Localized d-d excitations in NiO(100) and CoO(100).
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Journal Article↗
Biomedical subjects
H Merz
Publications and source records attributed to H Merz.
An immortalized cell line with features of human follicular dendritic cells. Antigen and cytokine expression analysis.
Follicular dendritic cells (FDC) are specialized cells residing primarily within lymphoid follicles. They bind immunocomplexes and play an important role in the presentation of antigen to follicular B cells. Isolation of FDC for in vitro studies, however, is difficult because they constitute only about 1% of the cells in lymphoid tissue and form tight clusters entrapping lymphocytes within their dendritic processes. The monoclonal antibody (mAb) Ki-M4, which is highly restricted in its binding to FDC, is used to identify these cells. In order to establish a new immortalized cell line with features of FDC, we applied a modified procedure to isolate and enrich FDC from human tonsils and fused them with the myeloma cell line SP2/0-Ag14. The new hybrid cell line, designated FDC-H1, is of both mouse lymphoid and human FDC origin. FDC-H1 was found to have unlimited growth potential and to consistently express the Ki-M4 antigen and other surface antigens of human FDC. Semiquantitative reverse-transcribed polymerase chain reaction (RT-PCR) of enriched FDC and FDC-H1 revealed the same highly restricted cytokine/mRNA profile for both, with detectable levels of interleukin (IL)-1 alpha and surface CD23 and a lack of mRNA for IL-1 beta, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, interferon-gamma, tumor necrosis factor-alpha, transforming growth factor-beta and granulocyte/macrophage-colony-stimulating factor. Additionally a weak but constant IL-6 mRNA expression was found in the cell line FDC-H1 by RT-PCR. In situ hybridization experiments in tonsils revealed IL-6 transcripts in cells with a staining pattern characteristic of a dendritic cell only in a few germinal centers. To our knowledge, FDC-H1 is the first cell line that constantly expresses surface antigens and a cytokine profile characteristic of FDC. It is, therefore, well suited for studying the biology of FDC and the functional relationship between FDC and normal or neoplastic lymphatic cells.
Animals↗
Cathepsin D and E co-expression in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) and Langerhans' cell histiocytosis: further evidences of a phenotypic overlap between these histiocytic disorders.
Nosological classification of sinus histiocytosis with massive lymphadenopathy (SHML; Rosai-Dorfman disease) is difficult, and the normal cellular counterpart of Rosai-Dorfman (RD) cells is uncharacterised. The peculiar S-100+ phenotype of RD cells suggests a relationship with the dendritic cell family. Recent investigations have revealed cathepsin E to be selectively concentrated in antigen-presenting cells, whereas cathepsin D was found to be expressed in cells of macrophage lineage. Cathepsin D and E distribution was investigated by immunohistochemistry in a series of SHML biopsies and in two types of dendritic cell proliferative lesions: dermatopathic lymphadenitis (DL) and Langerhans' cell histiocytosis (LCH). In SHML biopsies, RD cells and monocyte-related elements of the sinuses and pulp coexpressed cathepsin D and E. LCH cells also stained for both these aspartic proteinases. Conversely, in DL cathepsin E and D were localised to separate cells that resembled Langerhans' cells (LC) or macrophages, respectively, in morphology and distribution. Our data outline the peculiar immunophenotype of RD and LCH cells and suggest that caution should be exercised in the identification of their normal cellular counterpart. The common expression of cathepsin D and E and of S-100 protein suggests some phenotypic overlap between SHML and LCH cells, despite their striking morphological divergence.
Cathepsin D↗
Interleukin 7 as interleukin 9 drives phytohemagglutinin-activated T cells through several cell cycles; no synergism between interleukin 7, interleukin 9 and interleukin 4.
The effects of the interleukins IL-7 and IL-9 on cell cycle progression were investigated by conventional [3H]thymidine incorporation and by the bivariate BrdU/Hoechst technique. Both IL-7 and IL-9 drive phytohemagglutinin-activated T cells through more than one cell cycle, but IL-7 was more potent on cell cycle progression than IL-9. Neither synergistic nor inhibitory effects were seen between various combinations of the lymphokines IL-7, IL-9 and IL-4 compared to each lymphokine alone. When T cells are activated with phytohemagglutinin for 3 days, all or most IL-4 responsive cells respond to IL-7 as well, whereas only a part of IL-7 responders are IL-4 responders. In contrast, when T cells are activated with phytohemagglutinin for 7 days, the quantitative data of the cell cycle distribution suggest that the population of IL-7 responders is at least an overlapping, if not a real subset of the population of the IL-4 responders.
Cell Cycle↗
Thymic lymphomas in interleukin 9 transgenic mice.
Transgenic mice overexpressing the interleukin 9 gene were generated to study the biological activity of this cytokine in vivo. Although no major histological or morphological modifications of the lymphoid system were observed in most animals, approximately 7% of transgenic mice developed thymic lymphomas at the age of 3-9 months. The tumor cells, which were clonal, with unique T cell rearrangements, were double positive for the expression of CD4 and CD8. The need for additional transforming events, suggested by the low incidence of spontaneous tumors, was further indicated by the high susceptibility of the transgenic animals to injections of low doses of N-methyl-N-nitrosourea, a chemical carcinogen with a thymic tropism. Expression of interleukin 9 was required for optimal tumor growth in vivo, as one of the tumors studied, which had lost the transgene, was much more efficiently transplanted into transgenic than in normal mice. Moreover, the in vitro proliferative activity of interleukin 9 on cell lines derived from such transgene-negative tumors suggests that an autocrine loop mediates the proliferation of these cells in vivo. Taken together, these results indicate that dysregulated IL-9 expression could be involved in the development of some T cell malignancies.
Animals↗
Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene.
Mice deficient for interleukin-2 develop normally during the first 3-4 weeks of age. However, later on they become severely compromised, and about 50% of the animals die between 4 and 9 weeks after birth. Of the remaining mice, 100% develop an inflammatory bowel disease with striking clinical and histological similarity to ulcerative colitis in humans. The alterations of the immune system are characterized by a high number of activated T and B cells, elevated immunoglobulin secretion, anti-colon antibodies, and aberrant expression of class II major histocompatibility complex molecules. The data provide evidence for a primary role of the immune system in the etiology of ulcerative colitis and strongly suggest that the disease results from an abnormal immune response to a normal antigenic stimulus.
Aging↗
Constant detection of surface and cytoplasmic immunoglobulin heavy and light chain expression in formalin-fixed and paraffin-embedded material.
The introduction of microwave detection systems has significantly enhanced the sensitivity of immunohistochemistry in formalin-fixed, paraffin-embedded tissue. The combination of protease digestion and microwave treatment including the use of heavy metal salts or urea gives an Ig heavy and light chain detection system in formalin-fixed and paraffin-embedded material as good as that achieved using fresh frozen material, with the advantage of a well-preserved morphology. The sensitivity of this method depends on the heavy metal salt used and its concentration. The use of urea yields equally sensitive results, while avoiding the toxicity of heavy metal salts. Heating times in the microwave oven also have an important influence on the results. The microwave-based technique may allow for the improved accessibility of formalin-masked antigens, as was shown here for cytoplasmic and surface immunoglobulins. It was demonstrated that formalin-fixed specimens of Burkitt's lymphoma when subjected to the new protocol almost always showed surface Ig expression, giving results comparable to those obtained in frozen sections. Moreover, it could be shown that in cases of B-chronic lymphocytic lymphoma (B-CLL) or immunocytoma, surface and cytoplasmic Ig could be detected, so that the difference may be just a quantitative one and thus may no longer be safely used as a criterion in differential diagnosis. In future, the wide use of this technique will allow for the study of Ig expression at the single cell level in morphologically well-preserved material.
Formaldehyde↗
Inhibition of hepatitis B virus production by modified 2',3'-dideoxy-thymidine and 2',3'-dideoxy-5-methylcytidine derivatives. In vitro and in vivo studies.
The effect of analogues of both 2',3'-dideoxy-3'-fluorothymidine (FddThd) [2',3'-dideoxy-3'-fluorouridine (FddUrd), 2',3'-dideoxy-3'-fluoro-5-chlorouridine (FddClUrd), 2',3'-dideoxy-3'- fluoro-5-bromouridine (FddBrUrd) and 2',3'-dideoxy-3'-fluoro-5-bromovinyluridine (FddBVUrd)] and 2',3'-dideoxy-3'-fluorocytidine (FddCyt) [2',3'-dideoxy-3'-fluoro-5-fluorocytidine (FddFCyt), 2',3'-dideoxy-3'-fluoro-5-chlorocytidine (FddClCyt), 2',3'-dideoxy-3'-fluoro-5-methylcytidine (FddMeCyt), 2',3'-dideoxy-3'-fluoro-5-ethylcytidine (FddEtCyt), 2',3'-dideoxy-3'-chloro-5-methylcytidine (ClddMeCyt), 2',3'-dideoxy-3'-amino-5-methylcytidine (AmddMeCyt), 2',3'-dideoxy-3'-azido-5- methylcytidine (AzddMeCyt) and arabinosyl-5-methylcytosine (AraMeCyt)] were tested for their potential antiviral activity in vitro using the human hepatoblastoma cell line, Hep G2 2.2.15, which was transfected with a vector containing hepatitis B virus (HBV). It was found that FddThd, FddMeCyt, FddEtCyt, ClddMeCyt, AmddMeCyt and AraMeCyt display cytostatic activity at concentrations (CD50 values) between 0.54 (FddMeCyt) and 3.93 microM (FddEtCyt), while FddUrd, FddClUrd, FddBrUrd, FddBVUrd, FddCyt, FddFCyt, FddClCyt and AzddMeCyt do not affect cell growth at concentrations of up to 25 microM. Among the thymidine analogues tested, FddThd is the most effective antiviral agent: at a concentration of 0.03 microM a more than 90% reduction of HBV DNA synthesis was measured. On the other hand, the antiviral indexes displayed by FddClUrd, FddBrUrd and FddBVUrd are higher than tht of FddThd; FddUrd was completely inactive. The most powerful antiviral agents in the group of cytidine analogues tested in vitro were FddMeCyt (more than 90% reduction of HBVDNA synthesis at 0.10 microM) and ClddMeCyt (0.10 microM); FddClCyt, FddEtCyt, AmddMeCyt and AraMeCyt were of intermediate activity. None of the negligible antiviral activity was determined for FddUrd, FddCyt, FddFCyt and AzddMeCyt. FddThd and FddMeCyt displayed in vivo an antiviral effect in the duck/duck HBV (DHBV) animal system. Administration of 10 or 20 mg/kg (total daily dose) of FddThd and 5 or 10 mg/kg of FddMeCyt (i.m. daily) to ducks infected with DHBV for 12 days blocked virus production. Termination of treatment with FddThd of infected animals led to reappearance of the virus in the serum though at lower levels. The in vitro and the in vivo data suggest that FddThd and FddMeCyt might be promising antiviral agents for the treatment of infection caused by HBV in humans.
Animals↗
Activation of cytokines in Hodgkin's disease.
The complex histological pattern in Hodgkin's disease and in part in large cell anaplastic lymphomas (ALCL) suggests that close interactions exist between the tumor cells and reactive bystander cells. These interactions are most likely mediated by short ranged cytokines. The production of cytokines was analyzed in primary tissues and cell lines from Hodgkin's disease and ALCL by enzyme linked immunosorbent tests (ELISA), Northern blotting, immunohistological staining and in situ hybridization experiments. Our results indicate that Hodgkin's disease derived cell lines produce a variety of cytokines, such as IL1 alpha, IL4, IL5, IL6, IL8, IL9, TNF alpha and TNF beta but not IL1 beta, IL2, IL3 and G-CSF. In addition, the receptors for IL6 were detected in some of the cell lines. The expression of IL6 and IL6 receptors and IL9 has been confirmed for some primary tissues of Hodgkin's disease. From our data, we conclude that IL6, IL9 and additional cytokines are involved in the biology of Hodgkin's disease and ALCL.
Cell Line↗
HIV infection in human bone.
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Bone Diseases↗
[Cytokines and malignant lymphomas].
Cytokines are potent modulators of the physiological immune response. A number of reactive processes are associated with a deregulation of this cytokine expression. Animal models with transgenic mice or transfection experiments have shown that an autocrine or paracrine pathway might be involved in tumor progression and/or tumorigenesis. The study of cytokine expression in malignant lymphomas showed a heterogeneous expression pattern with a number of cases which quantitatively show indications for a marked deregulation of the cytokine expression. The expression od IL-7 and IL-9 seem to be special features of Hodgkin's disease and large cell anaplastic lymphomas. Transfection experiment with IL-9 into mouse T cells results in an autocrine loop and tumorigenesis of the transfected cells. These tumors share a number of similarities to Hodgkin's disease and large cell anaplastic lymphomas in human.
Animals↗
[HIV detection in the bone transplant with polymerase chain reaction].
In trauma surgery, bone transplantation was needed in nearly 15% of all operations for reconstruction of defects. A high risk of viral infection remains in transplantation, however, cocultivation procedures have shown that human immunodeficiency virus (HIV-1) resides in bone of HIV-infected persons. Safety guidelines for running bone banks were not always easy to follow, and physical or chemical procedures applied for disinfection failed to inactivate HIV-1. In the present study we show that the polymerase chain reaction technique is an appropriate and sensitive means of detecting the HIV-1 genome in bone material prior to transplantation and-used in this way-can help to diminish the risk of HIV-1 transmission via bone transplantation.
Bone Transplantation↗
Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma.
To test the possibility that interleukin-9 (IL-9), the human homologue of the mouse T-cell growth factor P40, may be involved in the pathogenesis of human lymphomas, we examined IL-9 expression in a variety of tumors both by Northern blot analysis and by in situ hybridization. Of 18 B-cell non-Hodgkin's lymphomas and 11 peripheral T-cell lymphomas, none expressed IL-9 message. By contrast, IL-9 message was found in two of six cases of large cell anaplastic lymphoma (LCAL) and in 6 of 13 cases of Hodgkin's disease (HD). In HD the strongest signals were observed in Hodgkin (H) and Sternberg-Reed (SR) cells, but IL-9 mRNA was also detected in small lymphocytic cells. A search for IL-9 message in a panel of 20 cell lines derived both from hematopoietic and nonhematopoietic tumors confirmed the unique association of IL-9 expression with HD and LCAL in as much as the only two cell lines with IL-9 message were derived from cases of HD and LCAL. These results suggest that IL-9 is not involved as an autocrine growth factor in the pathogenesis of most B- and T-cell lymphomas, but that it may play a role in HD and LCAL.
Blotting, Northern↗
Expression of interleukin-6 and interleukin-6 receptor in Hodgkin's disease.
Interleukin-6 (IL-6) is a multipotent lymphokine that can mediate differentiation of B cells into Ig-secreting cells, stimulate the growth of plasmacytomas, hybridomas, and T cells, and induce acute-phase proteins in liver cells. It has been suggested that IL-6 is involved in the pathogenesis of several diseases by autocrine or paracrine pathways. To examine whether IL-6 is possibly involved in the pathophysiology of Hodgkin's disease (HD), we analyzed the expression of IL-6 and IL-6 receptor mRNA and protein in cell lines and primary specimens from patients with HD. IL-6-specific transcripts were detected in three of six HD-derived cell lines by Northern blot analysis. In the culture supernatants of four HD-derived cell lines, IL-6 was detected by radioimmunoassay. Biologic activity of IL-6 was confirmed by proliferation of an IL-6-dependent cell line. In situ hybridization experiments showed IL-6-specific transcripts in Hodgkin (H) and Reed-Sternberg (RS) cells in primary tissues of two patients. In addition, mRNAs specific for the IL-6 receptor were detected in five HD-derived cell lines. Immunostaining experiments showed expression of IL-6 receptor molecules on H and RS cells in 8 of 16 cases with HD. Thus, our data suggest that IL-6 might be involved in the pathophysiology of HD.
Antibodies, Monoclonal↗
Regulation of IL-4 responsiveness in lymphoma B cells.
The responsiveness to IL-4 with and without costimulation with anti-IgM antibodies or phorbolester was studied in 35 cases of low grade non-Hodgkin lymphoma by analyzing enhancement of CD23 and HLA class II expression. The predominant phenotype responds directly to IL-4. Separate differentiation states can be distinguished according to coordinate or differential upregulation of CD23 and HLA class II molecules by IL-4 alone, and differences in responsiveness to anti-IgM antibodies. A particular subgroup of B-lymphoma cells defines a separate stage of B-cell differentiation. They fail to express high affinity binding sites for IL-4 and accordingly do not respond to IL-4-mediated signals. Cross-linking membrane IgM receptors or direct activation of protein kinase C via phorbolester induces IL-4 receptor expression and subsequent IL-4 reactivity.
Antibodies, Anti-Idiotypic↗
Interleukin 4 drives phytohemagglutinin-activated T cells through several cell cycles: no synergism between interleukin 2 and interleukin 4.
Cell kinetic studies of T cells stimulated with the interleukin 2 (Il-2), Il-4, or both lymphokines were performed with conventional [3H]thymidine incorporation and with the bivariate BrdU/Hoechst technique. Il-2 and Il-4 are able to drive phytohemagglutinin-activated T cells through more than one cell cycle. Neither synergistic nor inhibitory effect on T-cell proliferation was seen for the stimulation with both Il-2 and Il-4 as compared with the effect of Il-2 alone. The quantitative data of the cell cycle distribution of phytohemagglutinin-activated T cells suggest that the population of Il-4-responsive cells is at least an overlapping population, if not a real subset of the population of the Il-2-responsive cells.
Bisbenzimidazole↗
Cytokine expression in T-cell lymphomas and Hodgkin's disease. Its possible implication in autocrine or paracrine production as a potential basis for neoplastic growth.
The detection of an increasing number of cytokines and the demonstration of autocrine and paracrine mechanisms perpetuating tumor growth prompted the investigation of the expression of the cytokines IL-2, IL-3, IL-4, IL-5, IL-6, IFN gamma, Tac, and GMCSF in primary lymph-node biopsies of patients with peripheral T-cell lymphoma (n = 11), Hodgkin's disease (n = 13), and large-cell anaplastic lymphoma (n = 6) by means of Northern blot analysis and in situ hybridization (ISH); 15 of 28 cases had IL-6 message, predominantly in cases of Hodgkin's disease (HD) and large-cell anaplastic lymphomas (LCAL). Interferon gamma was found in about 50% of the cases among all entities. Other cytokine expression was rare except two cases of HD with high amounts of IL-4 mRNA. These results indicate that large amounts of growth factor transcripts are present in a variety of malignant lymphomas. The meaning of this expression is still unclear. It may be a loss of physiologic regulation within the cytokine network which may thus influence neoplastic cell growth as some cases have a quantity of cytokine expression which is similar or even above that of stimulated T cells. ISH demonstrates in individual cases that the expression is at least in part due to malignant cells.
Antibodies, Monoclonal↗
[Determination of HIV infection in human bones].
The human immunodeficiency virus type 1 (HIV-1) is harboured not only in lymphocytes and macrophages but also in other cells, e.g. brain cells. Hence, it is not surprising that HIV-1 is also present in bone of HIV-infected individuals. Here we present an assay system for detection of the virus in human bone pieces in vitro. Bone pieces (i) from uninfected individuals, which had been incubated with cell-free virus preparations or cells producing the virus, or (ii) from and AIDS patient were used. These specimens were coincubated with CEM cells, which in turn became infected; the infection was traced immunocytochemically and enzymatically. In addition, we show that infection of CEM cells by HIV-1 from bone of an AIDS patient in vitro can be blocked by Sulfoevernan, a compound recently discovered by our group.
Bone Transplantation↗