Search PubMed⌕ Search

Biomedical subjects

R Bataille

Publications and source records attributed to R Bataille.

At least 181 records · Page 10Linked to original sources
PubMed1989

Spontaneous secretion of tumor necrosis factor-beta by human myeloma cell lines.

Abnormal bone remodelling in the vicinity of tumor cells is a common, early feature of multiple myeloma, characterized by excessive bone resorption which is mediated by local soluble factors called osteoclast activating factors (OAF). Since interleukin-1 (IL-1) and tumor necrosis factors (TNF) are potent, synergistic OAF produced by cells of the B-cell lineage, the authors investigated the spontaneous secretion of these cytokines by 11 human myeloma cell lines (HMCL). No HMCL secreted either IL-1, the most powerful OAF, or contra IL-1. In contrast, all of the lymphoblastoid cell lines assayed produced significant IL-1 activity. Ten of the 11 HMCL secreted a significant TNF activity. This was completely eliminated by an anti-TNF beta monoclonal antibody but not affected by an anti-TNF alpha antiserum. The data from this study suggest that TNF beta is involved in myeloma bone resorption, but not IL-1, which is, however, known as one of the most potent OAF.

Antibodies, Monoclonal↗
PubMed1989

The defect in peripheral blood B-cell activation in patients with multiple myeloma is not due to a deficiency in the production of B-cell growth and differentiation factors.

The suppression of B lymphopoiesis is a major feature of multiple myeloma (MM). In this disease, there is a striking defect in the response of peripheral blood B cells to pokeweed mitogen (PWM). Normally, B-cell activation depends on B-cell growth factors (BCGFs) and B-cell differentiation factors (BCDFs), produced by peripheral blood mononuclear cells. We therefore evaluated whether the production of these cytokines was defective in patients with MM. We have studied the production of BCGFs (using the anti-mu assay) and, particularly, interleukin-2 and interferon-gamma, two well-documented BCGFs. No defect in the production of BCGFs, interleukin-2, and interferon-gamma was found in patients with active (N = 14) or stable (N = 10) MM, compared with healthy donors (N = 13). The production of BCDFs (i.e., overall activity) was also evaluated and, more particularly, that of interleukin-6 (IL-6). This cytokine is a potent BCDF which is essential in the PWM-induced activation of B cells, acting at the terminal stages of B-cell differentiation. Again, no defect in the production of BCDFs and IL-6 was found in patients with MM. Therefore, the ability to secrete cytokines controlling the process of B-cell activation is not affected in such patients. This indicates that the profound failure of humoral immune response is not due to deficiency of peripheral blood mononuclear cells producing these factors.

B-Lymphocytes↗
PubMed1989

No preferential use of the VH(V) family in human multiple myeloma.

A recently described immunoglobulin VH family (the VH(V) family) close to the DH and JH genes is preferentially rearranged in immature B-cell tumours. The question of the emergence of multiple myeloma (MM) from a tumorous pre-B cell is not yet resolved. To draw a comparison with chronic lymphocytic leukaemia (CLL), we studied the VH(V) rearrangements in 28 MM patients. A rearranged Hind III-Bam HI fragment of 9.5 kb was detected in only one patient instead of the rearranged fragment of 8.5 kb described in CLL. Rearrangements of a member of the VH(V) family in a 9.5 kb fragment were also observed in two out of 20 lymphoblastoid cell lines obtained from peripheral blood of MM patients. We report here that the VH(V) family is not preferentially involved in this pathology and that the size of the only rearrangement obtained is larger than the 8.5 kb fragment observed in CLL. These results do not favour the hypothesis of a pre-B cell involvement in MM.

Blotting, Southern↗
PubMed1989

No detectable malignant B cells in the peripheral blood of patients with multiple myeloma.

Previous studies have reported the presence of idiotypic B lymphocytes in the peripheral blood of patients with multiple myeloma (MM), suggesting that they may belong to the malignant clone. This led us to investigate by Southern blot analyses the presence of tumour-specific immunoglobulin-gene (Ig-gene) rearrangements in the peripheral-blood mononuclear cells of 21 MM patients. This method was shown to detect clonal cells when they represent as little as 2% of the cell population. B-cell-enriched fractions were also studied in nine cases. An occasional contamination by circulating malignant plasma cells was carefully evaluated using immunofluorescence. Clonal rearrangements were observed in only two cases, in which a contamination by myeloma cells was evident. In these cases the use of different endonucleases clearly demonstrated that these Ig-clonal rearrangements involved post-switched cells. No clonal rearrangement was found when contamination by myeloma cells was absent. Our results demonstrate the absence of detectable B cells involved in the myeloma clone in the peripheral blood of patients with MM.

Aged↗
PubMed1989

Therapeutic implications of myeloma staging.

Clinical staging, such as with the Durie-Salmon clinical staging method, remains the most easily usable available method to classify patients with untreated multiple myeloma. However, for the development of new treatment strategies and comparison with prior results, new and powerful prognostic factors are now available. Serum beta 2 microglobulin alone represents the most reliable prognostic factor in multiple myeloma. Beta 2 microglobulin alone allows simple and reproducible classification of patients into low grade myeloma with low serum beta 2 microglobulin versus high grade myeloma with high serum beta 2 microglobulin. Plasma cell labelling index is an additional factor which allows identification of patients with MGUS as well as subclassification of patients with low serum beta 2 microglobulin into those with relatively better or worse prognosis. For each grade of myeloma young (less than 63 years of age) patients have a slightly better survival. Independently of serum beta 2 microglobulin and labelling index, DNA content values allow the identification of a subset of patients with biclonal or hypodiploid tumors and high grade disease. New or more sophisticated methods for evaluating myeloma cells such as by immunophenotyping or assessment of multi drug resistance enable the development of specific approaches to treatment in individual cases. It should also prove possible to identify patients especially suitable for newer biologic agents such as alfa interferon, G or G-MCSF and the various interleukins.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias.

Using a specific and very sensitive (1 pg = 1 U) bioassay, we investigated the presence of IL-6, a potent myeloma cell growth factor, in the sera of 131 subjects with plasma cell dyscrasias. 22 had monoclonal gammopathy of undetermined significance (MGUS), 13 had smoldering myeloma (SMM), 85 had overt multiple myeloma (MM), and 11 had plasma cell leukemia (PCL). Significant serum IL-6 levels were detected in only 3% of the MGUS/SMM group, but in 35% of the overt MM group and 100% of the PCL group. During overt MM, IL-6 was detected in 37% of the patients at diagnosis, 13% of those with stable MM, and 60% of those with fulminating disease. These data demonstrate that serum levels of IL-6, a potent myeloma cell growth factor in vitro, correlate with disease severity in plasma cell dyscrasias. Serial studies performed in 3 patients and correlative studies with labeling index in vivo in 25 patients have confirmed this concept. Taken together, this suggests that this cytokine is probably involved in vivo during the progressive phase of MM. Thus, anti-IL-6 or anti-IL-6 receptor antibodies could be useful as therapeutic agents at this stage of the disease.

Humans↗
PubMed1989

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

Bone Diseases↗
PubMed1989

Antibody specificity of the human monoclonal immunoglobulins: the elusive target antigen.

Human monoclonal immunoglobulins (HMIGs) are encountered in different clinical conditions mainly including (auto)immune disorders, immunodeficiencies and B-cell malignancies. However, in some cases no associated-disease is evidenced and they are considered as "idiopathic". Their incidence increases with age. The factors involved in the emergence and regulation of the growth and differentiation of B-cell clones secreting HMIGs are unknown but might implicate T-cell dysfunction. One approach to elucidate the origin of such B-cell clones is to identify the putative target antigen. For this reason, we have reviewed the antibody (Ab) specificity of 8439 HMIGs described in the literature, the data coming from 24 systematic screenings. Very few HMIGs present anti-hapten activity (1%) or specificity for foreign antigens (0.3%). On the other hand, the data quoted strongly document an auto-Ab (Ab1 type) activity in a large percentage of the HMIGs, mainly of the IgM type (at least greater than 30%), with properties similar to those of naturally occurring auto-Abs. Furthermore, there is some evidence that HMIGs may express anti-idiotypic activity (Ab2) to human (auto)-Abs. Finally, many of the HMIGs which are devoid of detectable auto-Ab activity (i.e., mainly IgG, IgA) share cross-reactive idiotypes with natural auto-Abs. It may be speculated that some of these HMIGs actually represent either Ab of the Ab3 type i.e., anti-anti-idiotypic Ab to auto-Abs or Ab which have varied sufficiently to loose auto-or-foreign-antigen-binding activity but maintaining idiotype. As a whole, these data demonstrate that many HMIGs are the secretory products of the auto-reactive B-cell clones which produce natural auto-Abs (including anti-idiotypic and anti-anti-idiotypic Abs) and which are characterized by a very high degree of idiotypic connection. Since HMIGs arise from such clones, it may be postulated that the emergence of HMIGs might be due to a dysfunction of the system that normally regulates such an Ab production.

Antibodies, Anti-Idiotypic↗
PubMed1989

Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6.

To explore the mechanisms involved in the pathogenesis of human multiple myeloma (MM), we investigated the potential role of interleukin-6 (IL-6), a B-cell differentiation factor in humans, and a growth factor for rat/mouse heterohybridomas and murine plasmacytomas. Using a heterohybridoma assay, we found that two well-documented human myeloma cell lines, RPMI 8226 and U266, did not secrete IL-6 and did not express RNA messengers for IL-6. Neutralizing antibodies to IL-6 did not inhibit their proliferation, and recombinant IL-6 did not stimulate it. Taken together, these data show that IL-6 is not the autocrine growth factor of these human myeloma cell lines. A high production of IL-6 was found in the bone marrows of patients with fulminating MM, compared with patients with inactive or slightly active MM, or to healthy donors. This IL-6 production was assigned to adherent cells of the bone-marrow environment but not to myeloma cells. A spontaneous proliferation of myeloma cells freshly isolated from patients was observed in short-term cultures. Recombinant IL-6 was able to amplify it two- to threefold. The spontaneous proliferation of the myeloma cells was inhibited by anti-IL-6 antibodies and reinduced by recombinant IL-6. After 2 to 3 weeks of culture, the myeloma-cell proliferation progressively declined and no IL-6-dependent myeloma cell lines could be obtained despite repeated additions of fresh IL-6 and costimulation with other cytokines such as tumor necrosis factor (TNF)beta, or IL-1 beta. These data demonstrated a paracrine but not autocrine regulation of the growth and differentiation of myeloma cells by IL-6.

Aged↗
PubMed1989

Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma.

It has recently been demonstrated that interleukin-6 (IL-6) is a potent myeloma-cell growth factor in the majority of patients with multiple myeloma (MM). Using an anti-bromodeoxyuridine monoclonal antibody (MoAb) to specifically count myeloma cells in the S-phase (ie, labeling index, LI), we demonstrate that the IL-6 responsiveness of myeloma cells in vitro is directly correlated with their LI in vivo. Myeloma cells from all 13 patients with high LIs in vivo (greater than or equal to 1%) responded in vitro to IL-6, the strongest response occurring in cells from five patients with plasma-cell leukemia. In contrast, the cells of only two of eight patients with low myeloma-cell LIs in vivo (less than 1%) responded to IL-6 in vitro. After seven days of culturing with 1,000 U/mL recombinant IL-6 (rIL-6), the median LI value in the first group of patients (in vivo LI greater than or equal to 1%) was 11%, ie 11 times higher (P less than .01) than the median LI value (1%) in the second group of patients (in vivo LI less than 1%). Thus, the in vitro IL-6 responsiveness of myeloma cells is directly related to their in vivo proliferative status, and hence to the severity of the disease.

Cell Division↗
PubMed1988

Histologic evidence of an abnormal bone remodeling in B-cell malignancies other than multiple myeloma.

In a prospective study of the quantitative bone changes induced by B-cell cancers other than multiple myeloma (MM), but including chronic lymphocytic leukemia (CLL; n = 8), hairy cell leukemia (HCL; n = 3), and Waldenström disease (WD; n = 7), an abnormal bone remodeling close to malignant cells was found in 80% of the patients. This was observed more frequently in cases of diffuse, but not nodular, bone marrow involvement by tumor cells. More particularly, excessive bone resorption (a major feature of MM) associated with a normal to low bone formation (i.e., uncoupling bone disease) was the most frequent feature and in the same range of that observed in overt MM. However, as opposed to MM, this bone resorption was characteristically mediated by small mononucleated osteoclasts (i.e., microresorption). The same phenomena of abnormal bone remodeling, the uncoupling process, excessive bone resorption, and above all microresorption were confirmed by the detailed bone study of five cases of B-cell cancers other than MM presenting lytic bone lesions and hypercalcemia. The current findings are important for clarifying the biology of these B-cell malignant diseases, and also could be of diagnostic and prognostic value.

Adult↗
PubMed1988

Phenotypic and functional analysis of 1,25-dihydroxyvitamin D3 receptor mediated modulation of the human myeloma cell line RPMI 8226.

Several recent studies have demonstrated the presence of specific receptors for the 1,25-dihydroxyvitamin D3 (calcitriol) in activated normal lymphocytes. By DNA cellulose chromatography, we show evidence of such specific receptors in the human myeloma cell line RPMI 8226. Nanomolar concentrations of 1,25-dihydroxyvitamin D3 reduce the proliferation of RPMI 8226 cells significantly and simultaneously induce the appearance of both new properties and phenotype expression, such as butyrate esterase, enhanced expression of CD20 (B1), CD15 (Leu-M1) antigens and lambda chains, and decreased expression of the PC1 antigen using microfluorometric analysis. But such an increased expression of membrane lambda chains was not associated with an enhanced secretion of lambda chains. Furthermore, the bone resorbing activity produced normally by RPMI 8226 cells was reduced significantly after 1,25-dihydroxyvitamin D3 treatment. The possible mechanisms and significance of these new functional and phenotypic properties are discussed with respect to the B-cell lineage.

Bone Resorption↗
PubMed1988

Delay and not deficiency in cap formation of peripheral blood B cells in patients with multiple myeloma.

A major problem in the study of peripheral blood (PB) B cells from patients with multiple myeloma (MM) is the distinction between the cells really able to synthesize membrane (m) immunoglobulins (Ig) and those able only to absorb serum Ig passively, since the lymphocytes of such patients are bathed in very high concentrations of monoclonal Ig. In order to reappraise PB B cells (including putative pre-B cells) in MM, we have used three different criteria: (a) the capacity of PB B cells to cap mIg when triggered by an anti-Ig; (b) the presence of B-cell differentiation antigens (CD19, CD20, CD21, and CD37) as specific B-cell markers; and (c) the expression of cytoplasmic mu heavy chain as a marker of pre-B cells. We have found that, in active myeloma (N = 13), the percentages and absolute numbers of PB B cells able to cap mIg (4.25%; 45.43 cells/mm3) were significantly lower than those in healthy donors (8.4%; 151.2 cells/mm3) and those in stable MM (7.67%; 134.39 cells/mm3). In addition, the capping formation in patients with stable or active MM was significantly delayed compared to that in healthy donors. For all the normal individuals and patients investigated, there has been found an excellent correlation between the percentages and absolute numbers of PB B cells able to cap their mIg and those of PB mononuclear cells bearing the four B cell-specific differentiation antigens: CD19, CD20, CD21, and CD37. Finally, virtually no pre-B cells bearing cytoplasmic mu chains have been identified in the peripheral blood from healthy donors and patients with MM.

Adult↗
PubMed1988

Estrogen and progesterone receptors in some human myeloma cell lines and murine hybridomas.

The control of immune responses by sex hormones is well documented but the effect of sex hormones on lymphoid cell subsets is poorly understood. We have investigated the expression of receptors for androgens (AR), estradiol (ER) and progesterone (PR) by human cell lines of the B lymphocyte lineage and by murine myeloma or hybridomas. AR, ER and PR were determined by cytosol and nuclear binding assays. Eleven human lymphoblastoid cell lines obtained by in vitro infection of blood or tonsil B cells with Epstein-Barr Virus (EBV) B95, did not express AR or ER. Similarly, 10 Burkitt's lymphoma cell lines were AR, ER and PR negative with the exception of the pre-B RAJI cells which bear AR. Among 13 cell lines derived from patients with multiple myeloma none expressed AR but five were found to bear ER (20-164 fmol/mg DNA or 5-10 fmol/mg protein). Four of the latter group also bear PR (86-450 fmol/mg DNA). Two mouse hybridomas out of seven tested were ER and PR positive. The MOPC 315 myeloma expressed ER but not PR. The possible functional role of these sex hormone binding sites in cell proliferation and immunoglobulin secretion deserves further investigation.

Animals↗