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G Biron

Publications and source records attributed to G Biron.

At least 19 recordsLinked to original sources
PubMed1999

CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia.

Thrombospondin forms a 'molecular bridge' between phagocytic and apoptotic cells through interaction with alphavbeta3/CD36. We report here that engagement of CD47, a newly described thrombospondin receptor, by immobilized monoclonal antibody against CD47 or by thrombospondin induced in all B-cell chronic lymphocytic leukemia clones the cytoplasmic features of apoptosis (cell shrinkage, decrease in mitochondrial transmembrane potential and phosphatidylserine externalization) without the nuclear features (chromatin condensation, appearance of single-stranded DNA, DNA fragmentation and cleavage of poly ADP-ribose polymerase). These cytoplasmic events of apoptosis were not prevented by the addition of caspase inhibitor z-VAD-fmk, or by the presence of survival factors (such as interleukin-4 and gamma interferon) or cell activation. Morphological studies confirmed the integrity of the nucleus and showed swelling of the mitochondria. This caspase-independent death pathway may be relevant to the development of alternate therapeutic strategies in chronic lymphocytic leukemia, which remains an incurable disease.

Adult↗
PubMed1996

Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia.

Prognosis of B-cell chronic lymphocytic leukemia (CLL) is based on clinical staging whose limitation is the failure to assess whether the disease will progress or remain stable in early stage (Binet A, or Rai 0, I, II) patients. We previously reported that soluble CD23 (sCD23), a protein derived from the B-cell membrane CD23 Ag, is selectively elevated in the serum of CLL patients. This prospective study assessed the predictive value of serum sCD23 level measured at study entry on the overall survival of all CLL patients and on disease progression of stage Binet A patients. Prognostic value of repeated measurements of sCD23 over time in stage A patients was also analyzed. One hundred fifty-three CLL patients were prospectively followed with a median follow-up of 78 months. Eight clinical or biological parameters were collected from the date of the first sCD23 measurement. At study entry, by Cox model, Binet staging (P = .0001) and serum sCD23 level (P = .03) appeared as prognostic factors for survival. Patients with sCD23 level above median value (> 574 U/mL) had a significantly worse prognosis than those with lower values (median survival of 53 v 100+ months, P = .0001). During follow-up, sCD23 doubling time increased by 3.2 the risk of death (P = .001). Among stage A patients (n = 100), sCD23 determination at study entry was the sole variable predictive of disease progression, patients with sCD23 level above 574 U/mL had a median time progression of 42 months versus 88 months for those with lower levels (P = .0001). Stage A patients who doubled their sCD23 level exhibited a 15-fold increased risk of progression (P = .0001) and, in addition, the sCD23 increase preceded by 48 months disease progression. We conclude that in CLL patients, serum sCD23 level provides significant additional prognostic information in terms of overall survival. Most interestingly, among early stage patients, sCD23 determination at diagnosis and during the course of the disease may help to the early identification of patients who will rapidly progress to upper stages.

Adult↗
PubMed1995

The two CD23 isoforms display differential regulation in chronic lymphocytic leukaemia.

B lymphocytes from chronic lymphocytic leukaemia (B-CLL) patients express the two CD23 isoforms (type A and B), which differ only in their intracytoplasmic domain. The abnormal regulation of the CD23 antigen in response to IL-4, IFNs alpha and gamma results in CD23 over-expression on B-CLL cells. Our present study shows that the two CD23 isoforms are differentially and abnormally regulated on B-CLL cells. IL-4 selectively up-regulates CD23 type A mRNA in five different B-CLL patients, whereas in normal B cells it enhances CD23 type A and is the most potent inducer of type B. In contrast, phorbol esters (PMA) up-regulate both CD23 isoforms in the malignant B cells and specifically increases type B in normal B cells. We next postulated that cytokines other than IL-4 regulate CD23 B isoform in B-CLL cells and therefore examined the effect of IL-2, IFN-gamma and IFN-alpha. We found that the ability of a given cytokine to induce B-CLL growth (i.e. IL-2 and IFN alpha) is concurrent with a selective up-regulation of CD23 type B mRNA, whereas lymphokines that have no B cell growth activity (i.e. IL-4 and IFN-gamma) specifically increase CD23 type A mRNA. We next showed that IL-4 and IFN gamma prevent hydrocortisone-induced programmed cell death and that the rescued malignant B cells mainly express CD23 type A. Given that CD23 molecule has been reported to play a role in normal B cell proliferation and survival, it is therefore proposed that in B-CLL cells the expression of CD23 type A may be related to cell viability and that of type B to cell proliferation. These data suggest that the CD23 molecule may contribute to the physiopathology of the disease which is characterized by the accumulation of long-lived and slow-dividing monoclonal B cells.

Adult↗
PubMed1992

Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression.

B chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of slow-dividing and long-lived monoclonal B cells arrested at the intermediate stage of their differentiation. We previously showed that interleukin 4 (IL-4) not only inhibits but also prevents the proliferation of B-CLL cells. We report here that IL-4 protects the B-CLL cells from death by apoptosis (programmed cell death [PCD]). IL-4 inhibits spontaneous and hydrocortisone (HC)-induced PCD of highly purified B cells from 12 unselected CLL patients, as shown by sustained cell viability and lack of DNA fragmentation. IL-1, -2, -3, -5, -6, -7, tumor necrosis factor alpha, and transforming growth factor beta have no protective effect. The in vitro rescue from apoptosis by IL-4 is reflected by an increased expression of Bcl-2 protein, a proto-oncogene directly involved in the prolongation of cell survival in vivo and in vitro. Hence, IL-4-treated B-CLL cells express significantly more Bcl-2 than unstimulated, HC-treated, or fresh B-CLL cells. Furthermore, subcutaneous injection of IL-4 into one CLL patient enhances Bcl-2 protein expression in the leukemic B cells. These data may suggest that IL-4 prevents apoptosis of B-CLL cells using a Bcl-2-dependent pathway. Given our recent observations that fresh T cells from B-CLL patients express IL-4 mRNA, we propose that IL-4 has an essential role in the pathogenesis of CLL disease, by preventing both the death and the proliferation of the malignant B cells.

Adult↗
PubMed1992

Low-molecular weight B cell growth factor (BCGF-12KD) as an autocrine growth factor in B cell chronic lymphocytic leukemia.

The role of cytokines in the growth and spreading of human hematologic malignancies has been underlined in recent years. Here we report evidence that a human 12-kDa B cell growth factor (BCGF-12KD) may function as a growth stimulatory factor in B cell chronic lymphocytic leukemia (B-CLL). First, recombinant BCGF-12KD induced dose-dependent DNA synthesis in neoplastic B cells of four B-CLL patients tested. Second, seven different B-CLL clones secreted a BCGF-12KD-like product that accounted for their proliferation. A neutralizing monoclonal antibody (mAb; Ac8) directed against a BCGF-12KD synthetic peptide inhibited the spontaneous growth of the leukemic B cells. The same mAb blocked DNA synthesis in normal tonsillar B lymphocytes induced by the culture supernatant of spontaneously proliferating B-CLL cells. Finally, BCGF-12KD mRNA was expressed in freshly isolated (two of three patients) as well as in vitro proliferating B-CLL cells (three of three patients). These findings strongly suggest that BCGF-12KD can modulate the growth of B-CLL cells in vivo as well as in vitro. They may offer significant insights into the biology of this frequent B lymphoproliferative disorder.

Adult↗
PubMed1992

CD23 antigen regulation and signaling in chronic lymphocytic leukemia.

B lymphocytes from patients with chronic lymphocytic leukemia (B-CLLs), strongly express the CD23 antigen, a surface marker with significant prognostic importance in this disease. Because we previously reported that IL-4 shows a poor capacity for CD23 expression on B-CLLs, we first examined the possible mechanisms underlying CD23 overexpression on B-CLLs and found that mitogen-activated CLL T cells release soluble factors that are capable, in synergy with IL-4, of strongly inducing CD23. Using neutralizing Abs, we noticed that the T-cell-derived enhancing activity is entirely ascribed to the combined effects of IFN gamma (potent inhibitor of CD23 on normal B cells), TNF alpha (which has no effect on normal B cells), and IL-2 (which has a slight enhancing effect on both CLL and normal B cells). Furthermore, recombinant IFN gamma as well as IFN alpha, TNF alpha, and IL-2 (but not IL-3, IL-5, IL-6, IL-7, and lymphotoxin) significantly enhance CD23 protein and mRNA expression on B-CLLs, in the presence or absence of IL-4. Inasmuch as optimal CD23 expression absolutely requires the combination of IFN gamma, IL-2, TNF alpha (the production of which is increased in CLL disease), and IL-4, it was relevant to show that IL-4 mRNA is indeed expressed in fresh T-CLL cells. We next examined the possible role of CD23 in the regulation of B-CLL proliferation. Signaling through CD23 via ligation of the antigen by F(ab')2 anti-CD23 MAb but not Fab fragments inhibits the cytokine-induced B-CLL DNA synthesis. It is concluded that the CD23 gene is abnormally regulated in B-CLL disease and that cross-linking of CD23 molecule delivers a negative growth signal to the leukemic B cells.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

The in vivo expression of type B CD23 mRNA in B-chronic lymphocytic leukemic cells is associated with an abnormally low CD23 upregulation by IL-4: comparison with their normal cellular counterparts.

We recently reported that the sera of chronic lymphocytic leukemia (CLL) patients contained 3-500 times more soluble CD23 (or IgE-BF) than the sera of patients with other lymphoproliferative diseases or normal individuals and that their B cells (B-CLLs) overexpressed CD23 Ag. In the present report, we extended these studies and showed that CD5+ B cells from all CLL patients (n = 15) co-express CD23 Ag. We next identified two additional major differences between B-CLLs and normal adult B cells. First, in contrast to normal adult B cells which exclusively express type A CD23 mRNA, freshly isolated B-CLLs expressed both type B and type A CD23 mRNA. Second, although IL-4 is a potent inducer of type B CD23 mRNA on normal B cells, an optimal concentration of IL-4 infranormally upregulated CD23 on highly purified B-CLLs both at the protein and at the molecular levels. However, co-stimulation of CLL PBMC with phytohemagglutinin (PHA) and IL-4 strongly upregulated CD23 on B-CLLs, reconstituting the high level of CD23 expression observed in vivo. We next attempted to relate B-CLLs to the CD5+ B cell subpopulations present in peripheral blood mononuclear cells (PBMC, n = 3), cord blood mononuclear cells (CBMC, n = 6) and tonsillar lymphocytes (TONS, n = 3) by analysing their co-expression of CD20, CD5 and CD23 Ag and their phenotypic regulation by IL-4. Our results indicated that B-CLLs presented some features in common with the CD23+ umbilical cord blood B cells in as much as, like in B-CLLs; (i) all CD23+ cord blood cells co-expressed CD5 Ag, (ii) freshly isolated CBMC expressed both type A and type B CD23 mRNA, and finally (iii) these cells weakly re-expressed CD23 Ag upon IL-4 stimulation as compared to adult PBMC.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

Antiproliferative effect of interleukin-4 in B chronic lymphocytic leukemia.

Recombinant interleukin-4 (IL-4) profoundly inhibits the proliferative response of chronic lymphocytic leukemic B cells (B-CLLs) to recombinant interleukin-2 (IL-2). In the present study, we confirmed and extended these data by showing that IL-4 strongly suppresses the [3H]thymidine incorporation by B-CLLs stimulated by recombinant tumor necrosis factor alpha, recombinant interferon alpha, IL-2, and low molecular weight B cell growth factor in the absence of costimulant. Recombinant interleukin-4 inhibits spontaneous DNA synthesis suggesting that it also interferes with the autocrine proliferation of these cells. Kinetic studies indicate that IL-4 suppresses rather than shifts the peak of cytokine-induced DNA synthesis. Moreover, IL-4 blocks the progression of B-CLLs in or into G1 stage of the cell cycle as shown by the inhibition of cytokine-induced [3H]uridine incorporation. Finally, IL-4 pretreatment of B-CLLs prevents their subsequent proliferative response to the above cytokines, indicating that IL-4 confers to the B-CLLs a state of resistance to numerous stimulatory cytokines. The antiproliferative effects of IL-4 suggest that this lymphokine may have important therapeutic implications for the B-CLL patients.

Cell Cycle↗
PubMed1990

Expression of CD23 antigen and its regulation by IL-4 in chronic lymphocytic leukemia.

In our previous studies, we reported that the sera from CLL patients contain 3 to 500 times more IgE-BFs (or soluble CD23) than the sera from normal individuals (Sarfati M., Bron D., Lagneaux L., Fonteyn C., Frost H. & Delespesse G. (1988) Elevation of IgE-binding factors in serum of patients with B cell-derived chronic lymphocytic leukemia. Blood 71, 94). In the present study, we have investigated some of the mechanisms accounting for this observation. We report that the density of CD23 expression per cell is significantly higher on the B-CLLs than on the control cells, although the proportion of CD23+ B cells is comparable in both groups (70-90% of CD20+ cells express CD23 antigen). We have next examined the influence of IL-4 on the CD23 expression, the proliferation and the differentiation of B-CLLs. The results indicate that IL-4 (i) increases CD23 expression and IgE-BFs production by normal and CLL B cells; (ii) does not promote B-CLLs proliferation or differentiation, neither by itself nor in costimulation with either anti-IgM or PMA; (iii) significantly potentiates PMA-induced IgM and IgE-BFs production by B-CLLs. It is further shown that anti-CD23 Mab does not interfere with B-CLLs proliferation or differentiation. It is concluded that: (i) the excessive production of IgE-BFs in CLL patients results not only from the enlarged pool of CD23+ B cells but also from an over-expression of CD23 on B-CLLs; (ii) CD23 is not constitutively expressed on B-CLLS and it is upregulated by IL-4; and (iii) by contrast to normal B cells, CD23 on B-CLLs may not be associated with the functional LMW-BCGF receptor.

Aged↗
PubMed1984

Marginal leakage of class V cavity preparations.

Dentin-bonding materials, ferric oxylate (FO), addition reaction between N-phenylglycine and glycidyl methacrylate (NPG-GMA), and addition reaction product of pyromellitic acid dianhydride and 2-hydroxyethyl methacrylate (PMDM), were tested together for their ability to inhibit marginal leakage in Class V composite restorations in vitro. Sixteen experimental teeth were pretreated with FO, NPG-GMA, PMDM, and restored with composite. Sixteen control teeth were treated conventionally with composite. The teeth were then thermally cycled (5 and 55 degrees C) for 7 days, silver stained, and evaluated blindly for degree of marginal leakage on a scale of 0 (no leakage) to 7 (leakage into the pulp). The experimental group displayed significantly greater leakage values (p less than 0.01) than controls. The results of this study support the hypothesis that FO, NPG-GMA, and PMDM, together with composite inhibit marginal leakage.

Composite Resins↗
PubMed1984

Inhibition of marginal leakage with a dentin bonding agent.

Class V cavity preparations were treated in vitro with dentin bonding agents and composite. The teeth were thermally cycled, stained, and scored for marginal leakage, by a silver stain technique. The composite-only control group leaked significantly more than did the dentin-bonding-treated experimental groups. The coating of pre-treated dentinal walls with unfilled bonding resin offered no advantage with this dentin bonding system.

Acid Etching, Dental↗
PubMed1983

[Attempts at time-related control of bovine hypodermiasis at scattered or grouped farms].

The control was performed by a unic systemic autumn treatment on heifers and repeated topical spring treatments on dairy cows. After a four years programme, limited success are obtained. No difference in the efficacy are observed in isolated or grouped farms. A good estimation of infestation cannot be obtained by only one or two numerations of warbles in spring. Repetitive of topical spring treatments on dairy cows appears to be the major limitating factor of success in these programmes.

Animals↗