Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have determined the sequence of the light and heavy chains of mAb 3G-10 (IgG1), a monoclonal antibody competing with interleukin 2 (IL2) for binding to the human IL2 receptor Tac protein. The antibody-encoding genes were chimerized by introducing splice donor and part of the intron sequences into the cDNA and subsequently linking it to the constant parts of the human IgG1 gene. The chimeric mAb was produced in mouse myeloma cells and purified. Murine and chimeric mAbs showed similar properties with respect to inhibition of T-cell proliferation. In contrast to its murine counterpart, the chimeric mAb exhibited Ab-dependent cellular cytotoxicity and, when combined with an Ab recognizing a different epitope on the IL2 receptor Tac protein, was able to activate human complement. The chimerized mAb might therefore have improved therapeutic efficacy.
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PMID:Synthesis and functional characterization of a recombinant monoclonal antibody directed against the alpha-chain of the human interleukin-2 receptor. 174 99

To assess the role of the cytokine interleukin 2 (IL2) in the treatment of patients with multiple myeloma, we examined the sensitivity of plasma cell lines and malignant plasma cells from multiple myeloma (MM) patients to cell and cytokine-mediated killing induced by IL2. Unstimulated peripheral blood mononuclear cells (PBM) from normal donors produced little killing (mean lysis 1.0 +/- 1.0%, effector:target (ET) ratio 50:1), but cytotoxicity was modestly increased when PBM were incubated with IL2 prior to assay (8.0 +/- 2.9%). Unstimulated PBM from patients with MM also failed to kill autologous malignant plasma cells (mean 0.6 +/- 0.6%), but after exposure to IL2 they induced substantial lysis of autologous malignant cells (mean 55.3 +/- 22.1%). In addition, tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma), two cytokines released from mononuclear cells in response to IL2, also reduced the survival and thymidine uptake of malignant plasma cells in culture. To determine whether these potentially beneficial immunomodulatory effects could be reproduced by in vivo administration of IL2, we have administered seven courses of IL2 to four patients with MM after autologous bone marrow transplant (ABMT). No serious adverse effects were noted. Increases in natural killer (NK) and lymphokine-activated killer (LAK) activity of PBM occurred during IL2 infusion, although cells capable of killing autologous MM cells did not circulate. However, IL2 infusions also induced substantial increases in the production of the cytokines TNF and IFN-gamma from peripheral blood lymphocytes. These results suggest that the in vivo administration of IL2 in MM deserves further evaluation, particularly for its potential to control minimal residual disease.
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PMID:Malignant plasma cells are sensitive to LAK cell lysis: pre-clinical and clinical studies of interleukin 2 in the treatment of multiple myeloma. 211 92

6B2-B8 T cell hybridoma cells were used to immunize mice, and immune spleen cells were fused with NS/1 myeloma cells. One clone, designated RTH-7, reacted with 89.5% of rat thymocytes, 30.2% of rat spleen cells, and 42.3% of rat lymph node cells. The RTH-7 reacted with a subset of rat T cells but not with B cells. Double staining analysis demonstrated that RTH-7 stained a rat T cell subset distinct from R1-10B5-positive cells that were known to be equivalent to mouse Lyt-2. It was revealed that RTH-7 and W3/25 recognize different antigenic epitopes on the same molecule. The RTH-7 as well as W3/25 substantially inhibited the production of interleukin 2 by cells in mixed lymphocyte reaction and the lymphocyte proliferation induced by mixed lymphocyte reaction. The RTH-7 inhibited the lymphocyte proliferation induced by Con A whereas W3/25 failed to do so. The RTH-7 defined antigen has a molecular weight of 53,000 under reducing condition and 47,000 under nonreducing condition. The RTH-7 defined antigen showed a wide range of heterogeneity in pI (6.2-8.8). The associated molecule of approximate molecular weight of 27,000 was occasionally detected with the RTH-7 defined antigen in 6B2-B8 T cell hybridoma cells as well as peripheral T cells but not in thymocytes. Thus, RTH-7 detects a cell surface antigen of a functional T cell subset of rat origin.
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PMID:Characterization of rat T cell subset antigen by monoclonal antibody. 244 8

In an effort to derive monoclonal antibodies (mAb) which can induce production of macrophage-activating factor (MAF) by cloned murine cytolytic T lymphocyte (CTL) lines, we have fused spleen cells from a rat immunized with a CTL clone with the nonsecreting mouse myeloma X63-Ag8.653. Three mAb (designated I-22, III-5 and V-8) were found to stimulate MAF production by the immunizing CTL clone and (with a single exception) two other unrelated CTL clones. However, none of these mAb inhibited the cytolytic activity of the clones. Immunoprecipitation studies indicated that the three mAb reacted primarily with a 25-30-kDa protein which could not be distinguished from that precipitated by either a reference anti-Thy-1.2 mAb or a polyclonal rabbit anti-Thy-1 antiserum. Moreover, competition binding experiments demonstrated that the three mAb competed with each other and with the reference anti-Thy-1.2 mAb. Flow cytofluorometric analysis of the strain distribution of the molecules defined by the mAb revealed that two of the antibodies (I-22 and III-5) were directed against nonpolymorphic determinants of Thy-1, whereas V-8 mAb reacted only with Thy-1.2+ lymphocytes. One of the mAb (III-5) was also able to stimulate proliferation and interleukin 2 secretion by normal splenic T cells. Since mAb directed against a number of other surface structures on CTL clones did not stimulate MAF production, it thus appears that Thy-1 (or molecules associated with Thy-1) may play a functional role in T lymphocyte triggering.
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PMID:Production and characterization of monoclonal anti-Thy-1 antibodies that stimulate lymphokine production by cytolytic T cell clones. 258 90

Biological response modifiers such as interleukin 2 (IL2) may be most effective in the setting of minimal residual disease. In a phase I-II clinical trial, IL2 was administered to 10 patients in remission of acute myeloid leukaemia and three with multiple myeloma 1-4 weeks after treatment with ablative chemotherapy or chemotherapy and autologous bone marrow transplantation. The aim was to assess the capacity of these patients to tolerate IL2 after intensive therapy and to determine whether regenerating lymphocytes were capable of responding to IL2 with the generation of anti-leukaemic effector cells. Toxicity was severe in two patients treated with escalating doses of IL2 and 19 subsequent infusions administered to 11 patients on a fixed dose schedule for periods of 3-5 days were well tolerated. Major toxicity was confined to hypotension (two courses) which responded rapidly to treatment cessation. No patients required intensive care unit support. IL2 infusions produced no significant adverse effects on marrow regeneration; while there were transient falls in platelet counts there were no episodes of clinical bleeding and neutrophil counts increased from a mean of 1.1 pre-infusion to 2.5 x 10(9)l-1 during the infusion (P = 0.004). A significant biochemical abnormality was hypokalaemia which responded rapidly to correction. Cells with activity against leukaemic progenitor cells appeared in peripheral blood within 48 h of beginning treatment. We conclude that IL2 may be used in minimal residual haematological malignancy, and by producing anti-neoplastic effector cells has the potential, as yet unproven, to prolong disease-free survival of patients entering remission.
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PMID:A phase I clinical trial of recombinant interleukin 2 following high dose chemo-radiotherapy for haematological malignancy: applicability to the elimination of minimal residual disease. 280 33

We have established idiotope (Id)-specific T cell lines and clones derived from at least 4 different BALB/c mice immunized with the light chain (lambda 2(315] of the BALB/c myeloma protein M315 (alpha, lambda 2). Independently derived clones were indistinguishable in that they reacted to V lambda 2(315), one or more of the amino acids corresponding to somatically mutated codons 94, 95 and 96 of the third hypervariable region being essential for expression of the Id. While the Id was efficiently expressed on V lambda 2(315), Fv315 and lambda 2(315) fragments, about a 100-1000-fold higher molar concentration of Fab315 and M315 was needed to induce equivalent responses. Thus, Ig quaternary structure heavily influenced the availability of the Id for T cells. The V lambda 2(315)-specific T cells were Thy-1.2+, L3T4+, Ly-2.2- and I-Ed restricted. Some of the T cell clones produced interleukin 2 (IL2), IL3 and B cell growth and differentiation factors upon activation. In addition, T cells were cytotoxic in long-term assays for Ed beta Ek alpha-, but not Ek beta Ek alpha- transfected L cells in the presence of Id. The cytotoxic effect was the basis for an L cell growth inhibition assay for T cell activation that was at least 10-fold more sensitive than ordinary proliferation assays.
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PMID:Idiotope-specific T cell clones that recognize syngeneic immunoglobulin fragments in the context of class II molecules. 309 40

The generation of cytotoxic T lymphocytes (CTL) towards allogeneic cells was investigated in 19 patients with monoclonal gammopathy of undetermined significance (MGUS) and 31 patients with multiple myeloma (MM). This function was significantly decreased in all patients. The cytotoxic deficiency was more pronounced in MM with poor prognosis than MM with good prognosis and MGUS patients. A phenotypic analysis of PBT lymphocytes showed that poor prognosis MM also had the highest proportions of activated cells (HLA-DR+) in CD8+ subpopulations. CTL were generated after depletion of CD11+ lymphocytes (including suppressor cells) or after inhibition of suppressor function with deoxyguanosine. No increase of cytotoxicity was detected under these conditions. Exogenous supplementation of recombinant interleukin 2 (rIL-2) was also ineffective. These data indicate that MG PBT lymphocytes are unable to fully differentiate into CTL following allogeneic stimulation. This deficiency is most evident in MM patients already showing the poorest prognosis and the most altered T cell phenotype.
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PMID:Defective generation of alloreactive cytotoxic T lymphocytes (CTL) in human monoclonal gammopathies. 326 29

The production of interleukin 2 (IL-2) by peripheral blood mononuclear cells (PBMC) was studied in 15 normal controls (NC) and 29 patients with multiple myeloma (MM), including 19 patients with active disease (i.e. diagnosis, relapse) and 10 with inactive disease (i.e. complete remission and off-treatment plateau). IL-2 was produced after stimulation of PBMC with PHA alone or with PHA and PMA. The role of suppressor factors/cells on IL-2 production was evaluated using indomethacin and irradiation of PBMC. T cells and T cell subsets (i.e. helper/suppressor T cells) were defined using standard monoclonal antibodies (T3, T4, T8). The production of IL-2 in active MM was similar to that of NC, using either PHA or PHA and PMA. However, a constant defect of prostaglandin-mediated suppressor cells was observed in patients in plateau, with a significant increase of IL-2 production in comparison to that of NC or active MM. IL-2 is an essential factor involved in T cell proliferation. Recent data demonstrate that it plays a role in B cell proliferation and differentiation into antibody-secreting cells. Suppression of antibody synthesis is a major feature of active (but not inactive) MM. The fact that IL-2 production was not affected in MM, in spite of an imbalance of some T cell subsets, is of major interest.
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PMID:Production of interleukin 2 in multiple myeloma. 348 31

The present study deals with the effect of recombinant interleukin 2 (R-IL2) on in vivo growth of murine myeloma X5563. Administration of R-IL2 (5 X 10(4) J.U./mouse per day) s. c. starting 1 day after X5563 inoculation i.d. had a marginal effect on the growth of X5563, and all the mice repeatedly given R-IL2 from day 1 to day 17 died. However, daily administration of R-IL2 starting 7 days after the tumor inoculation was highly effective and significantly lengthened survival time compared with the control mice injected with vehicle alone. About 50% of the treated mice were completely cured, and survived for more than a month after the therapy ceased. In a representative experiment, where the growth of X5563 was slow because of the small number of inoculated tumor cells, all the mice (n = 6) given R-IL2 from day 11 to day 23 showed complete cure of the established X5563 solid tumor. These mice showed in vivo protective immunity and in vitro cytotoxic T cell responses to X5563 tumor antigens. Histologically, a large number of macrophages and lymphocytes had infiltrated the area around the necrotic X5563 tumor mass in the mice which had received R-IL2 therapy. These results suggest that repeated injections of R-IL2 at the local site after tumor development can augment antitumor immunological responses and subsequently induce tumor regression.
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PMID:Effect of recombinant interleukin 2 (R-IL2) on in vivo growth of murine myeloma X5563. 349 Mar 6

This study documents the autoregulation of B cell growth by an IgM autoantibody. This autoantibody is secreted by B lymphocytes upon stimulation by polyclonal activators and is identified by its potent inhibition of B cell growth induced by these agents (endotoxin, Fc fragment of human gamma-globulin, Mycoplasma bovirhinis, and anti-mouse Ig). The autoantibody specifically affects B cells: there was no effect on mitogen- or antigen-induced T cell proliferation and of responses to interleukin 1, interleukin 2, or interferon. Nonspecific effects were excluded by the ineffectiveness of serum and myeloma IgM. Also, IgG-IgM immune complexes were excluded. The binding specificity of the IgM autoantibody is not yet defined but appears to be a B cell surface structure distinct from membrane Ig. The autoantibody constitutes a ubiquitous, autoregulatory influence on B cell growth, which may be an important component in physiologic and pathologic states of B cell homeostasis.
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PMID:Autoregulation of B cell growth by an immunoglobulin M autoantibody. 387 25


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