvious differentiation, showed a c-fos/c-jun expression pattern similar to that of the parent line. The second group, with moderate differentiation, had a high degree of expression, which decreased on treatment with TPA. The third group, which had morphologic features resembling those of histiocytes, expressed minimal amounts of c-fos/c-jun, irrespective of TPA treatment. These findings provide further evidence that c-fos/c-jun expression is related to differentiation of H-RS cells, and that these proteins are not byproducts of TPA induction. Expression of c-fos/c-jun also was noted in a subpopulation of H-RS cells in tissues; and this expression also was enhanced when these cells were treated with TPA in culture. These findings indicate that H-RS cells can differentiate to become mature-appearing cells in tissues.
Adult↗
Differentiation-associated expression of prostaglandin H and thromboxane A synthases in monocytoid leukemia cell lines.
To elucidate the differentiation-associated expression of enzymes catalyzing arachidonic acid metabolism, we measured arachidonate metabolites by reverse-phase high pressure liquid chromatography in monocytoid leukemia (ML-1, THP-1, and U937) and myeloid leukemia (KG-1) cell lines. Undifferentiated ML-1 or THP-1 cells produced trace amounts of eicosanoids via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Upon differentiation induced by phorbol ester (phorbol 12-myristate 13-acetate [PMA]), metabolites via the COX pathway were increased by 100-fold in ML-1 and THP-1 cells, while the LOX products remained barely detectable. All the COX metabolites were elevated, but thromboxane A2 (TXA2) formation was threefold higher in ML-1 cells than in THP-1 cells. Similar time-related increases in COX metabolites were observed in THP-1 cells induced to differentiate with retinoic acid. Undifferentiated U937 cells were capable of generating a much higher quantity of COX products than ML-1 or THP-1 cells, but, upon PMA-induced differentiation, COX products were increased by only two-fold to threefold over the undifferentiated cells and the total COX products in differentiated U937 cells were only one-seventh of those produced by differentiated ML-1 or THP-1 cells. KG-1 cells had an entirely different metabolic profile. They produced a large quantity of a metabolite coeluted with prostaglandin D2, and PMA had no effect on inducing changes in arachidonic acid (AA) metabolism. Increased COX metabolite formation in differentiated THP-1 and ML-1 cells was due to an enhanced level of prostaglandin H synthase enzyme mass, as measured by Western blot analysis. The TXA synthase activity was also increased by approximately 100-fold in PMA-induced ML-1 cells and 10-fold in THP-1 cells. These findings indicate that increased expression of prostaglandin H and TXA synthase enzymes is a feature of differentiated monocytoid leukemia cell lines.
Arachidonic Acid↗
Two cell lines with epithelial cell-like characteristics established from malignant fibrous histiocytomas.
Two malignant fibrous histiocytoma (MFH) cell lines were established: one from a storiform-pleomorph subtype and the other from a myxoid one (codes, MFH-3 and MFH-4). Light microscopic examination revealed large rounded cells, growing mostly separately, in both cell lines. Their ultrastructure was different in various aspects. The MFH-3 cells showed abundant lysosomal activity, a well-developed Golgi apparatus, and a few desmosome-like cell contacts. The MFH-4 cells had a well-developed rough endoplasmic reticulum, delicate bundles of tonofilaments, the formation of pseudoacini, and the presence of small completely developed desmosomes. Based on immunostaining and immunoblotting assays of cultured cells, both cell lines expressed immunoreactivity for vimentin; cytokeratins 7, 8, and 18; desmin; and laminin, but they lacked reactivity for cytokeratins 10 and 19, neurofilament, alpha-smooth muscle actin, S-100 protein, collagen type IV, carcinoembryonic antigen, and antigens specific for macrophages. Fibronectin and, to a variable extent, glial fibrillary acid protein and epithelial membrane antigen (EMA) were detectable in MFH-3 cells only. Furthermore, a 60-kilodalton band was present in both cell lines which was reactive for cytokeratins 8 and 18. The MFH-3 cells had the capacity to grow as xenografts with a carcinoma-like pattern. The cells retained their immunoreactivity for vimentin and cytokeratin 8 and showed the presence of desmosomes. Several of these immunophenotypic features also were noticed in established sarcoma cell lines and in short-term cultures of fibroblasts, smooth muscle cells, and endothelial cells. However, experimental data on the two MFH cell lines show that the MFH cell line may express some immunophenotypic and ultrastructural features considered to be specific for epithelial cells. The MFH cells may originate from multipotential mesenchymal cells with a capacity to differentiate to fibroblast-like cells, and less frequently, to epithelial cells, smooth muscle cells, and Schwannian cells. Such a differentiation became evident when these cells were adapted to culture conditions or grew in nude mice.
Aged↗
Lymphomas of true histiocytic origin. Expression of different phenotypes in so-called true histiocytic lymphoma and malignant histiocytosis.
The authors determined the phenotypes of neoplastic cells in true histiocytic lymphoma and malignant histiocytosis by using a large panel of monoclonal antibodies and enzyme histochemistry procedures. Although the phenotypes overlapped slightly, the authors noted a distinct pattern in these tumors. The tumor cells of malignant histiocytosis generally expressed the monocyte markers CD11b, CD11c, CD14, and CD45, especially after induction with phorbol ester. In contrast, the tumor cells of true histiocytic lymphoma exhibited a marker expression very similar to that of Reed-Sternberg cells in Hodgkin's disease. These cells expressed markers CD30, 2H9, and 1A2, but rarely expressed CD11b, CD11c, CD14, or CD45. Regardless of their cytologic features, the tumor cells from both types of histiocytic lymphoma exhibited diffuse nonspecific esterase and acid phosphatase activities, and they expressed histiocyte markers CD15, CD68, LN5, 1E9, and M387 to varying degrees. The tumor cells from both lymphomas did not exhibit T- or B-cell markers, T-cell receptor or immunoglobulin gene rearrangements, or gene translation products, even when they were induced with phorbol ester. The phenotypic expression in these two histiocytic malignancies suggests that they are derived from different types of histiocytes, or from histiocytes in different stages of maturation or differentiation, or from histiocytes that have distinct mechanisms of tumorigenic transformation. The expression of circulating monocyte markers in malignant histiocytosis suggests that this tumor originates in monocytes or free histiocytes, whereas the phenotype of true histiocytic lymphoma is compatible with an origin in fixed histiocytes, which generally are devoid of the monocyte markers CD11b and CD14.
Adolescent↗
Expression of macrophage colony-stimulating factor (M-CSF) in two Hodgkin's Reed-Sternberg (H-RS) cell lines, HDLM-1 and KM-H2, and in H-RS cells in tissues.
The authors studied the production of macrophage colony-stimulating factor (M-CSF) and the expression of its receptor (c-fms) in two Hodgkin's Reed-Sternberg (H-RS) cell lines, HDLM-1 and KM-H2 and in H-RS cells in tissues. We found that both types of H-RS cell can produce M-CSF, as was confirmed by the presence of M-CSF mRNA and protein in the cells and by the presence of macrophage colony-stimulating activity in conditioned medium. M-CSF was also expressed by H-RS cells in lymph nodes from patients with Hodgkin's disease. In cultures, KM-H2 cells appeared to produce a lesser amount of M-CSF than did HDLM-1 cells, as indicated by weaker staining with anti-M-CSF in the former cells. In KM-H2 cells, most of the M-CSF was located in the cytoplasm, and in HDLM-1 cells, in the Golgi apparatus and/or on the cell membrane. The two types of cultured H-RS cell either did not express c-fms at all, or expressed it only extremely weakly, perhaps because of the loss of dependence on specific growth factors during culture. The production of M-CSF by H-RS cells may contribute to the clinical and pathologic changes seen in patients with Hodgkin's disease, such as the increased abundance of histiocytes in tissues infiltrated by H-RS cells. Alternatively, the expression of both M-CSF and c-fms could confer a growth advantage to some H-RS cells in an autocrine fashion.
Animals↗
Antitumor effects of ricin A chain immunotoxins prepared from intact antibodies and Fab' fragments on solid human Hodgkin's disease tumors in mice.
Three monoclonal antibodies which strongly bind to Hodgkin and Reed-Sternberg cells and two corresponding Fab' fragments were linked to deglycosylated ricin A chain (dg A) to evaluate their potential as immunotoxins for the treatment of Hodgkin's disease. Two of the antibodies, Ber-H2 and HRS-3, were shown to bind to the same epitope on the CD30 antigen, whereas the third antibody, IRac, bound to a different antigen. None of the antibodies significantly cross-reacted with normal human tissues as judged by indirect immunofluorescence and immunoperoxidase analyses on frozen sections from 28 normal tissues. All three antibodies formed potent and specific immunotoxins. They inhibited protein synthesis of the L540 Hodgkin's disease cell line in vitro by 50% at concentrations of 1 x 10(-11) M for IRac.dgA, 9 x 10(-11) M for HRS-3.dgA, and 2 x 10(-10) M for Ber-H2.dgA. HRS-3 Fab' and IRac Fab' immunotoxins were 7.8- and 60-fold less cytotoxic, respectively, than their intact counterparts in vitro. In vivo, a single i.v. injection of a dose of Ber-H2.dgA, HRS-3.dgA, or IRac.dgA corresponding to 40% of the LD50 induced lasting complete remissions in 38, 44, and 50%, respectively, of mice with solid s.c. L540 tumors of 60 to 80 mm3 size (0.5-cm diameter). At equivalent dosage (40% of the LD50), the HRS-3 Fab'.dgA and the IRac Fab'.dgA both induced lasting complete remissions in 25% of the mice, although the HRS-3 Fab'.dgA was significantly superior to IRac Fab'.dgA at retarding tumor growth in the remaining animals. The effectiveness of the immunotoxins depended on the size of the tumor at the time of injection, since IRac.dgA treatment induced complete remissions in 100% of mice with small tumors (10 to 20 mm3, approximately 0.3 cm in diameter) but only 13% of mice with larger tumors of 400 to 600 mm3 (approximately 1 cm in diameter). Tumors which regrew after IRac.dgA treatment mainly consisted of antigen-deficient mutants having reduced sensitivity to IRac.dgA but normal sensitivity to HRS-3.dgA. It is concluded that HRS-3.dgA, HRS-3 Fab'.dgA, and IRac.dgA are candidates for the treatment of Hodgkin's disease in humans.
Animals↗
The never-ending controversies in Hodgkin's disease.
Explore the source record for details and available documents.
Biomarkers, Tumor↗
Identification of an Mr 70,000 antigen associated with Reed-Sternberg cells and interdigitating reticulum cells.
We obtained a monoclonal antibody that has restricted reactivity with tumor cells [Hodgkin's mononuclear cells and Reed-Sternberg (H-RS) cells] in Hodgkin's disease by immunizing mice with 12-O-tetradecanoyl phorbol-13-acetate-induced H-RS cells. The antibody, anti-IRac, reacted with H-RS cells in 8 of 20 patients who had Hodgkin's disease, as well as with interdigitating reticulum cells in dermatopathic lymph nodes and with cells of three H-RS cell lines, HDLM-1, L428, and KM-H2. The antigen IRac is a protein of molecular weight 70,000 which we found to have the following properties. (a) After 12-O-tetradecanoyl phorbol-13-acetate induction, the expression of IRac was decreased slightly in HDLM and L428 cells but increased in KM-H2. This is in contrast to a rapid decrease in the expression of two other H-RS-cell-associated antigens, CD30 and 2H9, in all 12-O-tetradecanoyl phorbol-13-acetate-treated H-RS cells. Thus, IRac may be associated with H-RS cells at advanced stages of differentiation, and its expression may not be attributable solely to cellular proliferation. (b) IRac was detected rarely in normal or in antigen- or mitogen-activated lymphocytes but was observed frequently in virus-transformed B- or T-lymphocytes. These findings were similar to those with CD30 and 2H9, indicating that the expression of all three of these antigens is probably under a similar regulatory control. (c) IRac was absent from cells in most non-Hodgkin's lymphomas; its expression could not be modulated by treatment of cells with anti-IRac. We conclude that use of IRac could facilitate the diagnosis of Hodgkin's disease and that it may be suitable for immunotherapy or immunoimaging. The expression of IRac in both H-RS cells and interdigitating reticulum cells, along with earlier evidence, indicates that H-RS cells have antigenic and functional similarities to interdigitating reticulum cells or to cells of interdigitating reticulum cell/histiocyte lineage.
Animals↗
Immunohistochemistry.
The use of the ABC technique, in which an avidin-biotin interaction is used for immunohistochemical studies, is a simple and straightforward procedure. All required reagents are commercially available. The main advantages of this technique are its sensitivity, specificity, and flexibility. It is crucial for the success of this staining procedure that the antibodies, the type of tissues, and the fixatives that are used be selected properly. The method can easily be adapted for electron microscopy, flow cytometry, in situ hybridization, Western blotting, and ELISA.
Animals↗
Establishment and characterisation of an Epstein-Barr virus negative B immunoblastic lymphoma cell line.
Explore the source record for details and available documents.
B-Lymphocytes↗
Characterization of a porcine CD1-specific mAb that distinguishes CD4/CD8 double-positive thymic from peripheral T lymphocytes.
Porcine peripheral T-cells bear CD4 and CD8 cell surface antigens that distinguish helper from cytotoxic T-cells. In distinction from what has been found in other species, a large percentage of peripheral T-cells simultaneously express both CD4 and CD8. Monoclonal antibody 76-7-4 was found to stain all cortical and 7 +/- 3% of medullary thymocytes, Ia+ epidermal cells (i.e. Langerhans cells), no peripheral T-cells and 50% of peripheral B-cells. The antigen detected appears analogous to human CD1. All cortical thymocytes were also stained with CD4 and CD8 mAb. Since 76-7-4 did not stain peripheral T-cells, we conclude that CD4/CD8 dual-expressing peripheral T-cells are not simply immature thymic emigrants.
Animals↗