Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We performed a phase Ia/Ib study of interleukin 2 (IL2) in patients with cancer. Single doses of IL2 from 10(3) units/m2 to 10(7) units/m2 were well tolerated but failed to induce significant immunological changes. Chronic IL2 treatment for 5 days out of 7 for 3 weeks was well tolerated at doses below 10(7) units/m2 and was accompanied by significant immunological changes. Following chronic treatment with intramuscular injections of IL2 at 1 x 10(6) units/m2, we observed augmentation of peripheral blood natural killer activity and induction of peripheral blood LAK activity. Induction of LAK activity was most evident when IL2 was included in the cytotoxicity assay. There was a marked increase in the number of peripheral blood mononuclear cells bearing the Leu-19 marker in association with the observed increases in natural killer and LAK activity. A small percentage of Leu-19+ cells coexpressed CD3. There was heterogeneous expression of the low affinity Fc receptor (CD16). In vivo induced Leu-19+ cells could be divided into two populations, dim and bright, based on the intensity of fluorescent staining with antibodies to Leu-19. The majority of Leu-19 bright cells were CD16- while the majority of Leu-19 dim cells were CD16+. In addition, the intensity of CD16 staining was higher for Leu-19 dim cells than for Leu-19 bright cells. Increases in the amounts of CD38 and CD8 antigens were also observed. Significant increases in serum levels of the soluble IL2 receptor were observed during treatment. One partial remission was noted in a woman with non-Hodgkin's lymphoma.
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PMID:Immunomodulatory properties and toxicity of interleukin 2 in patients with cancer. 229 54

Thirteen lymphomas consisting of one particular cell type were selected from 135 cases of non-Hodgkin's lymphoma. The lymphoma cells were mainly characterized by irregularly shaped nuclei and faintly stained cytoplasm. The growth pattern of the tumour was diffuse. Immunological phenotyping of suspended cells showed that the tumour cells, irrespective of whether they were isolated from lymphoma tissue or from lymphoma tissue or from peripheral blood of leukaemic cases, bore a dense layer of surface immunoglobulin, lacked cytoplasmic immunoglobulin and receptors for mouse erythrocytes, and expressed both complement-receptor subtypes (i.e., receptors for C3b and C3d) in all but one case. The exceptional case was C3b receptor-positive and C3d receptor-negative. The number of IgG-Fc receptor-bearing cells was usually small. There was a consistently small proportion of non-malignant T cells in the tumour tissue. A comparison of the properties of these lymphomas with those of other types of non-Hodgkin's lymphoma and of non-malignant lymphoid cells, shows that the cells of this type of lymphoma (a) differ morphologically and/or immunologically from the cells of all other known types of non-Hodgkin's lymphoma and (b) resemble centrocytes (cleaved follicular-centre cells) of reactive germinal centres. Thus, this type of lymphoma appears to be an entity that is closely related to, or even derived from, centrocytes.
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PMID:Morphological and immunological definition of a malignant lymphoma derived from germinal-centre cells with cleaved nuclei (centrocytes). 737 Jan 58

Local tumor growth has been reported after subcutaneous and intraperitoneal injection of Hodgkin's disease (HD) derived cell lines into different immunodeficient mouse strains. An animal model with disseminated growth of tumor cells would be useful for studying the in vivo biology of HD cells as well as for preclinical testing of new therapeutic regimens. For this purpose the HD-derived cell lines L540, L540cy, L428, and KM-H2 were injected intravenously into SCID mice. In contrast to L428 and KM-H2, widespread neoplasia occurred after a period of four to six weeks following injection of L540 and the subline L540cy. Lymph nodes were found to be the preferred site of tumor growth. CD30 surface antigen expression on Hodgkin cells and the karyotype of the tumor cells were preserved in the animal host. Thus, to a large extent, the SCID mouse model mimics the dissemination pattern of Hodgkin's disease in man. To evaluate the role of adhesion molecule expression in the dissemination of HD-derived cell lines, CD44 and members of the immunoglobulin, integrin, selectin, and Fc receptor families were quantified by flow cytometry. CD30 expression was also measured. Although CD44 expression has been correlated with dissemination in non-Hodgkin's lymphoma (NHL), this was not the case in the Hodgkin's SCID mouse model. CD44 was not expressed on the disseminating cell lines L540 and L540cy but was expressed in the nondisseminating lines L428 and KM-H2.
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PMID:Disseminated growth of Hodgkin's-derived cell lines L540 and L540cy in immune-deficient SCID mice. 751 37

An increasing amount of literature has been published concerning the interaction of the CD40 antigen and its ligand with regard to normal B cell ontogeny. In this review, an overview of the CD40 antigen and the CD40 ligand is given, focussing on their possible role in B cell malignancies. Data on the expression of the CD40 antigen on various B cell malignancies (acute and chronic leukemias, non-Hodgkin's lymphoma and multiple myeloma) are presented. The recently developed novel culture "CD40 system" is described. This system is a powerful tool used to culture normal B cells, but also most malignant B cells. We demonstrate in addition a more prominent role of the human Fc receptor presenting murine fibroblasts in the "CD40 system", especially in relation to cultured plasma cells. Finally, some important applications of the "CD40 system" are also summarized.
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PMID:The role of the CD40 antigen on malignant B cells. 881 71

The anti-CD20 chimeric monoclonal antibody rituximab kills B cells by multiple mechanisms, including complement-dependent cytoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis. Rituximab can also sensitize cells to the effects of chemotherapy. To optimize treatment of non-Hodgkin's lymphoma and improve response rates, a fuller understanding of these mechanisms and their relative contributions to clinical efficacy is required. Therefore, this has been an area of active research in recent years. Preclinical studies have established that the human Fc region of rituximab is important in mobilizing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effector mechanisms. In addition, molecular consequences of CD20 binding, including redistribution of membrane lipid "rafts," activation of src kinases, phospholipases and caspases, and down-regulation of interleukin-10, have been identified. Clinical studies have also identified differences in patients' responses to rituximab associated with Fc receptor polymorphisms, and increases in enzymes involved in apoptotic pathways have been seen in the lymphocytes of patients following rituximab treatment. This article reviews the current understanding of the mechanisms of rituximab cell killing in the light of the latest clinical and preclinical data.
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PMID:The mechanisms of action of rituximab in the elimination of tumor cells. 1265 58

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell-, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti-mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcgammaRI- and FcgammaRIII-dependent pathways, whereas B cells were not eliminated in FcR common gamma chain-deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcgammaR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.
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PMID:The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. 1521 Jul 44

Immunotherapy became a feasible therapeutic approach following the development of monoclonal antibody technology. Despite many small clinical trials using a wide variety of antibodies, in hematologic malignancies, success has largely been restricted to a few antibodies generated against antigens expressed on the tumor cell surface: rituximab (anti-CD20) and alemtuzumab (anti-CD52) are the most widely used monoclonal antibodies. CD20 is expressed on B cells, and rituximab has been widely used in the treatment of various histologies of B-cell non-Hodgkin's lymphoma. The mode of action of rituximab is discussed in this article. Despite extensive empiric clinical trial experience, the critical factors important in the mechanism of tumor cell kill by monoclonal antibodies continue to be elusive and the subject of debate. The major immune mechanisms of action of rituximab include complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. While some investigations have suggested that the complement system is essential to tumor cell kill with rituximab; most lines of evidence point to the importance of antibody-dependent cellular cytotoxicity. Fc receptor binding appears to be critical in determining efficacy. Observations from several studies have shown that the response rate to single-agent rituximab is better in patients who have higher affinity polymorphisms in their Fc receptors. The other mechanisms that may play a role in rituximab therapy include direct anti-tumor effects mediated by the antibody binding to cell-surface CD20 antigen. Although this is more controversial, observations in tumor cell lines following CD20 ligation suggest that direct effects may be important.
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PMID:Concepts in radiotherapy and immunotherapy: anti-CD20 mechanisms of action and targets. 1578 22

Advances in the development of monoclonal antibodies have led to new agents rapidly incorporated into standard lymphoma therapy. The characteristics of the target antigen and the properties of the antibody including interaction with the host immune system have been found to correlate with outcome. Antibodies targeting the CD20 antigen on B cells have been most widely used, led by the chimeric antibody rituximab, now used in nearly all types of B-cell non-Hodgkin's lymphoma (NHL). New antibodies targeting CD20 with augmented complement or Fc receptor binding are now being evaluated and will eventually have to be compared with rituximab. Challenges to these new antibodies include the nearly universal use of rituximab early in NHL therapy, and its increasing use as maintenance therapy. It is not clear what the activity of these antibodies will be in rituximab-refractory patients. New antibodies targeting antigens such as CD40 and CD80 are also being tested alone and in combination with rituximab. Vaccine trials using patient-specific immunization with immunoglobulin idiotype (Ig-Id present on the surface of most B-cell NHL) isolated by molecular rescue or by cell hybridization techniques are also nearing completion. These approaches attempt to actively induce specific humoral or cellular immune responses to the Ig-Id by attaching the protein to a carrier protein and the use of an immunologic adjuvant such as granulocyte macrophage colony-stimulating factor. Prior rituximab appears to delay humoral responses to the idiotype but may still allow cellular responses. The incorporation of all these approaches into optimal NHL therapy remains a challenge.
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PMID:Immunotherapy for non-Hodgkin's lymphoma: monoclonal antibodies and vaccines. 1615 29

Monoclonal antibodies (mAb) are widely used in the treatment of non-Hodgkin's lymphoma and autoimmune diseases. Although the mechanism of action in vivo is not always known, the therapeutic activity of several approved mAbs depends on the binding of the Fcgamma regions to low-affinity Fcgamma receptors (FcgammaR) expressed on effector cells. We did functional genetic screens to identify IgG1 Fc domains with improved binding to the low-affinity activating Fc receptor CD16A (FcgammaRIIIA) and reduced binding to the low-affinity inhibitory Fc receptor, CD32B (FcgammaRIIB). Identification of new amino acid residues important for FcgammaR binding guided the construction of an Fc domain that showed a dramatically enhanced CD16A binding and greater than a 100-fold improvement in antibody-dependent cell-mediated cytotoxicity. In a xenograft murine model of B-cell malignancy, the greatest enhancement of an Fc-optimized anti-human B-cell mAb was accounted for by improved binding to FcgammaRIV, a unique mouse activating FcgammaR that is expressed by monocytes and macrophages but not natural killer (NK) cells, consistent with experimental and clinical data suggesting that mononuclear phagocytes, effector cells expressing both activating and inhibitory FcgammaR, are critical mediators of B-cell depletion in vivo. By using mice transgenic for human CD16A, enhanced survival was observed due to expression of CD16A-158(phe) on monocytes and macrophages as well as on NK cells in these mice. The design of new generations of improved antibodies for immunotherapy should aim at Fc optimization to increase the engagement of activating FcgammaR present on the surface of tumor-infiltrating effector cell populations.
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PMID:Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. 1787 30

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined and the in vivo effect of immunotherapy on tissue B cells and their subsets is generally unknown. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti-mouse CD20 monoclonal antibodies. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion utilized FcgammaRI-, FcgammaRIII- and FcgammaRIV-dependent pathways, while B cells were not eliminated in FcR common gamma chain-deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or NK cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3 complement components. The considerable factors that determine the effectiveness of anti-CD20 immunotherapy are following: the expression level of CD20 on B cell surface; the dosage of anti-CD20 mAb; the association of Fcgamma receptor with the isotype of the antibies; B cell subpopulations within different tissues. These findings have important clinical implications for anti-CD20 and other antibody-based therapies.
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PMID:[Molecular mechanisms of B lymphocyte depletion by CD20 immunotherapy]. 1925 75


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