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

The cure of human Hodgkin's tumors heterotransplanted into SCID mice can be achieved by two bispecific monoclonal antibodies (Bi-mAb) directed against the tumor-associated CD30 antigen and CD3 and CD28, respectively, and normal peripheral human blood T cells. We investigated the role of lymphocyte subsets and adhesion molecules in this Bi-mAb-mediated cytolysis. CD4+ lymphocytes were the most rapidly expanding subpopulation, but Bi-mAb-directed cytotoxicity was mediated preferentially by CD8+ lymphocytes and effector cells belonging to the CD45RO+ "memory" pool. Blocking of the LFA-1/ICAM-1 or CD2/LFA-3 adhesion pathways by mAb decreased Bi-mAb-mediated cytotoxicity. This was not due to inhibition of aggregate formation between Bi-mAb-coated T lymphocytes and target cells. Cross-linking of LFA-1 or CD2 molecules on lymphocytes prestimulated with Bi-mAb bound to CD3 and CD28 antigen lead to a more pronounced and prolonged rise in the intracellular concentration of free Ca2+. Additional CD2 cross-linking resulted in the tyrosine phosphorylation of distinct proteins. These findings indicate that adhesion molecules play a critical role and function as co-stimulatory signals rather than as cellular contact mediators in CD3 and CD28 Bi-mAb-stimulated T lymphocytes.
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PMID:The role of lymphocyte subsets and adhesion molecules in T cell-dependent cytotoxicity mediated by CD3 and CD28 bispecific monoclonal antibodies. 762 76

A glycoprotein (BLA.36), expressed on the plasma membrane of Hodgkin's cells and also on normal and malignant B lymphocytes and histiocytes, was identified by reaction with a monoclonal antibody. BLA.36 was not detectable on other hematopoietic, carcinoma or melanoma cell lines. BLA.36 was purified to homogeneity by extracting proteins from a Hodgkin's cell line (HDLM-3), followed by immunoaffinity chromatography, utilizing immobilized anti-BLA.36 antibody, and gel filtration on Sephacryl S-100 in the presence of protein dissociating agents. The purified component yielded a single band on sodium dodecyl sulphate/polyacrylamide gel electrophoresis under both non-reducing and reducing conditions, and closely related three isotypes of similar molecular weight and with the apparent isoelectric points that ranged from 5.0 to 5.2 on two-dimensional gel electrophoresis. The purified BLA.36 reacted with the original specific antibody, on both one- or two-dimensional gel electrophoresis, suggesting that antigenic determinant was not adversely affected during purification procedure. Competitive immunoprecipitation analyses and the determination of N-terminus sequence of the first 13 amino acid residues suggest that BLA.36 is unrelated to other known Hodgkin's or hematopoietic cell antigens. Finally, significance of BLA.36 expression on the growth of BLA.36-positive cell lines was studied. Blocking of BLA.36 with anti-BLA.36 antibody led to the in vitro growth-inhibition of BLA.36-positive cell lines. The antibody pre-absorbed with the purified BLA.36 was unable to exert growth-inhibition, demonstrating the specificity of reaction. In addition, the treatment of the BLA.36-positive cell lines with differentiation-inducing agent, alpha-interferon (alpha-IFN), down-regulated BLA.36 expression and also showed in vitro growth-inhibition of BLA.36-positive cell lines. Taken together, these results suggest a growth-related function of BLA.36.
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PMID:Purification and characterization of a Hodgkin's and B cell-associated glycoprotein. 1065 24

The chimeric anti-CD20 MAb rituximab has recently become a treatment of choice for low-grade or follicular non-Hodgkin's lymphomas (FL) with a response rate of about 50%. In this report, we have investigated the mechanism of action of rituximab on 4 FL and 1 Burkitt's lymphoma (BL) cell lines, 3 fresh FL samples and normal B cells in vitro. Rituximab efficiently blocks the proliferation of normal B cells, but not that of the lymphoma lines. We did not detect significant apoptosis of the cell lines in response to rituximab alone. All cell lines were targets of antibody-dependent cellular cytotoxicity (ADCC). On the other hand, human complement-mediated lysis was highly variable between cell lines, ranging from 100% lysis to complete resistance. Investigation of the role of the complement inhibitors CD35, CD46, CD55, and CD59 showed that CD55, and to a lesser extent CD59, are important regulators of complement-mediated cytotoxicity (CDC) in FL cell lines as well as in fresh cases of FL: Blocking CD55 and/or CD59 function with specific antibodies significantly increased CDC in FL cells. We conclude that CDC and ADCC are major mechanisms of action of rituximab on B-cell lymphomas and that a heterogeneous susceptibility of different lymphoma cells to complement may be at least in part responsible for the heterogeneity of the response of different patients to rituximab in vivo. Furthermore, we suggest that the relative levels of CD55 and CD59 may become useful markers to predict the clinical response. (Blood. 2000;95:3900-3908)
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PMID:Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. 1084 26

Afferent fibres of ampullary electroreceptor organs in electrosensitive fish fire spontaneously, that is, they fire without external stimulus. In the past it has been postulated that the spontaneous activity originates from a sustained level of neurotransmitter release delivered by the electroreceptor cells. The spontaneous activity can be modulated by electrical stimuli. Blocking of the chemical synapse, however, reduces the susceptibility to electrical stimuli to 2% or less, but the spontaneous activity to 60% only. By evaluating existing experimental evidence it is concluded that spontaneous firing of afferents is based on two processes. (1) A membrane bound oscillator, which does not depend on transmitter release, is almost free of frequency fluctuations, and is described by Hodgkin/Huxley-equations (HH-equations). (2) Release of neurotransmitter, which increases the firing level, adds frequency noise, and raises the susceptibility of the afferent to electrical stimuli. There is evidence that neurotransmitter release acts as a gating process, which makes the generator area of the afferents directly accessible to electrical stimuli from the outside. Apparently, the activated synapse behaves as a transmitter operated electrical synapse (TOES).
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PMID:Evidence for transmitter operated electrical synapses (TOES) in ampullary electroreceptor organs. 1719 25

Constitutive nuclear factor kappaB (NF-kappaB) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kappaB has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kappaB level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kappaB activation through IkappaB kinase activation in not only H-RS cell lines with wild-type IkappaBalpha, but also in those with IkappaBalpha mutations and lacking wild-type IkappaBalpha. Thus, both constitutive and inducible NF-kappaB are potential targets to treat HL. We also present the data that indicate the involvement of IkappaBbeta in NF-kappaB induction by topoisomerase inhibitors. A new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kappaB activity and induced apoptosis of H-RS cell lines. DHMEQ also inhibited the growth of H-RS cells without significant systemic toxicity in a NOD/SCID/gammac(null) (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NF-kappaB. Results of this study suggest that both constitutive and inducible NF-kappaB are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IkappaBbeta is involved in NF-kappaB activation in H-RS cells and IkappaBbeta substitutes for IkappaBalpha in H-RS cells lacking wild-type IkappaBalpha.
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PMID:IkappaBalpha independent induction of NF-kappaB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells. 1731 Feb 17

The nuclear factor of activated T cell 1 (Nfatc1) locus is a common insertion site for murine tumorigenic retroviruses, suggesting a role of transcription factor NFATc1 in lymphomagenesis. Although NFATc1 is expressed in most human primary lymphocytes and mature human T- and B-cell neoplasms, we show by histochemical stainings that NFATc1 expression is suppressed in anaplastic large cell lymphomas and classical Hodgkin's lymphomas (HLs). In HL cell lines, NFATc1 silencing correlated with a decrease in histone H3 acetylation, H3-K4 trimethylation, and Sp1 factor binding but with an increase in HP1 binding to the NFATC1 P1 promoter. Together with DNA hypermethylation of the NFATC1 P1 promoter, which we detected in all anaplastic large cell lymphoma and many HL lines, these observations reflect typical signs of transcriptional silencing. In several lymphoma lines, methylation of NFATC1 promoter DNA resulted in a "window of hypomethylation," which is flanked by Sp1-binding sites. Together with the under-representation of Sp1 at the NFATC1 P1 promoter in HL cells, this suggests that Sp1 factors can protect P1 DNA methylation in a directional manner. Blocking immunoreceptor signaling led to NFATC1 P1 promoter silencing and to a decrease in H3 acetylation and H3-K4 methylation but not DNA methylation. This shows that histone modifications precede the DNA methylation in NFATC1 promoter silencing.
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PMID:Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling. 1815 9

Research on B-cell non-Hodgkin lymphoma focuses mainly on oncogenic events occurring in lymphoma cells, but recently a new component has appeared that may be crucial in lymphomagenesis: the tumor microenvironment. Indeed, compelling evidence demonstrates the key role played by nonmalignant bystander cells in the establishment and proliferation of the tumor. Among these cells, stromal cells, monocytes/macrophages, and T cells in lymphoid organs have all been described as contributing to tumor progression. Interactions linked to cell-cell intimate contacts-but also mediated through soluble mediators such as cytokines and chemokines-do form a specific network. All these interrelations directed by the tumor create a friendly environment for lymphoma cells that permits them to proliferate. Blocking the cross-talk between the tumor microenvironment and lymphoma cells may thus represent a promising new strategy for treating B-cell malignancies.
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PMID:The host-tumor interface in B-cell non-Hodgkin lymphoma: a new world to investigate. 2042 8

Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.
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PMID:Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. 2081 59

Non-Hodgkin's lymphoma cells including lymphoma stem cells reside in a specific microenvironment in which a series of nonmalignant bystander cells and cytokines play a crucial role in the genesis and development of non-Hodgkin's lymphomas. In addition, tumor microenvironment has important prognostic significance in Non-Hodgkin's lymphomas. Blocking the cross-talk between the tumor microenvironment and lymphoma cells may thus represent a promising new strategy for treating Non-Hodgkin's lymphomas. This review summarizes the current advance in studies of the tumor microenvironment and non-Hodgkin's lymphomas, including cells in tumor microenvironment, role of mesenchymal stem cells and stromal cells, auxiliary role of T cell subsets, macrcphage and dentritic cells, cytokines, immune surveillance and so on.
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PMID:[Research progress of tumor microenvironment and non-Hodgkin's lymphomas]. 2172 85

In this paper, we analyze the effect of the redistribution of the transmembrane ion channels in an axon caused by longitudinal acoustic vibrations of the membrane. These oscillations can be excited by an external source of ultrasound and weak microwave radiation interacting with the charges sitting on the surface of the lipid membrane. It is shown, using the Hodgkin-Huxley model of the axon, that the density redistribution of transmembrane sodium channels may reduce the threshold of the action potential, up to its spontaneous initiation. At the significant redistribution of sodium channels in the membrane, the rarefaction zones of the transmembrane channel density are formed, blocking the propagation of the action potential. Blocking the action potential propagation along the axon is shown to cause anesthesia in the example case of a squid axon. Various approaches to experimental observation of the effects considered in this paper are discussed.
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PMID:Initiation and blocking of the action potential in an axon in weak ultrasonic or microwave fields. 2535 35


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