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Biomedical subjects

J Banchereau

Publications and source records attributed to J Banchereau.

At least 217 records · Page 12Linked to original sources
PubMed1993

Immunosuppressive effects of Pseudomonas aeruginosa exotoxin A on human B-lymphocytes.

In this study we investigated the effects of exotoxin A on proliferation and differentiation of human B-cells in vitro. Exotoxin A at a concentration of 1 microgram/ml inhibited the proliferation of B-cells preactivated by insolubilized anti-IgM antibody or by formalinized Staphylococcus aureus particles, plus IL-2 or IL-4. B-cell blasts obtained after preactivation of tonsillar B-cells produce IgG and IgM in culture supernatants, and this Ig production is enhanced by IL-2 or IL-4. Exotoxin A inhibited the production of IgG and IgM by the B-blasts at the concentration of 1 microgram/ml.

ADP Ribose Transferases↗
PubMed1993

Agonistic and antagonistic effects of cholera toxin on human B lymphocyte proliferation.

In our attempts to elucidate the mechanisms regulating the IL2- and IL4-induced proliferation of human B lymphocytes, we studied the effects of cholera toxin (CT) and other agents increasing adenosine 3', 5'-cyclic monophosphate (cAMP) levels on tonsil B cells activated through their antigen receptors. CT enhanced proliferation of anti-IgM-costimulated B cells in a dose-dependent fashion (1 ng/ml to 10 micrograms/ml), a property shared in part by other agents inducing cAMP, such as forskolin, prostaglandin E2 and dibutyryl-cAMP, but not by the purified B subunit of CT. However, when cytokine-dependent proliferation was studied, CT and cAMP-increasing agents inhibited IL2-induced DNA synthesis of anti-IgM-activated B cells. This blockade was not due to a modification of the kinetics of proliferation, but was rather a consequence of partial inhibition of IL2 receptor expression. In contrast CT and cAMP-elevating agents enhanced the latest phases of the IL4-induced DNA synthesis of anti-IgM-activated B cells. These results indicate that CT displays agonistic and antagonistic effects on human B cell proliferation, most of these effects being reproduced by cAMP-elevating agents. Thus limited activation of the cAMP pathway in B cells may facilitate the development of TH2-type immune responses.

B-Lymphocytes↗
PubMed1993

Detection of single cells secreting IFN-gamma, IL-6, and IL-10 in irreversibly rejected human kidney allografts, and their modulation by IL-2 and IL-4.

The frequency of isolated low-density graft-infiltrating cells (GIC) secreting IFN-gamma, IL-6, and IL-10 was studied in 8 cases of irreversible rejection of human renal allografts, using ELISA and SPOT-forming cells (ELISPOT) assays. The GIC were mostly CD8+ T cells, although CD4+ T cells, B cells, and macrophages could also be detected. On the average, in 10(6) cells, 189 secreted IFN-gamma, 747 IL-10, and 17114 IL-6. Culture of GIC in the presence of IL-2 resulted in an increase in the frequency of IFN-gamma-producing cells (IFN-gamma-PC), in a dose-dependent manner, with an optimal 6.5-fold increase at 50 U/ml. In contrast, 25 U/ml IL-4 decreased the frequency of spontaneous and IL-2-induced IFN-gamma-PC by 71.3% and 52.8%, respectively. Furthermore, IL-4 reduced the frequency of IL-6-PC (56.8%). By this new approach to graft rejection, it becomes easier to determine cytokine profiles within an allograft and to study their modulation by different agents. It could be a useful model of study for the development of new treatment.

Adjuvants, Immunologic↗
PubMed1993

Role of cytokines in human B lymphocyte growth and differentiation.

B lymphocytes express at their surface the CD40 antigen which belongs to the NGF receptor superfamily. The crosslinking of the CD40 antigen using a mouse fibroblastic cell line expressing the human Fc receptor (Fc gamma RII/CDw32) and anti-CD40 monoclonal antibody induces resting B lymphocytes to enter a state of sustained proliferation. Addition of IL-4 to such cultures results in the generation of factor dependent long-term normal human B cell lines and in the secretion of IgE following isotype switching. Addition of IL-10 results in limited cell proliferation but most importantly in very high immunoglobulin production which results from the differentiation of B cells into plasma cells. The combination of IL-10 and TGF beta induces naive sIgD+ sIgM+ B cells to secrete IgA1 and IgA2 as a consequence of isotype switching. The extracellular domain of CD40 binds with high affinity and high specificity to a 32 kDa glycoprotein transiently expressed on activated T cells. This interaction of the CD40 antigen on B cells with its ligand on T cells represents a key step in T cell dependent B cell activation.

Animals↗
PubMed1993

IL-10 and IL-13 as B cell growth and differentiation factors.

B lymphocytes express at their surface the CD40 antigen which belongs to the NGF receptor superfamily. The crosslinking of the CD40 antigen using a mouse fibroblastic cell line expressing the human Fc receptor (Fc gamma RII/CDw32) and anti-CD40 monoclonal antibody induces resting B lymphocytes to enter a state of sustained proliferation. Addition of IL-4 or IL-13 result in the proliferation of human B cells and in the secretion of IgE following isotype switching. Addition of IL-10 permits limited cell proliferation but most importantly results in very high immunoglobulin production following differentiation of B cells into plasma cells. In response to IL-10, unseparated B cells cultured in the CD40 system produced the four IgG subclasses in ratio comparable to those observed in the serum. IL-10 induces naive B cells to secrete low but reproducible amounts of IgG and IgA. The combination of IL-10 and TGF beta induces naive B cells to secrete IgA1 and IgA2 as a consequence of isotype switching. The extracellular domain of CD40 binds with high affinity and high specificity to a ligand transiently expressed on activated T cells. This interaction of the CD40 antigen on B cells with its counter-structure on T cells represents a key step in T cell dependent B cell activation.

Antigens, CD↗
PubMed1993

Characterization of a t(1;19) pre-B acute lymphoblastic leukemia (ALL) cell line which proliferates in response to IL-7.

The present study describes the establishment of the cell line Pre-Alp from the bone marrow of a pediatric patient with a t(1;19) pre-B acute lymphoblastic leukemia (ALL) at diagnosis. Proliferation of leukemic blasts was found to be initially dependent on the presence of autologous stromal cells. However, after five weeks of culture, the stromal cells were no longer necessary and cells began to grow autonomously, with a doubling time of approximately 24 hours. The established Pre-Alp cell line displays a pre-B cell phenotype (CD19+, CD10+, CD34-, c mu+, s mu-), with immunoglobulin (Ig) light chain DNA in germline configuration, and carries a (1;19)(p23;q13.3) chromosomal translocation identical to the freshly-isolated leukemic blasts. A unique feature of this cell line is represented by its ability to respond to interleukin 7 (IL-7). Thus, IL-7 enhances 3H-thymidine uptake by Pre-Alp cells in a dose-dependent manner, under conditions of low cell density and serum concentration, and increases cell recovery. Finally, Pre-Alp cells were found to remain at a pre-B stage even upon addition of various cytokines, which failed to induce a transition to surface Ig+ cells. The presently described cell line should constitute a useful model of t(1;19) pre-B ALL and permit the study of IL-7 dependent signal transduction in human pre-B cells.

Base Sequence↗
PubMed1992

Responsiveness of chronic lymphocytic leukemia B cells activated via surface Igs or CD40 to B-cell tropic factors.

Recent studies performed in the laboratory have established that interleukin-4 (IL-4) used in combination with anti-CD40 monoclonal antibody (MoAb) 89 presented on Ltk- mouse fibroblasts stably expressing human Fc gamma RII/CDw32 (referred to as the CD40 system) sustains long-term proliferation of normal human B cells. In the present study, B-cell chronic lymphocytic leukemias (B-CLLs) activated through slgs or CD40 were examined for their capacity to proliferate and differentiate in response to various cytokines. Our results indicate that the outcome of IL-4 stimulation on the in vitro growth of B-CLL depends on the signalling pathway used for their activation. Whereas IL-4 did not display any growth-stimulatory effect on B-CLL activated by Ig cross-linking agents, it could stimulate DNA synthesis and enhance the viable cell recovery when leukemic B cells were cultured in the CD40 system. Most B-CLL samples were induced for IgM synthesis upon Staphylococcus aureus strain Cowan I stimulation. This Ig response was potentiated by IL-2 and antagonized by IL-4. Anti-CD40 MoAb used alone or in combination with cytokines (IL-1 alpha to IL-6, interferon gamma, tumor necrosis factor gamma, and transforming growth factor beta) failed to induce Ig secretion from B-CLL cells. No evidence for Ig isotype switching was obtained with the cytokines listed above, regardless of the mode of activation. Taken together, our results suggest that B-CLL cells can be partially released from their apparent maturation block by IL-2 and Ig cross-linking agents. In contrast, combinations of IL-4 and cross-linked anti-CD40 antibodies induced entry of B-CLL cell into cycle, but poorly stimulated their differentiation into Ig secreting cells.

Adult↗
PubMed1992

[In situ production of interferon gamma and interleukin 6 by infiltrating cells from human kidney allografts in irreversible rejection. Modulation by cytokines].

Using ELISPOT assays, we detected a significant number of cells secreting interferon-gamma and interleukin 6 among 8 irreversibly rejected kidney allografts compared with normal kidneys. Interleukin 2 increases the frequency of interferon-gamma producing cells and interleukin 4 decreases the frequency of both interferon-gamma and interleukin 6 producing cells.

Depression, Chemical↗
PubMed1992

GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells.

Dendritic cells comprise a system of highly efficient antigen-presenting cells which initiate immune responses such as the sensitization of T cells restricted by major histocompatibility complex molecules, the rejection of organ transplants and the formation of T-cell-dependent antibodies. Dendritic cells are found in many non-lymphoid tissues, such as skin (Langerhans cells) and mucosa, and they migrate after antigen capture through the afferent lymph or the bloodstream to lymphoid organs, where they efficiently present antigen to T cells. Dendritic cells are difficult to isolate and, although they originate from bone marrow their site of maturation and the conditions that direct their growth and differentiation are still poorly characterized. Granulocyte macrophage-colony stimulating factor (GM-CSF) favours the outgrowth of dendritic cells from mouse peripheral blood. Here we extend this finding to man and demonstrate that cooperation between GM-CSF and tumour necrosis factor-alpha (TNF-alpha) is crucial for the generation of human dendritic/Langerhans cells from CD34+ haematopoietic progenitors. The availability of large numbers of these cells should now facilitate the understanding of their role in immunological regulation and disorder.

Antigens, CD↗
PubMed1992

Interleukin-4 stimulates collagen gene expression in human fibroblast monolayer cultures. Potential role in fibrosis.

A role for the cytokines produced by tissue-infiltrated inflammatory cells (mainly T-lymphocytes and mast cells) in the pathophysiology of fibrosis has been suggested by several groups. Among the products of these cells, interleukin-4 (IL-4) might be one of the factors involved in the initiation of the fibrotic process. We studied the effects of recombinant human IL-4 on human fibroblast monolayer cultures. IL-4 (10 and 100 U/ml) induced a dose-dependent increase of collagen production. Non-collagen protein synthesis was not significantly altered. A concomitant increase of pro-alpha 1(I) collagen mRNAs was observed, showing that IL-4 acts at a pre-translational level.

Blotting, Northern↗
PubMed1992

Interferon-gamma enhances factor-dependent myeloid proliferation of human CD34+ hematopoietic progenitor cells.

Numerous studies have shown that interferon-gamma (IFN gamma) inhibits the proliferative effects of colony-stimulating factors (CSFs) on human bone marrow cells. In the present study we investigated the effects of IFN gamma and other described inhibitory factors on the proliferation of highly purified CD34+ human hematopoietic progenitor cells (HPC) in response to recombinant CSFs. While transforming growth factor-beta (TGF beta) and IFN alpha were highly inhibitory, IFN gamma strongly potentiated interleukin-3 (IL-3) and, to a lesser extent, granulocyte-macrophage-CSF (GM-CSF) induced growth of CD34+ HPC. IFN gamma had no significant proliferative effect per se, and did not affect granulocyte-CSF (G-CSF)-dependent cell proliferation. Within 10 days the number of viable cells generated in the presence of IL-3 + IFN gamma was two times higher than in the presence of IL-3 alone. Limiting dilution analysis showed that IFN gamma acts directly on its target cell to increase the frequency of IL-3-responding cells without affecting the average size of the IL-3-dependent clones. Enhanced frequency of IL-3- and GM-CSF-responding cells was also observed in colony assays where the addition of IFN gamma increased by twofold to threefold the number of granulocyte colony-forming units (CFU-G), macrophage CFUs (CFU-M), granulocyte-macrophage CFUs (CFU-GM), and mixed erythroid (E-MIX). In contrast, IFN gamma did not affect the generation of erythroid burst-forming units (BFU-e) in such cultures. In longer-term culture, the combination of IFN gamma and IL-3 did not alter the lineage distribution of the cells when compared with IL-3 alone. However, after 15 days, when mature cells were present in the cultures, IFN gamma displayed cell concentration-related growth-inhibitory effects. Thus, IFN gamma appears to stimulate the early stage of myelopoiesis by enhancing the frequency of growth factor-responding cells but, unlike tumor necrosis factor alpha (TNF alpha), does not alter cell differentiation.

Adult↗
PubMed1992

Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes.

Interleukin 10 (IL-10), originally identified as a TH2 helper T-cell product able to inhibit cytokine production by TH1 cells, is highly homologous to BCRF1 (viral IL-10), an open reading frame in the Epstein-Barr virus genome. Here, we show that human and viral IL-10 stimulate DNA replication of B lymphocytes activated either via their antigen receptor or via their CD40 antigen. IL-4 and IL-10 display additive effects and induce a strong increase in the number of viable cells. Moreover, IL-10 induces activated B cells to secrete large amounts of IgG, IgA, and IgM, and the combination of IL-10 and IL-4 results in the secretion of the four immunoglobulin isotypes. Thus, IL-10 may play an important role in the amplification of humoral responses.

Antibody Formation↗
PubMed1992

Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A.

In the present report, we have investigated the in vitro differentiation of surface(s) sIgD+ and sIgD- human B cells into Ig-secreting cells in response to various stimuli. sIgD+ B cells homogeneously expressed some of the antigens identifying mantle zone B cells, but lacked expression of germinal center markers, thus confirming that the B cell populations positively selected on the basis of sIgD expression were highly enriched for naive B lymphocytes. Conversely, sIgD- B cells expressed some of the antigens specifically associated with germinal center B cells. T cell-independent differentiation of sIgD+ and sIgD- B cells could be achieved by simultaneous crosslinking of sIgs and CD40 in the presence of a mouse Ltk- cell line stably expressing human CDw32/Fc gamma RII (CDw32 L cells). In this experimental system, sIgD+ B cells were exclusively proned for IgM synthesis, whereas sIgD- B cells produced IgG, IgM, and IgA. Both the human and viral forms of interleukin 10 (IL-10) strongly increased the Ig secretion by sIgD+ and sIgD- B cells simultaneously activated through sIgs and CD40. IgM and IgG constituted the predominant Ig isotype produced by sIgD+ and sIgD- B cells, respectively, in response to IL-10. sIgD+ B cells could be induced for IgA synthesis upon co-culturing with transforming growth factor beta (TGF-beta) and IL-10, in the presence of an anti-CD40 monoclonal antibody presented by the CDw32 L cells. In contrast, TGF-beta suppressed the IL-10-mediated IgG, IgM, and IgA secretions by sIgD- B cells. sIgD+ B cells could not be induced for IgA synthesis by TGF-beta and IL-10 after crosslinking of their sIgs, suggesting that ligation of CD40 was one of the obligatory signals required for commitment of naive B cells to IgA secretion. Limiting dilution experiments indicated that the IgA-potentiating effect of TGF-beta was due to its capacity to increase the frequency of IgA-producing cells, most likely as a consequence of class switching. Taken together, our data strongly suggest that TGF-beta is involved in the regulation of IgA isotype selection in humans.

Antibody-Producing Cells↗
PubMed1992

Antiproliferative effects of interleukin-4 on freshly isolated non-Hodgkin malignant B-lymphoma cells.

The pattern of in vitro growth response of freshly isolated non-Hodgkin malignant lymphoma B cells (NHML) to cytokines was investigated. Ten tumor specimens of low- or intermediate-grade malignancy were selected for study. To assess their proliferative capacity in vitro, B-lymphoma cells were activated through ligation of their surface Ig receptor with insolubilized anti-IgM antibodies or Staphylococcus aureus strain Cowan I (SAC). In the great majority of cases, interleukin-2 (IL-2) was the sole factor that significantly and reproducibly stimulated DNA synthesis in NHML activated through their surface Igs. Other B-cell tropic factors, including IL-4, IL-5, IL-6, and tumor necrosis factor-alpha (TNF-alpha), failed to elicit a growth response in most of the IL-2-responsive neoplastic samples. However, one specimen among 10 exhibited the opposite pattern of response and proliferated following culture with IL-4 and anti-Ig reagents, but not after IL-2 stimulation. Three specimens could also be induced for DNA synthesis on cross-linking of their surface Igs in the absence of exogenous growth factors. Although IL-4 could not support the in vitro growth of the majority of NHML cases, it strongly suppressed the proliferative signals delivered to these cells by anti-Ig reagents used alone or in combination with IL-2. Our data suggest that, in most cases, IL-4 essentially provides growth-inhibitory signals to NHML when they are activated through their surface Ig receptors and as such may be considered to be a valid candidate for future therapy of this type of mature B-cell malignancy.

Antibodies, Anti-Idiotypic↗
PubMed1992

Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis.

OBJECTIVE: To assess the spontaneous production of proinflammatory cytokines and immunoglobulins in rheumatoid arthritis (RA) synovitis and modulation by interleukin-4 (IL-4). METHODS: We developed an ex vivo model of RA synovitis using pieces of RA synovium, and have studied the regulation of the production of IL-1 beta, IL-6, tumor necrosis factor alpha (TNF alpha), IgM, and IgG. RESULTS: Spontaneous production of proinflammatory cytokines in vitro was active, with prolonged cytokine gene transcription and translation. IL-6 was produced at higher levels than either IL-1 beta or TNF alpha, and explants produced more IgG than IgM. In contrast, IL-4 and interferon-gamma were undetectable. When pieces of synovium were incubated in the presence of IL-4, reduction of spontaneous proinflammatory cytokine and Ig production was observed. CONCLUSION: These results extend the observations of the antiinflammatory properties of IL-4 to an ex vivo situation, and provide the rationale for the clinical use of IL-4 in RA.

Adult↗
PubMed1992

Proliferation and differentiation of human CD5+ and CD5- B cell subsets activated through their antigen receptors or CD40 antigens.

The pan-T cell antigen CD5 has been shown to delineate two different mouse B cell subsets, originating from distinct progenitors. In man, on average, 30% of the tonsillar B cell pool expresses this antigen. In the present report, a detailed comparison of the CD5+ and CD5- B cell response to cytokines, following activation via surface immunoglobulins (sIg) or CD40 antigen, was undertaken. CD5+ B cells were positively selected by panning or by sorting from tonsils. Two-color immunofluorescence analysis performed on tonsillar B cell populations showed that CD5+ B cells displayed most of the phenotypic features of mantle zone B cells. CD5+ B cells could be stimulated for DNA synthesis by mitogenic concentrations of Staphylococcus aureus, Cowan I strain (SAC), insolubilized anti-IgM antibodies, immobilized anti-CD40 antibodies and phorbol 12-myristate 13-acetate (PMA). The growth-response of small dense CD5- B cells to these T cell-independent mitogens was comparable to that of CD5+ B cells, whereas the low-density, in vivo-activated, CD5- B cells were only marginally stimulated by Ig-cross-linking agents and PMA. Following ligation of sIg, both B cell subsets proliferated essentially in response to interleukin (IL)-2 and IL-4. When used in co-stimulation with immobilized anti-CD40 antibodies, IL-4 promoted growth of CD5+ and CD5- B cells, whereas IL-2 displayed only moderate stimulatory effects. CD5+ and CD5- B cells differentiated into Ig-secreting cells when they were co-cultured with SAC or cross-linked anti-CD40 antibodies and IL-2. However, IgM constituted the major component of the Ig response of CD5+ B cells, whereas high levels of IgG were secreted by CD5- B cells.

Antigens, CD↗