Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD40 is a membrane glycoprotein expressed on normal and neoplastic B lymphocytes. Stimulation through CD40 regulates important cellular functions, but the effects depend on its membrane density. While extensive studies have characterized CD40 in non-Hodgkin lymphomas of immunocompetent individuals, little is known on the characteristics of this molecule in lymphomas arising in immunocompromised hosts. The aim of this study was to characterize the pattern of CD40 expression in an in vitro model constituted by AIDS small non-cleaved lymphoma (SNCCL) cell lines. The analysis of CD45 isoforms, a group of molecules alternatively spliced during B cell differentiation, has been chosen to correlate this process to the number of CD40 molecules per cell in these cell lines. Since Apo 1/Fas expression is upregulated on B lymphocytes after CD40 ligation and this expression is functionally relevant, we wanted to know whether a different CD40 pattern in AIDS-SNCCL cell lines could influence CD95 expression. We have shown that 3 of these cell lines (PA 682, Es III, and HBL-2) have high membrane CD40 expression (> 100,000 molecules/cell); they release large amounts of soluble CD40 (sCD40) in culture supernatants (>500 pg/ml), are CD45RA/RO double labelled, and express the Apo 1/Fas (CD95) antigen. On the contrary, low CD40 membrane antigen cell lines (BRGIgA, HBL-2, NC 71, AS 283A, and LAM C3+, < 50,000 molecules/cell) release low amounts of sCD40 (<300 pg/ml), are CD45RA+ but CD45RO-, and do not express CD95. EBV has no role in CD40 and CD45 isoform behaviour, because EBV superinfection of the EBV negative, low membrane CD40 HBL-2 cell line does not modify CD40 membrane expression, sCD40 production, or CD45 isoform and CD95 expression. Our data suggest that membrane CD40 in AIDS-SNCCL cell lines might be a key element in the regulation of their pathophysiology by influencing the expression of CD45 isoforms and of CD95, and by the release of its soluble form.
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PMID:High CD40 membrane expression in AIDS-related lymphoma B cell lines is associated with the CD45RA+, CD45RO+, CD95+ phenotype and high levels of its soluble form in culture supernatants. 905 40

CD40 is a 48 Kd integral membrane protein expressed by cells of B cells, origin, dentritic cells, monocytes, epithelial cells, endothelial cells and tumor cells including carcinomas, B cell lymphomas/leukemias and Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's disease (HD). CD40 has been clustered as a member of the nerve growth factor (NGF)/tumor necrosis factor (TNF) receptor superfamily with the corresponding counterstructure, the CD40 ligand (L) being mainly expressed by activated CD4+ T cells, but also some activated CD8+ T cells, basophils, eosinophils, mast cells and stromal cells. CD40L shares significant amino acid homology with TNF particularly in its extracellular domain ("TNF homology region") and is therefore viewed as a member of the TNF ligand superfamily. Binding of CD40L+ T cells to CD40+ B cells is thought to play a major role in T cell-dependent B cell activation, B cell proliferation, Ig isotype switching, memory B cell formation and rescue of B cells from apoptotic death in germinal centers. Mutations of the CD40L gene have been associated with the X-linked hyper-IgM immunodeficiency syndrome, pointing to the critical role of the CD40/CD40L interaction in the T cell-B cell interplay. Accordingly, expression of CD40 by human lympho-hematopoietic tumors has been shown in most of the B cell neoplasias, H-RS cells and HD and some carcinomas. In contrast, CD40L+ tumor cells are almost invariably restricted to CD4+/CD8- T cell lymphomas. Overall, functional CD40/CD40L interactions appear to be critical for cellular activation signals during immune responses and neoplastic tumor cell growth. The understanding of the biology of CD40L has improved our diagnostic and therapeutic repertoire in the management of several human diseases, including CD40+ tumors.
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PMID:CD40/CD40 ligand interactions in normal, reactive and malignant lympho-hematopoietic tissues. 908 33

CD30 is present on the surfaces of malignant cells from patients with Hodgkin's lymphoma, anaplastic large cell lymphoma, and other lymphomas. The yeast two hybrid genetic screen method was used to identify molecular effectors which mediate CD30 signalling events. Clones corresponding to genes coding for TRAF1, TRAF2, and TRAF3 molecules, postulated to be involved in signalling via the TNF and CD40 receptors, were isolated. In this report, we show that the CD30 intracellular tail contains two motifs that bind TRAFs. The more amino terminal motif, 558PHYPEQET565, binds TRAF2 and 3, while the more carboxyl terminal motif, 576MLSVEEEG583, binds TRAF1 and 2. We show that these amino acid motifs are conserved in TNFRp75 and CD40 and that sequences in these receptors homologous to TRAF-binding sequences found in CD30 can selectively bind the TRAFs in a predictable manner.
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PMID:Binding sites of cytoplasmic effectors TRAF1, 2, and 3 on CD30 and other members of the TNF receptor superfamily. 916 96

G28-5 sFv-PE40 is a single-chain immunotoxin targeted to CD40, which is highly expressed on human hematologic malignancies, including non-Hodgkin's lymphoma, B-lineage leukemias, multiple myeloma, and Hodgkin's disease, as well as certain carcinomas. In vitro analysis showed that this monovalent immunotoxin had a binding affinity of 3 nmol/L, within 15-fold of the bivalent parental monoclonal antibody. G28-5 sFv-PE40 was stable when incubated in mouse serum at 37 degrees C for 6 hours and cleared from the circulation of mice with a half-life of 16.7 minutes. This immunotoxin was effective in treating human Burkitt's lymphoma xenografted SCID mice with complete responses, defined by an asymptomatic phenotype for greater than 120 days, obtained at doses of 0.13 to 0.26 mg/kg. The efficacy of treatment was dependent on the schedule used, with every three days for five injections being the most effective tested. The toxicity of G28-5 sFv-PE40 was examined in SCID mice, rats, and monkeys, with the maximum tolerated dose being 0.48, 1.0, and 1.67 mg/kg, respectively. Comparative immunohistology showed that the G28-5 specificity was qualitatively similar between human and monkey tissue. In summary, G28-5 sFv-PE40 was effective at inducing complete antitumor responses in lymphoma xenografted mice at doses that were well tolerated in mice, rats, and monkeys.
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PMID:In vivo efficacy and toxicity of a single-chain immunotoxin targeted to CD40. 919 73

Human immunodeficiency virus (HIV)-1 infection is associated with the development of aggressive extranodal B-cell non-Hodgkin's lymphomas. Using microvascular endothelial cell (MVEC)-enriched bone marrow stromal cultures, HIV infection of stromal MVECs from lymphoma patients induced the outgrowth of malignant B cells. MVECs were the only HIV-infected cells in the stroma, and purified brain MVECs also induced a phenotype supportive of neoplastic B-cell attachment and proliferation. HIV infection of MVECs stimulated surface expression of CD40 and allowed preferential induction of the vascular cell adhesion molecule VCAM-1 after CD40 triggering. B-lymphoma cells expressed the CD40 ligand (CD40L), and blocking of CD40-CD40L interactions between HIV-infected MVECs and B-lymphoma cells inhibited B-cell attachment and proliferation. These observations suggest that HIV promotes B-lymphoma cell growth through facilitating attachment of lymphoma cells to HIV-infected MVECs and represent a novel mechanism through which viruses may induce malignancies.
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PMID:HIV-1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS-associated B-cell lymphomas. 935 99

Two genes encoding the latent membrane protein 1 (LMP1) of the Epstein-Barr virus (EBV) were isolated from a single case of Hodgkin's disease (HD) and were tested for their biological activities. The LMP1 gene from the Reed-Sternberg cells contained point mutations relative to the prototype LMP1 gene, leading to amino-acid exchanges. The LMP1 gene from passenger lymphocytes showed identical point mutations, but also had an in-frame insertion of 132 base pairs within the 33-bp repeat region. This insert encoding 44 amino acids contained the sequence PSQQS, corresponding to the potential TRAF-binding motif PXQXT/S. When compared to the B95.8 gene, both HD-derived LMP1 genes showed an increase in the transformation of Rat-1 rodent fibroblasts. The transforming ability of the LMP1 gene with the insertion was greater than that of the other HD-derived LMP1, and was comparable with the highly transforming LMP1-Cao gene derived from a nasopharyngeal carcinoma. The HD-derived genes stimulated expression of the cell-surface markers, CD40 and CD54, similarly to the LMP1-B95.8 gene, while the LMP1-Cao gene had a significantly reduced ability to induce these proteins. In contrast, the LMP1-Cao transactivated an NF-kappaB-response element more efficiently than did the HD-derived genes. Transfer of the 132-bp insert alone into the B95.8 gene did not increase its transforming activity to the LMP1-Cao level, indicating that additional mutations in the LMP1 gene are necessary for modulating this function.
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PMID:Isolation and analysis of two strongly transforming isoforms of the Epstein-Barr-Virus(EBV)-encoded latent membrane protein-1 (LMP1) from a single Hodgkin's lymphoma. 953 80

The Fas receptor (APO-1/CD95) is capable of inducing apoptosis of lymphoid cells and is expressed in some non-Hodgkin's lymphomas (NHLs). Fas expression is up-regulated at the surface of normal B cells upon triggering of the CD40 receptor. In this report, we investigated the sensitivity of NHLs to Fas-mediated apoptosis induced by anti-Fas monoclonal antibodies (MAbs) and its possible modulation by CD40 ligation in 18 NHL biopsy samples of various histological subtypes. Flow cytometric analysis showed that the fraction of Fas-expressing lymphoma cells was highly variable from sample to sample (from 1% to 93%, mean value 46%). The frequency of apoptotic cells was not significantly increased upon treatment with an anti-Fas MAb compared with control MAb in the 18 NHL cases analysed. The sensitivity of lymphoma cells to Fas-mediated apoptosis was correlated neither with the histological subtypes nor with the level of Fas expression. Activation of neoplastic B cells by CD40 ligation resulted in significant increases in Fas expression and Fas-induced apoptosis among the five B-NHL cases tested. The overall increase in apoptotic rates was moderate and remained lower in tumour samples than in control CD40-activated normal tonsil B cells. Altogether, our results indicate that the sensitivity to Fas-induced apoptosis is null or weak in NHL cells, irrespective of their histological subtype, and that it can be increased to a moderate and variable degree by CD40 ligation on neoplastic B cells. This may be an impediment to the development of Fas-based therapies for NHLs.
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PMID:Sensitivity to Fas-mediated apoptosis is null or weak in B-cell non-Hodgkin's lymphomas and is moderately increased by CD40 ligation. 968 98

The tumor cells in most cases of Hodgkin's disease (HD) have been recently recognized to originate from the B-cell lineage, but their precise differentiation stage is not fully clarified. Recently, we have reported that the histogenesis of B-cell lymphomas may be assessed by monitoring the expression pattern of BCL-6, a transcription factor expressed in germinal center (GC) B cells, and CD138/syndecan-1 (syn-1), a proteoglycan associated with post-GC, terminal B-cell differentiation. In this study, we have applied these two markers to the study of HD histogenesis. We have found that in nodular lymphocyte predominance HD (NLPHD) tumor cells consistently display the BCL-6(+)/syn-1(-) phenotype, indicating their derivation from GC B cells. Conversely, classic HD (CHD) is heterogeneous because the tumor cells of a fraction of CHD display the BCL-6(-)/syn-1(+) phenotype of post-GC B-cells, whereas another fraction of CHD is constituted by a mixture of tumor cells reflecting the GC (BCL-6(+)/syn-1(-)) or post-GC (BCL-6(-)/syn-1(+)) phenotypes. BCL-6(-)/syn-1(+) tumor cells of CHD are mostly found surrounded by T cells expressing CD40L, consistent with the observation that CD40 signaling downregulates BCL-6 expression. These data indicate that tumor cells of NLPHD uniformly display a GC B-cell phenotype, whereas the phenotype of tumor cells of CHD appears to be modulated by the surrounding cellular background, particularly CD40L+ reactive T cells.
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PMID:Expression status of BCL-6 and syndecan-1 identifies distinct histogenetic subtypes of Hodgkin's disease. 974 58

Hodgkin's disease is a common malignancy of the lymphoid system. Although the scarce Hodgkin and Reed-Sternberg (HRS) tumor cells in involved tissue synthesize major histocompatibility complex (MHC) class II and costimulatory molecules such as CD40 or CD86, it is unclear whether these tumor cells are operational antigen-presenting cells (APC). We developed an immunofluorescence-based assay to determine the number of MHC class II molecules present on the surface of single living HRS cells. We found that in fresh Hodgkin's disease lymph node biopsies, a subset of HRS cells express a substantial number of surface MHC class II molecules that are occupied by MHC class II-associated invariant chain peptides (CLIP), indicating deficient loading of MHC class II molecules with antigenic peptides. Cultured Hodgkin's disease-derived (HD) cell lines, however, were found to express few MHC class II molecules carrying CLIP peptides on the cell surface and were shown to generate sodium dodecyl sulphate (SDS)-stable MHC class II alphabeta dimers. In addition to showing deficient MHC class II antigen presentation in a subset of HRS cells, our results show that the widely used HD-cell lines are not ideal in vitro models for the disease. The disruption of MHC class II-restricted antigen presentation in HRS cells could represent a key mechanism by which these tumor cells escape immune surveillance.
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PMID:Deficient major histocompatibility complex class II antigen presentation in a subset of Hodgkin's disease tumor cells. 974 62

Costimulatory molecules are essential in cognate interactions between T and B lymphocytes. To study the prerequisites of functional interactions between malignant B cells and intermingled T cells in B-cell non-Hodgkin's lymphomas (B-NHL), we examined the expression of CD40, CD80 and CD86 and their ligands CD40 ligand (CD40L, CD154), CD28 and CTLA4 (CD152) using immunohistochemistry and confocal laser scanning microscopy. Almost all mucosa-associated lymphoid tissue (MALT) NHL were positive for CD40 and CD80 and in nine out of 14 cases were positive for CD86. The majority of follicle centre cell lymphomas (FCCL) expressed CD40, but were heterogeneous in their expression of CD80 and CD86. Most diffuse large cell lymphomas (DLCL) were CD80+, but lacked expression of CD86. These patterns reflect the differences in phenotype of normal marginal-zone B cells (as counterparts of MALT NHL) and germinal centre cells (as counterparts of FCCL and DLCL). Counter-receptors on T cells were detectable in 13 of 14 MALT NHL, 12 of 16 FCCL but only occasionally in DLCL (three of 12 cases). A subgroup of FCCL was identified with T-cell expression of CD40L, CD28 and CTLA4 simultaneously with strong expression of CD40 and CD86 on the tumour B cells. These results indicate that MALT NHL and a subset of FCCL are most optimally equipped for functional interactions with T cells. This may be supported by the demonstration of cytokine production - mainly in T cells - in MALT NHL [interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-10] and FCCL (IL-2, IFN-gamma) and to a lesser extent in DLCL.
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PMID:Localization in situ of costimulatory molecules and cytokines in B-cell non-Hodgkin's lymphoma. 976 48


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