Biomedical subjects

J Banchereau

Publications and source records attributed to J Banchereau.

At least 199 records · Page 11Linked to original sources

PubMed1994

Interleukin 10 induces B lymphocytes from IgA-deficient patients to secrete IgA.

We have previously shown that human B lymphocytes cultured in the CD40 system, composed of an anti-CD40 mAb presented by a CD32-transfected fibroblastic cell line, proliferate but do not secrete antibodies. However, the addition of particles of Staphylococcus aureus Cowan (SAC) induces B cell differentiation even in the absence of exogenous cytokines (CD40/SAC system). Additionally, B lymphocytes cultured in the CD40 system in the presence of human IL-10, produce IgM, IgG, and IgA, and Ig levels are further increased by SAC. Here, we have studied the capacity of peripheral blood lymphocytes from patients with IgA deficiency (IgA-D) to secrete Igs, particularly IgA after CD40 triggering. Peripheral blood mononuclear cells (PBMNC) from IgA-D patients cultured in the CD40/SAC system produced IgM and IgG, but not IgA. The addition of IL-10 to the cultures, enhanced the production of IgM and IgG and most strikingly induced the production of high amounts of IgA. The addition of IL-10 to PBMNC from IgA-D patients activated through CD40 alone resulted in the production of IgA. Thus, SAC and anti-CD40 mAb stimulate B cells to differentiate into cells secreting IgG and IgM whereas IL-10 plays a central role in inducing B cells from IgA-D patients to differentiate into IgA secreting cells.

Adolescent↗

PubMed1994

Localization of the human CD40 gene to chromosome 20, bands q12-q13.2.

CD40 is a surface glycoprotein, member of the nerve growth factor receptor family, which is expressed on B cells and plays an important role in their development, growth, and differentiation. Using chromosomal in situ hybridization, we localized the CD40 gene to the long arm of chromosome 20, bands q12-q13.2. This localization correlates well with the mapping of the murine CD40 gene to the distal region of chromosome 2, syntenic to the human 20q11-q13 region.

Antigens, CD↗

PubMed1994

IL-13 has only a subset of IL-4-like activities on B chronic lymphocytic leukaemia cells.

The recently described interleukin-13 (IL-13) has been shown to share many of the effects of IL-4 on normal B cells, including growth-promoting activity and induction of CD23. In this study, we compared the effects of IL-13 and IL-4 on B chronic lymphocytic leukaemias (B-CLL) cells. After anti-CD40 activation, both IL-13 and IL-4 promoted the DNA synthesis of B-CLL cells and increased the recovery of viable cells. The time kinetics of the proliferative response of B-CLL cells to IL-13 or IL-4 were superimposable and showed the long-lasting effect of both cytokines. As on normal B cells, both IL-4 and IL-13 synergized with IL-10 to enhance B-CLL DNA synthesis. Moreover, IL-13, like IL-4, was able to increase CD23 expression on anti-CD40-activated leukaemic B cells. The CD23 up-regulation and the DNA synthesis induced by IL-13 on anti-CD40-activated B-CLL cells, were significantly reduced when B-CLL cells were cultured with anti-IL-4 receptor monoclonal antibody, suggesting a common pathway for IL-13 and IL-4 signalling. However, after cross-linking of surface IgM, IL-4 strongly inhibited the IL-2-induced DNA synthesis of B-CLL cells, whereas IL-13 did not inhibit IL-2-driven proliferation of anti-IgM-activated B-CLL cells. Furthermore, while IL-4 strongly up-regulated the expression of CD23 on anti-IgM-activated leukaemic B cells, IL-13 only marginally increased it. Finally, IL-13, in contrast to IL-4, did not prevent the entry of B-CLL cells into apoptosis. Thus IL-13 and IL-4 display comparable effects on anti-CD40-activated B-CLL cells, which are blocked by anti-IL-4 receptor (IL-4R) monoclonal antibodies. However, IL-13-dependent effects are absent or inefficient in non-activated or anti-IgM-activated B-CLL cells. This suggests that such cells may lack functional IL-13 receptors, though IL-13R and IL-4R on B-CLL cells share a common component.

Antibodies, Monoclonal↗

PubMed1994

Human interleukin 4.

Human IL-4 is a mature glycoprotein of 129 amino acids, mostly secreted by activated T cells. It is a pleiotropic cytokine which acts on T and B lymphocytes, monocytes, polymorphonuclears, fibroblasts and endothelial cells. In addition, it acts at various stages of cell differentiation, and its effects are also dependent on the cytokine environment. In particular, IL-4 blocks some of the effects of IL-2 whereas interferon-gamma blocks some of the effects of IL-4. In vitro and in vivo experiments in mouse and in vitro experiments in man have shown that IL-4 plays a crucial role in the induction of IgE production whereas interferons counteract this effect. Human IL-4 binds to a high-affinity receptor which is composed at least of one 130 kDa glycoprotein of 800 amino acids which is a member of the newly described hematopoietin receptor superfamily. IL-4 may prove useful as an anti-tumoral and anti-inflammatory agent.

B-Lymphocytes↗

PubMed1994

[Interleukin-4: from B-lymphocyte to fibroblast].

Interleukin-4 (IL-4) has been characterized in 1982 by its ability to induce the proliferation of anti-IgM stimulated B-lymphocytes and IgG1 secretion by these same cells after activation by lipopolysaccharide. It's activity on B-cells explain that it received the former names of B-Cell Growth Factor-1 (BCGF-1) or B-Cell Stimulatory Factor-1 (BSF-1). More recent works have shown that IL-4 exerts pleiotropic effects on a large number of cells. Particularly, it is able to activate the production of extracellular matrix components by fibroblasts. The aim of the present paper is to review main data about this cytokine, with a particular emphasis on its role on the regulation of connective tissue cell activities and on its possible implication in pathophysiological events such as fibrosis, wound healing, and tumor invasion.

Arthritis, Rheumatoid↗

PubMed1993

Interleukin 4 inhibits the production of some acute-phase proteins by human hepatocytes in primary culture.

Interleukin 4 (IL4) has been shown to exhibit anti-inflammatory effects by inhibiting the secretion by monocytes of proinflammatory cytokines such as interleukin 1 (IL1), interleukin 6 (IL6), and tumor necrosis factor (TNF) and by inducing the secretion of the IL1 receptor antagonist. We investigated the role of this cytokine on the production of acute-phase proteins in primary human hepatocyte cultures. Cells were exposed to either IL4 and/or IL6, the most potent mediator of hepatic acute phase proteins. IL4 led to decreased production of haptoglobin, C-reactive protein and albumin while alpha 1-antitrypsin and fibrinogen remained unaffected. These inhibitory effects of IL4 were also observed at the mRNA level. In addition, IL4 inhibited the IL6-induced production of haptoglobin although it had no effect on the induced C-reactive protein and fibrinogen. Our results demonstrate that IL4 can affect the production of a subset of acute-phase proteins by human hepatocytes and can antagonize some of the effects of IL6. These observations reinforce the notion that IL4 can be considered as an anti-inflammatory cytokine.

Acute-Phase Proteins↗

PubMed1993

Interleukin 10 (IL-10) upregulates functional high affinity IL-2 receptors on normal and leukemic B lymphocytes.

Interleukin 10 (IL-10) has recently been shown to induce normal human B lymphocytes to proliferate and differentiate into immunoglobulin (Ig)-secreting cells. Herein, we show that IL-10 also promotes DNA synthesis and IgM production by anti-CD40 activated B cell chronic lymphocytic leukemia (B-CLL). Most strikingly, IL-2 and IL-10 were found to synergize to induce the proliferation and differentiation of B-CLL cells. This synergy between IL-2 and IL-10 was also observed with normal B cells which proliferated strongly and secreted large amounts of IgM, IgG, and IgA. The observed synergy is likely to be due to the IL-10-induced increase of high affinity IL-2 receptors on both normal and leukemic B cells. This increase of high affinity receptor is associated to an increase of Tac/CD25 expression that can be detected by flow cytometric analysis. Taken together, these results indicate that IL-10 permits anti-CD40 activated B cells to respond to IL-2 through an induction of high affinity IL-2 receptors. This effect of IL-10 may partly explain how T cells, which activate B cells in a CD40-dependent fashion, induce B cell proliferation and differentiation mostly through IL-2.

B-Lymphocytes↗

PubMed1993

IL-4 inhibits growth factor-stimulated rheumatoid synoviocyte proliferation by blocking the early phases of the cell cycle.

A major feature of rheumatoid arthritis is an uncontrolled proliferation of synoviocytes. This is consistent with the active production of factors such as platelet-derived growth factor (PDGF) and IL-1 by the synovitis, which act in vivo as well as in vitro as potent synoviocyte growth factors. We have previously shown that IL-4 is able to inhibit growth factor production in an ex vivo model of synovitis. Herein, we show that IL-4 strongly inhibited PDGF and IL-1 beta stimulated rheumatoid arthritis synoviocyte proliferation in a dose-dependent manner and through its 130 kDa receptor. This antiproliferative effect of IL-4 directly correlated with a blockade of the synoviocyte cell cycle at the G0 + G1 phases. We also observed that IL-4 induced striking morphologic changes in IL-1 beta or PDGF-stimulated synoviocytes, including increased volume and granulosity. These changes led to major perturbations of the cell monolayer, associated with a marked decrease of synoviocyte viability. Taken together, these data indicate that IL-4 inhibits growth factor-induced proliferation of synoviocytes by interfering with the cell cycle, and by decreasing cell survival.

Arthritis, Rheumatoid↗

PubMed1993

Myofibroblastic stromal cells isolated from human bone marrow induce the proliferation of both early myeloid and B-lymphoid cells.

Normal human bone marrow stromal cells (BMSC) were isolated from Dexter-type long-term cultures according to their capacity to adhere to plastic and to their lack of hematopoietic antigens. The BMSC displayed a homogeneous appearance and a myofibroblastic phenotype in culture. The stromal cells (SC) were shown to support the proliferation of purified CD34+ hematopoietic progenitors and permitted us to maintain myeloid cells for several weeks in culture. In addition, the BMSC induced the proliferation of purified CD10+ s mu- fetal BM B-cell precursors (BCP). The capacity of the BMSC to induce the proliferation of early myeloid cells was shared by several other human fibroblastic-like cell types. In contrast, the BMSC were far superior to other adherent cells for induction of BCP proliferation. This capacity was largely mediated by endogenously produced interleukin-7 (IL-7), because it could be inhibited by anti-IL-7 antibody. In line with this finding, addition of IL-7 considerably enhanced BCP proliferation in cocultures with skin fibroblasts or synoviocytes. Thus, production of IL-7 appears to be a critical parameter that determines the ability of fibroblastic-like cells to induce BCP proliferation. Taken together, our data show that normal human myofibroblastic BMSC induce the proliferation of both early myeloid and B-lymphoid cells in the absence of accessory hematopoietic cells. The present system should constitute a model to study interactions between native human BM myofibroblastic stroma and various hematopoietic cell subsets.

Antigens, CD↗

PubMed1993

Serum interleukin-10 in non-Hodgkin's lymphoma: a prognostic factor.

Serum interleukin-10 (IL-10) was measured retrospectively in 153 patients with a fully documented history of non-Hodgkin's lymphoma (NHL) using an enzyme-linked immunosorbent assay (ELISA) detecting both human IL-10 and the Epstein-Barr virus (EBV) molecule BCRF1/viral IL-10. IL-10 was detectable in 47 (46%) of the 101 patients with active NHL, 3 of 52 (6%) patients in first partial or complete response, and none of the 60 healthy blood donors. Serum IL-10 was detectable with a similar frequency in all subtypes of NHL and in all clinical stages, as well as in EBV-seropositive and EBV-negative patients. In patients with intermediate or high-grade NHL, the presence of detectable serum IL-10 at diagnosis was correlated to a significantly shorter overall (P = .025) and progression-free (P = .030) survival. Patients with stage IV disease and detectable serum IL-10 had a particularly poor prognosis (4 years of survival: 0%). Multivariate analysis showed that IL-10 was an independent prognosis factor. These results indicate that IL-10 is detectable in a subgroup of patients with active NHL and correlates to a poor survival in patients with intermediate or high-grade NHL.

Adolescent↗

PubMed1993

Expression and factor-dependent modulation of the interleukin-3 receptor subunits on human hematopoietic cells.

Interleukin-3 (IL-3) regulates growth and differentiation of multipotential as well as lineage-committed progenitor cells. The human IL-3 receptor (IL-3R) consists of the alpha and common beta (beta c) subunits. The alpha subunit (IL-3R alpha) is specific for IL-3 and binds IL-3 with low affinity. In contrast, the beta c subunit does not bind any cytokine by itself, but forms a high-affinity receptor with IL-3R alpha. As the same beta c subunit also forms high-affinity receptors for IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) with the respective cytokine-specific alpha subunit, the expression of the alpha subunits is responsible for specificity of cytokines. To examine the expression of IL-3R alpha, we have developed a monoclonal antibody (MoAb), N3A. N3A specifically bound to cells expressing IL-3R alpha and immunoprecipitated a 75 Kd glycoprotein, which became 43 Kd on N-glycosidase digestion. N3A and an anti-beta c antibody, CRS1, were used in double color fluorescence-activated cell sorter (FACS) staining with several lineage markers to see the IL-3R expression pattern in peripheral blood (PB), cord blood (CB), and bone marrow (BM) cells. Both IL-3R subunits were expressed on myeloid cell lineages (CD13+, CD14+, CD15Lo, or CD33+). To further study the IL-3R expression on hematopoietic progenitor cells, the CD34+ populations were isolated from both BM and CB cells. Those populations showed positive staining profiles with the N3A MoAb and were weakly stained with the CRS1 MoAb. Furthermore, anti c-kit antibody staining of the CD34+ fraction from CB, but not from BM, showed two intensities and the IL-3R alpha expression seemed to be higher in a fraction of low c-kit expression. Because IL-1, IL-6, G-CSF, stem cell factor (SCF), interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha are known to enhance IL-3-dependent colony formation, we have examined whether this enhancement could be correlated with upregulation of the IL-3R expression. Incubation of CD34+ cells with TNF-alpha for 2 days significantly increased the level of beta c and G-CSF increased the number of cells with high level expression of alpha, while other factors did not affect the IL-3R expression. Thus, different cytokines appear to have different mechanisms for enhancement of IL-3-dependent proliferation.

Antibodies, Monoclonal↗

PubMed1993

Human B cell precursors proliferate and express CD23 after CD40 ligation.

The CD40 surface membrane molecule plays an important role in the activation of mature human B cells, but its role in earlier stages of B lineage development is unknown. Here, we have investigated the effects of triggering the CD40 antigen on B cell precursors (BCP) by crosslinking with anti-CD40 antibody presented by Fc gamma-receptor type II-transfected murine Ltk- cells (CD40 system). CD10+ surface immunoglobulin negative (sIg-) BCP, freshly isolated from fetal bone marrow or precultured on stromal cells, proliferated in the CD40 system. This effect required the presence of IL-3, which acted as a specific cosignal among a panel of cytokines examined. The association of IL-10 and IL-7 potentiated the observed IL-3 and CD40-dependent BCP proliferation, demonstrating that IL-10 can act on early B lineage cells. CD40-dependent activation of fetal BCP did not favor maturation to sIg+ B cells, but resulted in the induction of high levels of surface membrane CD23. The emerging CD23+ BCP lacked sIg and CD10, and represented an important proportion of the cycling cells in the CD40-dependent cultures. Taken together, our data demonstrate that stimulation of the CD40 antigen induces expression of the CD23 gene, and regulates cell proliferation during normal human B cell ontogeny.

Animals↗

PubMed1993

Tumor necrosis factor alpha cooperates with interleukin 3 in the recruitment of a primitive subset of human CD34+ progenitors.

We have recently demonstrated that tumor necrosis factor alpha (TNF-alpha) potentiates interleukin 3 (IL-3) and granulocyte/macrophage colony-stimulating factor-induced growth of CD34+ hematopoietic progenitor cells (HPC), and favors the generation of dendritic/Langerhans cells. The stimulatory effect of TNF-alpha was detailed in the present study. Thus, CD34+ HPC entering in cycle (S/G2M) after a 48-h pulse with IL-3 expressed the transferrin receptor (TfR), and fluorescence-activated cell sorter-separated TfR+ HPC, but not TfR-HPC, showed a high proliferative response to IL-3. In contrast, TfR-HPC were found to undergo strong proliferation in response to IL-3 + TNF-alpha. Limiting dilution experiments indicated that TNF-alpha increased both the frequency and the average size of clones generated from TfR-HPC as a result of the development of a higher number of large clones. In contrast, TNF-alpha did not enhance the IL-3-dependent proliferation of TfR+ HPC. Preculturing CD34+ HPC for 48 h with TNF-alpha enhanced the subsequent generation of IL-3-dependent colony-forming units. Precultures with TNF-alpha or cultures with suboptimal doses of TNF-alpha allowed the recruitment of cells with both granulocytic and monocytic differentiation potential. Taken together, our results indicate that TNF-alpha recruits a subpopulation of CD34+ HPC hyposensitive to IL-3, with high proliferative capacity and some features of multipotential progenitors, that are likely to be more primitive than those responding to IL-3 alone.

Antigens, CD↗

PubMed1993

Culture of human fetal B-cell precursors on bone marrow stroma maintains highly proliferative CD20dim cells.

Growth of human B-cell precursors (BCP) was achieved by plating fetal CD10+ surface-mu (s mu)- cells in liquid medium onto bone marrow-derived fibroblastic stromal cell layers deprived of hematopoietic cells. Proliferation of the fetal BCP was strongly potentiated by the addition of interleukin-7 (IL-7) to the cultures. Cultures included both a stroma-adherent and -nonadherent fraction of lymphoid cells, allowing us to expand the number of input BCP to 13-fold. In the presence of exogenous IL-7, proliferation was dose-dependent relative to the number of stromal cells, demonstrating that soluble IL-7 does not act alone to promote optimal growth. We further showed that the lymphoid cells recovered remain CD10+ sIg- BCP and that most cells expressed the maturation-associated CD20 antigen when IL-7 was added to the cultures. Whereas both freshly isolated CD20- and CD20bright BCP proliferated in the presence of stroma, we observed that high-proliferative capacity CD20dim cells were maintained in the cultures. Finally, CD20dim sorted cells were shown to subsequently acquire high levels of CD20 expression in culture, thus demonstrating a partial maturation sequence. The present culture system thus represents a useful model for studying the regulatory signals in early human B lymphopoiesis.

Antigens, CD↗

PubMed1993

Epstein-Barr virus transformation induces B lymphocytes to produce human interleukin 10.

Interleukin 10 (IL-10) is a pleiotropic factor that enhances proliferation of activated human B lymphocytes and induces them to secrete high amounts of immunoglobulins. Here we show that several human B cell lines were able to constitutively secrete human (h)IL-10. Whereas none of the pre-B nor the plasmocytic cell lines tested produced hIL-10, 25 of the 36 tested mature B cell lines (lymphoblastoid and Burkitt lymphoma cell lines) secreted hIL-10. Moreover, 24 of these 25 hIL-10-producing B cell lines contained the Epstein-Barr virus (EBV) genome, suggesting a relationship between hIL-10 production by human B cell lines and EBV expression. Accordingly, whereas polyclonal activation via triggering of surface immunoglobulins or CD40 antigen induced highly purified normal human B lymphocytes to produce only low (0.3-0.4 ng/ml) but significant amounts of hIL-10, EBV infection induced them to secrete high amounts of hIL-10 (4-9 ng/ml). Furthermore, addition of exogenous hIL-10, simultaneously to EBV infection, potentiated cell proliferation, whereas a blocking anti-IL-10 antiserum inhibited it. Thus, hIL-10 produced by infected human B lymphocytes appears to be involved in the mechanisms of EBV-induced B cell proliferation.

B-Lymphocytes↗

PubMed1993

Interferon gamma inhibits interleukin 10 production by monocytes.

Interleukin 10 (IL-10) was first described for its ability to inhibit interferon gamma (IFN-gamma) production. Herein, we studied the balance between IFN-gamma and IL-10 production by human peripheral blood mononuclear cells (PBMC) in response to Staphylococcus aureus Cowan (SAC) or lipopolysaccharide (LPS). Monocyte depletion reduced IL-10 production by 90% and resulted in an increased IFN-gamma production. Addition of anti-IL-10 antibody to PBMC cultures also strongly increased IFN-gamma production. In contrast, among various cytokines, only IFN-gamma strongly reduced IL-10 synthesis by SAC- or LPS-activated PBMC and monocytes. Thus, IFN-gamma has proinflammatory effects through the combination of two mechanisms: (a) induction of early tumor necrosis factor alpha (TNF-alpha) and IL-1 beta synthesis; and (b) inhibition of the delayed production of IL-10, an inhibitor of TNF-alpha and IL-1 beta synthesis. Taken together, the present data indicate that IFN-gamma and IL-10 antagonize each other's production and function.

Cells, Cultured↗

PubMed1993

Increased production of soluble CD23 in rheumatoid arthritis, and its regulation by interleukin-4.

OBJECTIVE: To assess CD23 status in rheumatoid arthritis (RA) patients, as defined by the levels of CD23 expression on peripheral blood mononuclear cells (PBMC), the levels of soluble CD23 (sCD23) in sera, and the production of sCD23 by PBMC cultures and its regulation by interleukin-4 (IL-4). METHODS: CD23 expression as determined by double fluorescence-activated cell sorter analysis and sCD23 production as determined by immunoradiometric assay were investigated in 24 RA patients and 21 controls. Soluble CD23 was measured in sera and supernatants of PBMC, activated with polyclonal activators (pokeweed mitogen [PWM] or Staphylococcus aureus Cowan strain 1, [SAC]) used either alone or in combination with IL-2 or IL-4. RESULTS: The percentage of B cells expressing CD23 and serum levels of sCD23 were increased in patients with RA. IL-4 was a potent inducer of sCD23 production in supernatants, whereas IL-2 was inactive. Costimulation with SAC or PWM did not increase the effect obtained with IL-4 alone. When sCD23 levels in RA and control supernatants were compared, spontaneous production was found to be increased in RA PBMC: This difference from control values was even more pronounced when sCD23 levels in PBMC and purified B cells in response to IL-4, either alone or in combination with SAC or PWM, were tested. In the same supernatants, the increased secretion of sCD23 induced by IL-4 was associated with an inhibitory effect of IL-4 on Ig production, a phenomenon that was more pronounced in RA PBMC than in controls. CONCLUSION: CD23 status in RA is characterized by increased expression of CD23 on B cells, increased production of sCD23 in sera and supernatants, and increased sensitivity of RA PBMC and B cells to IL-4.

Adolescent↗

PubMed1993

Expression of a 32-kDa ligand for the CD40 antigen on activated human T lymphocytes.

To identify the ligand(s) of the human CD40 antigen, a cDNA encoding the extracellular domain of the CD40 antigen was fused to a cDNA encoding the constant region (Fc) of human IgG1. The CD40-Fc fusion protein was able to specifically bind to CD4+ and various CD8+ T cell clones activated with immobilized anti-CD3. The 125I-labeled CD40-Fc fusion protein bound anti-CD3 activated CD4+ T cell clone (MT9) with an equilibrium dissociation constant (Kd) of 10-20 nM. The human CD40-binding protein expressed on the cell surface of activated T lymphocytes is a monomeric protein of approximately 32 kDa. Minor components of 29 kDa and 17 kDa were also detected. A small proportion of CD4+ and CD8+ blood mononuclear T cells activated by anti-CD3 expressed the CD40 ligand but its detection was best observed following depletion of B cells. Addition of B cells to purified T cells abolished the binding of CD40-Fc obtained after anti-CD3 activation.

Antigens, CD↗