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)

In the present study, we show by Northern blot analysis and enzyme linked immunosorbent assay that the Hodgkin's disease (HD)-derived cell lines HDLM-2 and KM-H2 express a variety of cytokine genes either constitutively or upon induction with phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Cytokine genes expressed by HD-derived lines include granulocyte-macrophage colony-stimulating factor (CSF), macrophage-CSF, interleukin (IL)-1-alpha, IL-3, IL-5, IL-6, IL-8, leukemia inhibitory factor, tumor necrosis factor-alpha, tumor necrosis factor-beta, and transforming growth factor-beta, while transcripts and the corresponding proteins for granulocyte-CSF, IL-1-beta, IL-2, IL-4, IL-7, IL-10, and the JE/macrophage chemoattractant and activating factor gene were not detectable in cytoplasmic RNA and culture supernatants obtained from both lines. In addition, IL-2 receptor (R) p55 and macrophage-CSF R (c-fms) genes were expressed by both lines. HDLM-2, but not KM-H2 cells, exhibited the IL-6 R p80 and the IL-2 R p75 chain. Analysis of nuclear proteins that bind to oligonucleotides containing the consensus sequences of the transcription factors activation protein 1, nuclear factor (NF) kappa B, and NFAT 1 revealed a pattern for HD lines resembling that of activated T-cells: HDLM-2 and KM-H2 cells constitutively expressed NF binding to the NF of activated T-cells (type 1), previously described to be T-cell specific. In addition, NF kappa B-binding proteins obtained from both lines showed, in electrophoretic mobility shift assays, the same migration pattern as T-cell-derived proteins but differed from monocyte- and B-cell-derived proteins. UV cross-linking experiments confirmed that NF kappa B-binding proteins of M(r) 85,000, 75,000, and 50,000/55,000 were detectable in nuclear extracts obtained from T-cells and both HD lines, while monocytes and B-cells displayed the M(r) 50,000/55,000 and 75,000 NF kappa B complex only. Both HD lines also constitutively expressed transcripts for c-fos and c-jun, which are involved in heterodimeric formation of the transcription factor activation protein 1, as well as for the NF kappa B/KBF1 gene.
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PMID:Expression of cytokine genes, cytokine receptor genes, and transcription factors in cultured Hodgkin and Reed-Sternberg cells. 159 93

Tumor necrosis factor alpha (TNF alpha), which is produced by germinal center dendritic reticulum cells (DRC) in lymphoid tissue, plays a regulatory role in a local immune response. However no information is available on the nature and location of cells responding to this cytokine. Thus TNF receptor distribution was investigated in situ by immunohistochemistry using monoclonal antibodies directed against the p75 and p55 receptor proteins. Receptor expression was unique and restricted to the lymphoreticular tissue. The p75 receptor was found on activated lymphocytes and interdigitating reticulum cells of the T-cell area, whereas the p55 receptor was confined to the germinal center DRCs, which are the main site of TNF alpha production. The two receptor proteins were expressed on distinct cell populations of the lymphoid system and no coexpression was observed. Preliminary results indicate that TNF receptor (TNFR) expression is regulated; Upregulation of TNFR proteins was found in reactive hyperplasia together with increased TNF alpha expression. In lymphoproliferative disorders, expression of the p75 receptor and TNF alpha was found mainly in high-grade malignant non-Hodgkin lymphomas. In summary, TNF alpha produced by germinal center DRCs might regulate an in vivo immune response through autocrine and paracrine pathways. Thus TNF alpha might signal, through the distinct TNFR proteins, the p55 and p75 receptor, which are expressed on different cell types in lymphoid tissue.
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PMID:Tumor necrosis factor receptors in lymphoid tissues and lymphomas. Source and site of action of tumor necrosis factor alpha. 164 57

The authors studied the secretion of interleukin-2 (IL-2), the expression of interleukin-2 receptors (IL-2R; p55/Tac and p75), and the response to exogenous IL-2 by cultured Hodgkin's Reed-Sternberg cells (cell lines HDLM-1, HDLM-1d, and KM-H2) and T cells (H9, HuT78, HuT102, MOLT-4, and MT-2). All of these cells did not produce IL-2 or produced it in undetectable amounts, and their growth was not affected by the addition of anti-IL-2 or anti-IL-2R antibodies. This indicates that H-RS cells in long-term culture, as well as T cells, can grow independently of IL-2. The three H-RS cell lines, as well as two of the T-cell lines (HuT102 and MT-2), expressed Tac, whereas the other three T-cell lines were Tac negative. Expression of p75 was noted in the two Tac-positive T-cell lines, but not in cultured H-RS cells. The expression of Tac and p75 in HuT102 and MT-2 cells correlated well with their capacity to proliferate on treatment with exogenous IL-2. On IL-2 treatment, nucleic-acid uptake in Tac/p75-positive T cells increased approximately four- to sixfold, whereas the Tac/p75-negative T cells did not show increased proliferation. Unlike the T cells, the Tac-positive H-RS cells did not respond to IL-2. The lack of a proliferative response to IL-2 appears to be related to the absence of p75 in H-RS cells. A similar pattern (Tac positivity and p75 negativity) was noted in H-RS cells in lymph nodes involved by Hodgkin's disease. Thus the exogenous IL-2 released by surrounding T lymphocytes may not cause the proliferative activity of H-RS cells because of the lack of high-affinity IL-2 receptors in the latter cells. In contrast to H-RS cells in culture, H-RS cells in tissues were stained by a specific anti-IL-2 monoclonal antibody. This indicates that the expression of IL-2 or an IL-2-like substance by H-RS cells in tissues may be responsible, in part, for the great increase in the number of reactive T lymphocytes in tissues involved by Hodgkin's disease.
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PMID:Expression of p55 (Tac) interleukin-2 receptor (IL-2R), but not p75 IL-2R, in cultured H-RS cells and H-RS cells in tissues. 169 91

CD30 is a member of the tumor necrosis factor (TNF) receptor superfamily. CD30 is expressed on normal activated lymphocytes, on several virally transformed T- or B-cell lines and on neoplastic cells of Hodgkin's lymphoma. The interaction of CD30 with its ligand induces pleiotropic effects on cells resulting in proliferation, differentiation, or death. The CD30 cytoplasmic tail interacts with TNF receptor-associated factors (TRAFs), which have been shown to transduce signals mediated by TNF-R2 and CD40. We demonstrate here that TRAF2 also plays an important role in CD30-induced NF-kappa B activation. We also show that TRAF2-mediated activation of NF-kappa B plays a role in the activation of HIV transcription induced by CD30 cross-linking. Detailed site-directed mutagenesis of the CD30 cytoplasmic tail reveals that there are two independent binding sites for TRAF, each interacting with a different domain of TRAF. Furthermore, we localized the TRAF-C binding site in CD30 to a 5-7 amino acid stretch.
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PMID:CD30/TNF receptor-associated factor interaction: NF-kappa B activation and binding specificity. 879 Mar 94

The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and possible antitumor activity of a ligand fusion-protein, DAB389IL-2, in a phase I trial. This was a multicenter, open-label, dose-escalation trial. Patients with preserved organ function and histologically confirmed relapsed cutaneous T-cell lymphoma (CTCL), other non-Hodgkin's lymphomas (NHL), or Hodgkin's disease (HD) were eligible if their cancer was shown to express the interleukin (IL)-2 receptor by an immunohistochemical assay for the p55 or the p75 subunit. Patients received up to eight courses of DAB389IL-2 given as a short intravenous infusion daily for 5 days with subsequent courses every 21 days. The maximum tolerated dose (MTD) and tumor response was determined according to standard criteria. Seventy-three patients (44 men/29 women), aged 16 to 81 years (mean, 50.7) with CTCL (n = 35), NHL (n = 17), and HD (n = 21) were enrolled. The patients were extensively treated, failing 0 to 15 previous therapies (median, 4). Patients received one to six courses (mean, 3.3) of DAB389IL-2 over a range of 3 to 31 micrograms/kg/day. The dose-limiting toxicity was asthenia, establishing the maximum tolerated dose of 27 micrograms/kg/day. Approximately half of all patients had significant titers of antibody to diphtheria toxin or to DAB389IL-2 at the time of enrollment compared with 92% with titers at the end of treatment. The presence of antibody did not preclude clinical response. There were five complete (CR) and eight partial (PR) remissions in patients with CTCL with one CR and two PR occurring in NHL. The median time to response was 2 months and the duration of response was 2 to 39+ months. No responses were documented in patients with HD. DAB389IL-2 is well tolerated with an MTD of 27 micrograms/kg/day. This ligand fusion-protein showed antitumor effects in patients with IL-2 receptor expressing CTCL and NHL. Additional trials in these diseases are warranted.
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PMID:Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. 942 92

A prospective study was performed to assess the use of plasma measurement of tumour necrosis factor (TNF), lymphotoxin alpha (LT alpha) and their soluble receptors (p55 and p75) for prognostic risk assignment in 61 patients with Hodgkin's disease. Plasma levels of TNF, p55 and p75, but not of LT alpha, were higher in Hodgkin's disease patients than in healthy controls. Plasma levels of TNF, p55 and p75 were associated with several prognostic factors for Hodgkin's disease, including those related to the host (age, performance status) and to the tumour (disease stage, extranodal site involvement, bulky tumour, serum levels of LDH and beta2-microglobulin, histology). Elevated plasma levels of TNF, p55 and p75 were also associated with several parameters reflecting an immune activation, including the presence of B symptoms, elevated serum levels of gammaglobulins, alkaline phosphatase and fibrinogen, as well as peripheral monocytosis, anaemia and low serum albumin levels. Finally, elevated TNF ligand receptor plasma markers were associated with a lower incidence of complete response to therapy and predicted shorter free-from-progression survival and overall survival of the patients. These results indicate that the plasma levels of TNF and its soluble receptors correlate with clinical features and outcome of patients with Hodgkin's disease.
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PMID:Plasma levels of tumour necrosis factor and its soluble receptors correlate with clinical features and outcome of Hodgkin's disease patients. 964 58

We have studied tissue expression of the cytokine receptors using a high sensitivity biotin-streptavidin system on cryostat sections. We used a panel of monoclonal antibodies from the 6th International Workshop on Human Leukocyte Differentiation Antigens, namely CD25 (IL-2R alpha), CD95 (FAS antigen), CD116 (GM CSFR), CD117 (SCFR), CD120 alpha (TNFR I), CD120b (TNFR II), CD121a (IL-1R I), CDw123 (IL-3R), CD124 (IL-4R), CD126 (IL-6R), CD127 (IL-7R), CDw128 (IL-8R), CD130 (gpl130), CD131 (IL-3R), CD132 (IL-2R gamma), CD134 (OC-40), CD135 (FLT3/FLK2). Examined tissues (lymph nodes and spleens) were obtained from 12 patients with folicular non-Hodgkin's lymphoma, periferal T non-Hodgkin's lymphoma, B lymphoma, myeloma, Hodgkin's disease, two cases of T cell rich B-lymphoma, autoimmune haemolytic anemia and two cases of rudimentary trombocytopenic purpura. Our results indicate that immunohistological technology using native tissues on cryostat sections, monoclonal antibodies and the visualisation with biotin-streptavidin is a particularly suitable supplementary staining procedure for detection of the cytokine receptors in tissues.
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PMID:[Immunohistochemical detection of cytokine receptors on cryostat tissue sections]. 1037 62

Tumor necrosis factor (TNF) production and non-Hodgkin lymphoma (NHL) outcome was found to be related to the TNF(-308) polymorphism. To explore whether this could be linked to neighboring polymorphisms, we genotyped the TNF(-376,-308,-238,-163), lymphotoxin alpha (LTalpha)(+252), and HLA DRB1 alleles in 204 patients with NHL and 120 controls. TNF(-308A) was the only allele associated with higher TNF and its p55 and p75 receptors' levels (P =.009, P =.03, and P =.007) and lower complete remission rates (P =.006). Freedom from progression (FFP) and overall survival (OS) were shorter in patients with TNF(-308A) (P =.009 and P =.02), null HLA DRB1*02 allele (P =.007 and P =.14), or both genetic markers (P =.004 and P =.005). Multivariate analysis incorporating International Prognostic Index (IPI) identified TNF(-308A) (P <.0001, relative risk [RR] = 1.63; P <.0001, RR = 1.51) and null HLA DRB1*02 alleles (P =.015, RR = 1.18; P <.0001, RR = 1.25) as independent factors for FFP and OS. These results indicate the existence of at least 2 inherited factors involved in NHL outcome.
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PMID:Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome. 1235 19

DAB(389)IL-2 (ONTAK) is a fusion protein consisting of the ADP-ribosyltransferase and membrane translocating domains of native diphtheria toxin and the full-length sequence for interleukin-2 (IL-2) gene. In vitro data demonstrates that DAB(389)IL-2 is cytotoxic to cells expressing the high affinity IL-2 receptor (IL-2R). In Phases I and II clinical trials of patients whose tumor cells express a component of the IL-2R, the response rates were 18% for B-cell non-Hodgkin lymphoma (NHL) and 30% for cutaneous T-cell lymphoma (CTCL). In this study, we examined the effects of arginine butyrate on IL-2R expression and susceptibility of leukemia cells to intoxication by DAB(389)IL-2. We demonstrate that the p75 subunit of the IL-2R (IL-2Rbeta) is upregulated in the presence of low concentrations of arginine butyrate (0.06mM) which had no direct growth inhibitory effect on the cells. To explore mechanisms of this upregulation, we examined the effect of 0.06mM arginine butyrate on relevant transcriptional elements and on histone deacetylase and found activation of cAMP response element (CRE) but not NFAT or NFKB, as well as inhibition of histone deacetylase (HDAC). Our results suggest that the effects of physiologically achievable concentrations of butyrate on IL-2R expression could be exploited to enhance the susceptibility of intermediate and low-affinity IL-2R expressing leukemia cells to DAB(389)IL-2.
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PMID:Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene. 1244 77

One of the main functions of the tumor necrosis factor receptor (TNFR) family is induction of apoptosis. CD30, a member of the TNFR superfamily is overexpressed in highly proliferating tumors such as anaplastic large cell lymphoma (ALCL) and Hodgkin's lymphoma (HL). CD30 stimulation leads to apoptosis and growth arrest in cultured ALCL, but not in Hodgkin-Reed-Sternberg cells. To identify changes in the transcriptional program responsible for these opposing effects, we performed gene expression analysis in CD30-stimulated ALCL (Karpas 299) and HL (KM-H2) cell lines using cDNA microarrays. Selected genes were validated by real-time PCR. Hierarchical clustering was applied to the whole dataset and separated the cell lines clearly with respect to their origin. In HL, there were only minor CD30-specific alterations, whereas ALCL unequivocally showed a pronounced CD30-specific transcriptional response. Ninety-three genes (6.6% of total) were deregulated by more than a factor of two after CD30 stimulation in ALCL cells. The majority of genes identified are involved in cell cycle regulation and apoptosis. mRNA expression patterns further indicate that in contrast to HL, CD30 stimulation in ALCL induces cell death via the CD95-CD95 ligand (CD95L) pathway and the TNF-R1/TNF-R2 crosstalk. These data provide a detailed view on the transcriptional changes upon CD30 stimulation and may explain the observed functional differences of HL and ALCL.
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PMID:mRNA expression patterns indicate CD30 mediated activation of different apoptosis pathways in anaplastic large cell lymphoma but not in Hodgkin's lymphoma. 1619 18


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