Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

JD118 is a murine immunoglobulin M monoclonal antibody (mAb) under study as a therapeutic agent that is capable of potent human complement-mediated cytotoxicity (CMC) against B-cell lymphoma and leukemia targets. The JD118 antigen target was upregulated on fresh human B cells and B-cell neoplasms after brief in vitro incubation in media containing calf serum. To determine if cytokines could also lead to upregulation of JD118 antigen, alpha-interferon (alpha-IFN), gamma-interferon (gamma-IFN), interleukin 2 (IL-2), or IL-4 were added to fresh neoplastic B cells in serum-free media and changes in JD118 antigen expression were evaluated by flow cytometry (FCM). IL-4 was found to be the predominant cytokine responsible for inducing upregulation of the JD118 antigen. Marked JD118 upregulation by IL-4 was seen in 14 out of 14 chronic lymphocytic leukemia (CLL) samples tested, with 50 to 750-fold increases in four samples, 11 to 49-fold increases in four samples, and up to 10-fold increase in six samples. One B-cell lymphoma specimen was upregulated 18-fold, but no up-regulation was demonstrated in one hairy cell leukemia and two acute myelogenous leukemia specimens tested. The specificity of the IL-4 up-regulation was demonstrated by the elimination of its activity by blocking with a neutralizing anti-IL-4 mAb. IL-4 upregulation allows JD118 mAb CMC against otherwise antigen-negative targets and argues for phase I trials using a combination of IL-4 cytokine and mAb for B-cell neoplasms.
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PMID:Interleukin-4 priming enhances a target for human complement-mediated cytotoxicity of CLL. 768 3

The B7/BB1 molecule has recently been found to be expressed on professional antigen-presenting cells and to be the natural ligand for CD28 and CTLA-4 on T cells. On binding of B7/BB1, CD28 transduces a signal that synergizes with triggering of the T-cell antigen receptor, resulting in enhanced cytokine secretion. In view of the data supporting an antigen-presenting function of Reed-Sternberg cells, we evaluated the expression of B7/BB1 in lymph nodes affected by Hodgkin's disease. B7/BB1 was found to be strongly expressed by the Reed-Sternberg cells in all 47 cases of Hodgkin's disease studied. Moreover, Reed-Sternberg cells were frequently surrounded by CD28-expressing T cells. Evidence for a functional role of B7/BB1 on Reed-Sternberg cells was obtained by our findings that T-cell proliferation and interleukin-2 (IL-2) production in the primary allogenic mixed lymphocyte reaction (MLR), using the B7/BB1-expressing Hodgkin's disease-derived cell lines L428 and KM-H2 as stimulators, could be partially blocked by adding anti-B7 monoclonal antibody. B7/BB1 expression was also evaluated in a group of non-Hodgkin's lymphomas (n = 46). Whereas B7/BB1 was not expressed by the neoplastic cells of most non-Hodgkin's lymphomas, including T-cell-rich B-cell lymphoma (n = 11), it was present on the neoplastic cells of anaplastic large-cell lymphoma (Ki-1 lymphoma) (n = 5) and follicular lymphoma (n = 4). Our data provide further evidence for an accessory cell function of Reed-Sternberg cells. The accessory cell function of Reed-Sternberg cells might lead to pronounced T-cell activation in vivo, which might contribute to the Hodgkin's syndrome. In addition, our study indicates that B7/BB1 may be a useful marker for differentiating Hodgkin's disease from morphologically similar conditions such as T-cell-rich B-cell lymphoma.
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PMID:The B7/BB1 antigen is expressed by Reed-Sternberg cells of Hodgkin's disease and contributes to the stimulating capacity of Hodgkin's disease-derived cell lines. 769 51

IgG-RFB4-SMPT-dgA consists of deglycosylated ricin A chain (dgA) coupled to the monoclonal antihuman CD22 antibody, RFB4. This study determined the maximally tolerated dose (MTD) of this immunotoxin (IT) administered as a continuous 8-day infusion to 18 patients with B-cell lymphoma (30% CD22+ tumor cells) over 8 days. The MTD was 19.2 mg/m2/192 h (maximum toxicity grade 1), with vascular leak syndrome (VLS) as dose-limiting toxicity (DLT) at 28.8 mg/m2/192 h (grades 3 through 5 in 7 of 11 patients). Predictors of severe VLS included serum IT concentrations greater than 1,000 ng/mL and the absence of circulating tumor cells. Decreased urine sodium excreted in 24 hours provided evidence for mild VLS without notable changes in serum albumin. Four partial responses, 3 minor responses, 6 stable disease, and 3 progression of disease were observed. The mean maximal serum concentration (Cmax) in initial courses at the MTD (19.2 mg/m2) was 443 +/- 144 ng/mL (n = 3; range, 326 to 604). At 28.8 mg/m2/192 h, the Cmax was highly variable (n = 11; mean, 1,102 +/- 702; range, 9.6 to 2,032 ng/mL). Human antimouse or antiricin antibodies developed in 6 of 16 (37.5%) patients after one course of IT. However, 10 eligible patients received multiple courses of IT. Changes in serum cytokines and cytokine receptors did not correlate with toxicity but decreased soluble interleukin-2 receptor concentrations correlated with clinical response. Comparison to a prior study with the same IT administered by intermittent bolus infusions (Amlot et al, Blood 82:2624, 1993) suggests similar clinical response, toxicity, and immunogenicity.
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PMID:Continuous infusion of the anti-CD22 immunotoxin IgG-RFB4-SMPT-dgA in patients with B-cell lymphoma: a phase I study. 778 Jan 33

The intrathecal synthesis of interleukin 10 (IL-10) was investigated in 120 paired cerebrospinal fluid (CSF) and serum specimens from patients with various inflammatory and non-inflammatory diseases of the central nervous system (CNS). IL-10 was not demonstrated in the sera, but detectable levels were found in the CSF from: patients with acute viral ("aseptic") meningitis, but only within 48-72 h of symptom onset; human immunodeficiency virus type 1 (HIV)-infected patients with HIV-related encephalitis/leukoencephalopathy or cryptococcal meningitis; a patient with primary B cell lymphoma of the CNS, and a patient with encephalomeningeal sarcoidosis (in whom IL-10 was demonstrated in all CSF collected over a period of 6-months). In chronic meningeal infections/inflammations, IL-10 seems to be continuously produced within the CSF. Our findings suggest that IL-10, a cytokine which exerts many immunosuppressive actions, may play different immunomodulatory roles in CNS diseases; in particular, its intrathecal synthesis may explain why some infectious and inflammatory meningeal diseases may have slow development and chronic evolution.
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PMID:Intrathecal synthesis of interleukin-10 (IL-10) in viral and inflammatory diseases of the central nervous system. 783 46

The use of inhibiting cytokine-binding-proteins (CBPs) such as soluble cytokine receptors and anticytokine antibodies is considered for the treatment of cytokine-dependent diseases. The pleiotropic cytokine interleukin-6 (IL-6) is a target for immunointervention in numerous pathologic situations, including multiple myeloma, B-cell lymphoma, and rheumatoid arthritis. An antitumor response was obtained in the treatment of a patient with multiple myeloma. A controversial issue is to evaluate whether the carrier effect of the CBPs might limit their efficiency in blocking the target cytokine. We analyzed the pharmacokinetics of radiolabeled IL-6 in mice treated with various combinations of anti-IL-6 antibodies. We show that injection of one or two antibodies led to the stabilization of the cytokine. Conversely, simultaneous treatment with three anti-IL-6 antibodies, binding to three distinct epitopes, induced the rapid uptake of the trimeric immune complexes by the liver and the elimination of IL-6 from the central compartment. The use of cocktails of three antibodies binding simultaneously to a cytokine thus provides a new means of enhancing the clearance of the target molecule and should help in the design of antibody-based clinical trials by overcoming the problem of the accumulation of the cytokine in the form of monomeric immune complexes.
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PMID:Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6 antibodies. 784 13

beta-Endorphin affects mononuclear cell proliferation, cytokine production and calcium uptake in a naloxone-resistant manner. The presence of naloxone-insensitive binding sites for beta-endorphin have been demonstrated on murine EL4-thymoma cells, transformed human mononuclear cells and normal murine splenocytes. Since murine splenic B cells have been shown to express naloxone-resistant receptors for beta-endorphin in response to the mitogen, concanavalin A (Con A), the A20 B-cell lymphoma line was used to further study regulation of this site by Con A and dexamethasone. Analyses showed two sites: a high-affinity site, Kd1 = (8.7 +/- 2.3) x 10(-11) M and binding capacity (Bmax1) of (2.6 +/- 2.0) x 10(3) receptors/cell; and a low-affinity site, Kd2 = (2.2 +/- 0.8) x 10(-8) M with Bmax2 of (1.5 +/- 0.8) x 10(5) receptors/cell. Competition studies showed that N-acetyl-beta-endorphin was approx. 5-fold and beta-endorphin6-31 10-fold less potent than beta-endorphin1-31. Neither beta-endorphin1-27 nor naloxone, morphine or other opioid receptor agonists displaced [125I]beta-endorphin. Con A (20 micrograms/ml) significantly increased the Bmax (3.5-fold; expressed per cell) and resulted in a loss of the higher-affinity site. However, the increased Bmax occurred in proportion to the Con-A-induced increase in protein/cell. Dexamethasone (Dex) also increased Bmax, primarily by increasing (2-3-fold) the number of lower affinity sites. In contrast to Con A, two binding sites persisted after treatment with Dex, which exerted a minimal effect on protein/cell. Therefore, binding/cell and binding/protein/cell were both significantly enhanced by Dex. The combined effects of Dex and Con A on binding failed to show additivity or synergy. When binding was analyzed per protein/cell, the effect of Con A appeared to dominate; the Dex-enhanced binding/protein/cell was no longer evident in the presence of Dex plus Con A. Thus, Dex and Con A may enhance binding by independent mechanisms.
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PMID:Expression of naloxone-resistant beta-endorphin binding sites on A20 cells: effects of concanavalin A and dexamethasone. 785 49

Cytokines play important roles in the pathogenesis of lymphomas via an autocrine or a paracrine mechanism, or both. The characteristic clinical and histopathological features of malignant lymphomas may be due in part to elevated serum or tissue levels of cytokines. Determination of the effects of cytokines on the growth or differentiation of lymphoma cells is often complicated by the fact that more than one cytokine is responsible, and by the failure of anti-cytokine antibodies or antisense oligonucleotides to block the proliferation in vitro of lymphoma cells. However, it appears that IL-6 and/or IL-9 may play a prominent role in the tumor cell proliferation of Hodgkin's disease (HD), anaplastic large-cell lymphoma, or immunoblastic lymphoma. IL-6 may also be responsible for the plasmacytoid differentiation of lymphoma cells in polymorphic immunocytoma. The histopathological changes as a result of paracrine effects are most noticeable in HD. The malignant (H-RS) cells of HD have been shown to express IL-1, IL-5, IL-6, IL-9, TNF-alpha, M-CSF, TGF-beta, and CD80, and, less frequently, IL-4 and G-CSF. These cytokines may be responsible for the increased cellular reaction and fibrosis observed in tissues involved by HD and for the immunosuppression found in patients with HD. In contrast to H-RS cells, most non-HD lymphoma cells do not produce cytokines in excess amounts and reveal only a minimal cellular reaction. Exceptions include T-cell-rich B-cell lymphoma, angiocentric T-cell lymphoma, and angio-immunoblastic lymphadenopathy (AILD-like T-cell lymphoma. IL-4 is responsible for the T-cell reaction in T-cell-rich B-cell lymphoma, whereas IL-6 accounts for the plasma cell reaction in AILD-type T-cell lymphoma. The authors extensively review the role of cytokines in lymphomas because this may lead to major advances in the understanding of the molecular processes involved in the histopathogenesis of lymphomas.
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PMID:Autocrine and paracrine functions of cytokines in malignant lymphomas. 785 53

Striking antigenic changes were elicited by interleukin 4 (IL-4) in the Farage human B-cell lymphoma line. After 2 days of incubation with IL-4 the expression of CD23, CD54 (ICAM-1), CD58 (LFA-3) was increased while the levels of CD21, CD22, CD38 were diminished. Prolonged incubation of Farage cells with IL-4 for 6-8 days led to increased expression of CD11a (LFA-1) CD39, CD40, and to disappearance of CD21 and CD38. The modulation of antigenic properties of Farage cells was associated with enhancement of their homotypic adhesiveness and the formation of giant clumps of cells. The recovery of Farage cells which had been exposed to IL-4 for six days was not complete and eleven days after withdrawal of the cytokine, these cells still displayed a lower level of CD21 and of CD38 than control cells. Cycling and non-cycling cells did not appear to differ in their antigenic properties, indicating that modification of the antigenic profile did not result from cell selection or cell arrest. These results showed that the pleiotropic effect of IL-4 on various cell surface structures on malignant human B cells proceeds at different rates suggesting that distinct metabolic pathways may regulate their expression.
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PMID:Kinetics of the pleiotropic effect of interleukin 4 on the surface properties of human B-lymphoma cells. 786 83

We evaluated eosinophils morphology, physical properties and antileukemic activity in autologous bone marrow transplanted (ABMT) patients treated with subcutaneous recombinant interleukin 2 (rIL-2) and recombinant human interferon alpha 2a (IFN alpha) given as outpatient immunotherapy. All patients receiving rIL-2/IFN alpha therapy developed peripheral blood eosinophilia of 20-40% peaking at 2-4 weeks of therapy. While on rIL-2/IFN alpha therapy the eosinophils became hypodense and hypersegmented. The antibody dependent cell-mediated cytotoxic activity (ADCC) of the eosinophils against the human B-cell lymphoma cell line (Raji) was depressed post-ABMT. Prolonged (28 days) in vivo rIL-2/IFN alpha immunotherapy enhanced ADCC activity of the eosinophils and brought them to normal levels. Similarly, rIL-2/IFN alpha immunotherapy enhanced the depressed cytotoxic activity of neutrophils post-ABMT to normal levels. Thus, eosinophils and neutrophils from rIL-2/IFN alpha-treated ABMT recipients may be targeted toward tumor cells by antibody, and express tumoricidal activity. No effect of rIL-2/IFN alpha was observed on monocyte-dependent ADCC activity which remained normal post-ABMT. We conclude that in addition to their effect on lymphocytes, cytokine-mediated immunotherapy consisting of subcutaneous low doses of riL-2 and IFN alpha may mediate their therapeutic effects in cancer therapy by increasing the number of eosinophils and enhancing the antitumor activity of eosinophils and neutrophils, provided that tumor-specific or tumor-associated antibodies are present.
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PMID:Eosinophils activation in post-autologous bone marrow transplanted patients treated with subcutaneous interleukin-2 and interferon-alpha 2A immunotherapy. 805 77

B cell dysfunction associated with HIV infection includes polyclonal B cell activation and hypergammaglobulinemia. There is also an elevated frequency of B cell malignancies, especially non-Hodgkin's lymphoma, in HIV infection. It is believed that chronic polyclonal activation of B cells might increase the chances for the occurrence of a genetic accident, resulting in tumorigenesis. Long-term zidovudine use in people with HIV infection has been reported to be associated with a particularly high incidence of B cell lymphoma. This may be due to an increase in life span associated with antiretroviral treatment, placing treated individuals at risk for developing lymphoma for a greater period of time. However, zidovudine could be directly contributing to lymphoma-genesis in HIV-infected individuals, perhaps by enhancing B cell activation, since B cell hyperactivation and elevated levels of IL-6, a B cell stimulatory cytokine, are seen in HIV infection. Also, people treated with zidovudine may inherently be at higher risk for developing lymphoma because of the relatively greater degree of immune impairment seen in those that receive treatment with this drug. To examine if exposure to zidovudine resulted in enhanced B cell activation, we determined whether or not the presence of zidovudine enhanced B cell activation or IL-6 production in vitro or in vivo. Exposure to zidovudine in vitro did not enhance spontaneous immunoglobulin or IL-6 secretion by cells from HIV-infected (or uninfected) subjects and did not enhance B cell activation induced by EBV or affect the ability of T cells to regulate EBV-activated B cells. Neither serum immunoglobulin or IL-6 levels, nor the expression of cell surface activation markers on circulating B cells, were seen to increase following zidovudine treatment. These results indicate that zidovudine does not induce B cell activation in vivo or in vitro, suggesting that zidovudine treatment does not contribute to lymphomagenesis by enhancing B cell hyperstimulation.
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PMID:Effects of zidovudine on B lymphocyte activation. 808 61


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