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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The reduced capacity of patients with multiple myeloma to respond to antigen challenge is well recognized. Response to antigen involves antigen recognition, cell proliferation, and synthesis and secretion of antibody. This study examines this sequence of events in peripheral blood lymphocytes from untreated and treated patients with myeloma, from individuals with benign monoclonal gammopathy, and from normal healthy donors. Antigen-binding capacity was assessed by testing the ability of lymphocytes to bind radio-labeled pneumococcal polysaccharide, tetanus toxoid, or diptheria toxin. The in vitro proliferative response to these antigens as well as to pokeweed mitogen and streptokinase-streptodornase was evaluated. The secretion of immunoglobulin in response to pneumococcal polysaccharide, tetanus toxoid, and pokeweed mitogen by 2-4 x 10(6) lymphocytes in 7-day cultures was determined. The effects of coculture of myeloma peripheral blood lymphocytes and normal peripheral blood lymphocytes on immunoglobulin production and mixed leukocyte reactions were explored. All myeloma patients had normal numbers (3-8/5,000 cells) of antigen-binding cells. However, most showed a diminished antigen-induced blast transformation as measured by uptake of [(125)I]5-iodo-2'-deoxyuridine in culture. Immunoglobulin production in response to specific antigen in myeloma lymphocytes was 30-80% less than in normal lymphocytes. Immunoglobulin synthesis and mixed leukocyte responses by normal peripheral blood lymphocytes could be suppressed by myeloma lymphocytes. Multiple suppressor populations were present. Thus, the immune defect in myeloma is beyond the antigen recognition step and involves both the proliferation of antigen-sensitive cells and immunoglobulin production. Further suppressive effects are imposed on normal cells, implying defects in immunoregulation in this disease.
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PMID:Studies on the pathogenesis of an immune defect in multiple myeloma. 1 39

The difficulty of working with the intact brain in vivo has led to the increasing use of nerve cell cultures in neurobiology. However, dissociated cells cannot be unambiguously identified by morphological criteria before the third week in culture, for it is not until then that the basic morphology and size of neurones become stable so that these and other cell types can be easily distinguished. However, cultured neurones can be identified by various cytochemical techniques based on (1) the detection of neurotransmitters or receptors for transmitters, (2) the presence of the Thy 1 antigen and the receptor for tetanus toxin, which are present on the membrane of most neurones, and (3) the presence in neurones of neurone-specific enolase (NSE), a cytoplasmic enzyme, which can only be identified on fixed specimens. Furthermore, other cell types in culture can also be specifically labelled. For instance, antisera to galactocerebroside bind selectively to oligodendrocytes, and antibodies to a neural tumour bind selectively to Schwann cells. We report here the selective interaction of phosphorylcholine-binding myeloma proteins (PC-BMP) with mouse neurones in culture and in suspension. Phosphorylcholine (PC) is found as part of lecithin and sphingomyelin molecules in variable amounts in eukaryotic and prokaryotic membranes, including plasma membranes.
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PMID:A new neuronal marker identified by phosphorylcholine-binding myeloma proteins. 48

Despite advances in the in vitro immunization of human B cells (Borrebaeck et al. 1988) and the development of immunodeficient mice (McCune et al. 1988) for the reconstitution of the human immune system ex vivo, immortalization of antigen-specific human B cells remains the limiting step in the generation of human monoclonal antibodies. Typically this is performed with the aid of Epstein-Barr virus transformation followed by subcloning, confirmation of antigen binding and hybridization of the B lymphoblasts to a suitable fusion partner such as GLI-H7. This general approach is effective and widely used; however, it is time-consuming with erratic results. These were the immediate reasons we and others devised methods to directly obtain the variable regions from small numbers of human B cells (Larrick et al. 1987). The success of the PCR-based approach is illustrated above. In the present studies we successfully captured and stably produced antibodies from the V regions of two potent human anti-tetanus antibodies secreted by heteromyelomas that were too unstable for scale-up production. Although further preclinical evaluation of these antibodies is in progress, results to date indicate that the recombinant antibodies produced in myeloma-based cell lines or CHO cells are equivalent in binding specificity and activity to the native heteromyeloma-derived antibodies. Recent studies from this laboratory indicate that effective anti-tetanus protection will require a cocktail of anti-tetanus antibodies. Details of this work will be the subject of a future communication (Lang et al., in preparation).
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PMID:Therapeutic human antibodies derived from PCR amplification of B-cell variable regions. 128 73

Protective human monoclonal antibodies (HuMAbs) are superior to hyperimmune sera and murine monoclonal antibodies as far as human immunotherapy is concerned. In this report, we describe the successful generation of triomas secreting HuMAbs to tetanus toxin (tt). Lymphoblastoid cell lines secreting anti-tt antibodies were stabilized by back-fusion with a mouse x human heterohybrid myeloma partner, SBC-H20. One of the antibodies so produced, confers total protection of mice from tetanus, unlike a few recent reports where only partial protection (delay in the onset of tetanus) was achieved with single HuMAbs. Experiments to localize the neutralizing epitope(s) of the toxin using the protective monoclonal antibodies revealed that the antibody recognizes a conformational determinant that is destroyed on SDS-treatment. Preliminary studies show that Fab preparations of the protective antibody are capable of neutralizing tetanus toxin, suggesting that it might be possible to clone and express the Fab in a stable vector for large scale production.
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PMID:A single human monoclonal antibody that confers total protection from tetanus. 137 15

The characteristics of T and B lymphocyte profile and B lymphocyte specificity repertoire were compared in patients with Waldenstrom's macroglobulinemia (WM), IgM monoclonal gammopathy of undetermined significance (IgM MGUS), multiple myeloma (MM), and age-matched normal subjects. Patients with MM had both significantly reduced frequency and number of sIg+ (surface Ig) B cells, whereas patients with WM and IgM MGUS had a reduced frequency but normal numbers of sIg+ B cells in circulation as detected in a capping assay. WM was distinguished by the large numbers of cells in the peripheral blood lymphocyte (PBL) pool that expressed CD9 (BA-2) and CD24 (BA-1) and were monoclonal, based on light chain analysis using flow cytometry. The profile of T lineage cells showed that the ratio of CD4:CD8 was significantly reduced in both MM and WM due to a reduction in the CD4 set. The CD4+ cells were qualitatively abnormal as well, with an enriched proportion of the 4B4+ (CDw29) subset and decreased proportion of the Lp220+ (CD45R) subset. This appeared to be an effect of the disease process on the relatively immature Lp220+ set. From clonal analysis, those patients with WM or IgM MGUS (unlike MM patients) did not exhibit enhanced reactivity with auto-Ig determinants, and most WM patients (7/8) and half of the IgM MGUS patients (3/6) did not have enriched proportions of B cells reactive to tetanus toxoid (TT). The TT-specific B cells in both WM and IgM MGUS, in contrast to MM, appeared fully functional in secretion of anti-TT IgM in vivo. We speculate that the more severe immunodeficiency in MM may be controlled or exacerbated by the presence of an anti-Ig network. The absence of this network in WM allows a relatively more effective immune response, but the immunodeficiency that is observed in these patients involves some abnormality in normal lymphocyte differentiation (is also present in MM).
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PMID:Abnormalities in lymphocyte profile and specificity repertoire of patients with Waldenstrom's macroglobulinemia, multiple myeloma, and IgM monoclonal gammopathy of undetermined significance. 253 15

The objectives of this study were firstly, to compare the immunophenotype of patients with monoclonal gammopathy of undetermined significance (MGUS) with that of patients with newly diagnosed, untreated multiple myeloma (Unt. MM). Our second objective was to determine which variables might distinguish patients with MGUS and early MM. The CD4/CD8 ratio in both patient groups differed significantly from normal as a result of a decrease in the proportion of CD4+ cells. Similarly, surface immunoglobulin-positive (Ig+) B cells were significantly reduced in both groups. Also, some impairment of Ig secretion was observed. An in vitro specificity study of B cells showed an enriched proportion of B cells specific for tetanus toxoid (which may be indicative of enrichment for memory B cells) in both MGUS and Unt. MM patients. Further to this, in MM patients but not in MGUS patients, there was an enriched proportion of B cells specific for determinants on the F(ab')2 fragment of Ig. This suggests an anomalous auto-immune reactivity to polyclonal Ig molecules. In one of the two patients studied, who progressed from MGUS to MM, disease progression was accompanied by an increase in this anti-Ig reactivity. In both patients there was a decrease in CD4/CD8 ratio.
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PMID:Comparative analysis of immunodeficiency in patients with monoclonal gammopathy of undetermined significance and patients with untreated multiple myeloma. 278 25

Antigen-specific human monoclonal antibodies (hMoAb) were investigated with particular emphasis on the stability and scale-up of production. Peripheral blood lymphocytes from a healthy donor previously vaccinated with tetanus toxoid (TT) were resensitized in vitro with the antigen in the presence of pokeweed mitogen (PWM). Three days after the stimulation, lymphocytes were infected with Epstein-Barr (EB) virus. Among EB virus transformants, several lymphoblastoid cell clones producing anti-TT hMoAb were established. One of these clones, 3G6, produced about 10 micrograms/ml of IgM (K) in the culture supernatant. Furthermore, 3G6 cells were fused with murine myeloma cells (X63-Ag8 X 653) and three heterogeneous hybridoma clones (HE719, HE810 and HE811) were obtained after careful hybrid selection in hypoxanthine-aminopterin-thymidine-ouabain containing medium and cloning by limiting dilution technique. These hybrid clones contained human HLA and mouse H-2d antigens together with mouse-human mixed karyotype. When these mouse-human hybridomas were injected i.p. into pristane-treated nude mice of BALB/c origin, ascites were found and a large amount of anti-TT hMoAb up to 0.5 mg/ml were produced there. These hybridomas have retained their anti-TT antibody-producing capabilities over 10 months. The approach described here has a potential application for the production of other antigen-specific hMoAb.
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PMID:Characterization of stable Epstein-Barr (EB) virus transformed cell lines and mouse-human hybridomas producing a large quantity of anti-tetanus toxoid (TT) monoclonal antibody. 300 6

Patients with multiple myeloma are generally immunodeficient, with pronounced depression in primary antibody responses. We have attempted to delineate the reasons for the humoral immunodeficiency by analyzing the specificity repertoire of the surface immunoglobulin (Ig)-positive B cells in patients with multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS), in comparison with normal donors. B lymphocytes from 26 patients with multiple myeloma, 12 patients with MGUS, and 8 normal donors were transformed with Epstein-Barr virus (EBV) and cultured at limiting dilution for clonal analysis. The Ig secreted by each clone was analyzed for class and anti-tetanus toxoid (TT) specificity to determine the frequencies of IgM, IgG, anti-TT IgM, and anti-TT IgG antibody-secreting clones. Our objective was to establish whether the inability to mount humoral responses to common environmental pathogens was due to a lack of specific B cells or to inhibition of B-cell function. Our results indicate that the quantitative B-cell deficiency in patients was due to a nonrandom loss of selected sets of B cells. Although most patients had a reduced aggregate number of B cells, the number of TT-specific B cells was normal. There was, on average, a threefold increase in the proportion of the B-cell specificity repertoire devoted to recognition of TT. Forty-four percent of the patients with MGUS were also affected. In addition, the TT-specific B cells in multiple myeloma patients were severely compromised in their ability to secrete antibody or to differentiate to antibody-secreting cells in vivo. This arrest in differentiation appears to be extrinsic to the B cells, as they were fully able to secrete anti-TT antibody after transformation and culture in vitro. We postulate the existence of an autoimmune inhibitory network mediating the arrest in B-cell differentiation and the humoral immune deficiency.
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PMID:Humoral immune deficiency in multiple myeloma patients due to compromised B-cell function. 302 34

Monoclonal antibodies against tetanus toxin were generated by fusion of mouse NS-1 myeloma cells with spleen cells from BALB/C mice immunized with tetanus toxoid. Twenty seven hybridomas against tetanus toxin were obtained. Six hybridoma clones, designated as 1A6B12, 1H7D9, 3A8G9, 3A9F2, 3F9H9, 4A6D11 were selected for further studies. All of them were IgG1, k chain and bound specifically to tetanus toxin and toxoid. All six clones were injected intraperitoneally into pristane-primed BALB/C mice. Antibodies with titer up to 10(6) were obtained in the ascites. Results obtained from in vivo neutralization test showed that 1A6B12, 3A8G9, 3F9H9, 4A6D11 mAbs did have neutralizing activities against tetanus toxin. Monoclonal antibody 4A6D11 had the strongest neutralizing activity. 4A6D11 were purified from ascites by DEAE-52 ion exchange chromatography. Comparing to U.S.A. standard antitetanus toxin antiserum, 50 micrograms purified 4A6D11 mAb had 1 international unit neutralizing activity. The purified 4A6D11 mAb was also coupled to cyanogen bromide-activated sepharose to make an affinity column. Pure tetanus toxin can be obtained by passing crude tetanus toxin through this column and eluting the adsorbed toxin with 4M urea. Large scale purified tetanus toxin could be obtained by this method.
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PMID:Protective murine monoclonal antibodies to tetanus toxin. 315 81

A human-mouse myeloma analogue termed HMMA2.11TG/O was constructed by fusion of the mouse myeloma cell line P3x63Ag8.653, a mutant derivative of MOPC21, with bone marrow mononuclear cells from a patients with IgA myeloma. The HMMA2.11TG/O cell line is resistant to 6-thioguanine and ouabain and sensitive to HAT. The cell line secretes no detectable immunoglobulin and has a hybrid karyotype and cell surface phenotype. An average fusion efficiency for growth of hybridomas of 1/17,000 fused cells was obtained in fusions with human peripheral blood mononuclear cells (PBM), Pokeweed Mitogen (PWM) stimulated PBM, and Epstein-Barr Virus (EBV) transformed polyclonal B cell lines. Over 75% of hybrids secrete detectable immunoglobulin and the cloning efficiency of the hybrids at 1 cell/well averages 25%. Antibody secreting cloned hybridoma cell lines were obtained by fusion directly with PBM from an immunized volunteer and by fusion with in vitro, secondarily immunized, EBV transformed polyclonal cell lines. Five hybridomas secreting human monoclonal IgM anti-tetanus antibodies and 2 secreting human monoclonal IgG anti-tetanus antibodies were selected and cloned from 6 fusions performed specifically for anti-tetanus antibody. Immunoglobulin and antibody secretion by cloned hybrids has been stable for 5-10 months at present. Immunoglobulin and antibody secretion in routine cultures passaged every 3-4 days has been 8-42 micrograms/ml. This human-mouse myeloma analogue should prove useful for the routine production of human monoclonal antibodies.
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PMID:The construction and use of a human-mouse myeloma analogue suitable for the routine production of hybridomas secreting human monoclonal antibodies. 343 25


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