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1.
O S?derberg I Christiansen G Nilsson M Carlsson K Nilsson 《Canadian Metallurgical Quarterly》1997,11(8):1298-1304
We have previously shown that Staphylococcus aureus Cowan strain 1 particles (SAC) + thioredoxin (Trx) + IL-2 may induce B-chronic lymphocytic leukemia (B-CLL) cells to proliferate. In this paper we have examined IL-15, which has activities similar to IL-2, for its ability to stimulate B-CLL cells and compared its activity with that of IL-2. We found that B-CLL cells could be induced to DNA synthesis upon treatment with IL-15 + Trx. The presence of Trx was essential for the IL-15-induced DNA synthesis. This contrasts to the effect of IL-15 + Trx on normal CD5+ and CD5- B cells, where IL-15 + Trx alone only induced limited DNA synthesis. IL-15 was as effective in the induction of DNA synthesis in B-CLL cells as IL-2, but about 100-fold less potent with an EC50 of 200 ng/ml. In addition we found that the IL-15 + Trx-induced proliferation was inhibited by CD40 stimulation. We conclude that IL-15 together with a proper costimulus can induce B-CLL cells to proliferate in vitro. 相似文献
2.
Production of IgM, IgG and IgA was induced from human blood B lymphocytes by culturing with a CD40 MoAb and IL-2 for 9 days. Replacement of IL-2 by IL-10 markedly enhanced production of all three isotypes. High levels of immunoglobulin production also occurred when activated irradiated autologous T cells replaced the CD40 MoAb, and when IL-10 replaced IL-2 in these cultures a spectacular increase in IgG production occurred. The effectiveness of the T cell stimulus depended on the mode of purification of the T cells and the nature of the stimulant used to activate them. Differences in the kinetics and level of expression of CD40L on the various T cell preparations were observed, but did not account for variations in immunoglobulin-inducing efficiency. Immunoglobulin production from sIgD+ and sIgD- B cells was investigated. IgG and IgA were found in sIgD+ cultures, indicating that some isotype switching had occurred, but the major part of the IgG and IgA secreted was from cells already committed to these isotypes. Anti-IgD or anti-IgM MoAbs enhanced the proliferation of B cells induced by anti-CD40 antibody, but immunoglobulin production was not enhanced. Factors affecting the balance of proliferation and differentiation are discussed. 相似文献
3.
Human interleukin 10 induces naive surface immunoglobulin D+ (sIgD+) B cells to secrete IgG1 and IgG3 总被引:1,自引:0,他引:1
F Brière C Servet-Delprat JM Bridon JM Saint-Remy J Banchereau 《Canadian Metallurgical Quarterly》1994,179(2):757-762
During antigen-induced immune responses, human B cells switch isotype from immunoglobulin M (IgM)-IgD to IgG1-4, IgA1-2, or IgE. In the human, no cytokines have yet been demonstrated to act as switch factors for IgG1, IgG2, and IgG3. In this paper, we report that in response to interleukin 10 (IL-10), anti-CD40 activated tonsillar surface IgD+ (sIgD+) B cells are induced to secrete large amounts of IgM, IgG1, and IgG3 but neither IgG2 nor IgG4. Cord blood purified B cells and lymphocytes from Hyper-IgM patients also produced IgG1 and IgG3 after culture with anti-CD40 and IL-10. In contrast, sIgD- isotype-committed B cells produce IgG1, IgG2, and IgG3 when activated through CD40 in the presence of IL-10. Thus, in addition to its growth-promoting and differentiating activities on human B cells, IL-10 may represent a switch factor for IgG1 and IgG3. 相似文献
4.
Activation of human B cells in vitro either by cross-linking of surface immunoglobulins (sIg) or by triggering CD40 antigen, in the presence of interleukin-10 (IL-10) and interleukin-2 (IL-2), may result in high levels of immunoglobulin secretion in vitro. We studied the combined effects of ligation of the B-cell receptor (BCR) and CD40 [with anti-CD40 monoclonal antibody (mAb)] on B-cell proliferation and production of human immunoglobulin. For this purpose highly purified splenic B cells were cultured with various combinations of anti-CD40 and IL-10/IL-2 or IL-4 in the presence of CD32-transfected L cells. Simultaneous cross-linking of the BCR was achieved by mAb held on CD32-L cells or Staphylococcus aureus (SA). We found that dual BCR and CD40 ligation with IL-10/IL-2 leads to reduced immunoglobulin G (IgG) secretion compared with B cells stimulated with either anti-CD40 and IL-10/IL-2, or compared with B cells stimulated with SA or anti-BCR mAb and IL-10/IL-2. Dual BCR and CD40 ligation with anti-immunoglobulin mAb (anti-kappa + anti-lambda light chains) but not with SA induced a similar reduction in IgM production. The reduced immunoglobulin secretion found during dual ligation is accompanied by increased proliferation. This was independent of cytokine stimulation but SA/CD40-induced proliferation was increased in the presence of IL-10/IL-2, although not with IL-4. The combination anti-kappa and anti-lambda with anti-CD40 showed a long-term suppression of IgG and IgM production (at least 14 days), while anti-kappa or anti-lambda alone, or SA, allowed a moderate recovery of immunoglobulin production by day 14. These results suggest that simultaneous B-cell antigen receptor cross-linking and CD40 engagement via CD40L on T cells induces strong initial proliferation. This may be followed later by antibody production depending on the strength of the BCR signal and the presence of the appropriate cytokines. 相似文献
5.
M Inaba K Inaba Y Fukuba S Mori H Haruna H Doi Y Adachi H Iwai N Hosaka H Hisha 《Canadian Metallurgical Quarterly》1995,25(5):1244-1248
We have previously found that thymic B cells, particularly thymic CD5+ B cells, show low responsiveness to the usual B cell stimulants such as lipopolysaccharide or anti-IgM plus interleukin (IL)-4, although they proliferate and produce antibodies after direct interaction with major histocompatibility complex class II-restricted T blasts. These findings raise the possibility that a CD40-CD40 ligand (L) interaction is involved in the activation of thymic B cells. In the present study, we therefore examine this possibility using CD40L-transfected Chinese hamster ovary (CHO) cells or anti-CD40 monoclonal antibody (mAb). When B cells in the spleen and peritoneal cavity were stimulated, they proliferated and produced immunoglobulin (Ig) in the presence of CD40L-CHO cells or anti-CD40 mAb alone. However, another signal delivered by IL-10 in addition to CD40L-CHO cells or anti-CD40 mAb was found to be necessary for thymic B cells to proliferate and secrete Ig. Other interleukins acting on B cells, such as IL-4, IL-5, and IL-6, had no effect on the activation of thymic B cells, which thus have unique characteristics not found in peripheral B cells. This report discusses the physiological significance of IL-10- and CD40-driven signals in the activation of thymic B cells. 相似文献
6.
7.
M Baba Y Kikuchi S Mori H Kimoto S Inui N Sakaguchi J Inoue T Yamamoto T Takemori M Howard K Takatsu 《Canadian Metallurgical Quarterly》1997,9(10):1463-1473
The germinal center (GC) develops in secondary lymphoid tissues in response to thymus-dependent (TD) antigens. To investigate the molecular mechanism of B cell differentiation in GC, we enriched GC B cells from spleen of TD antigen-immunized wild-type and X-linked immunodeficient (XID) mice, and examined the differentiation of GC B cells into antigen-specific IgG1 antibody-forming cells (AFC) in response to anti-CD40 mAb and cytokines. A significant proportion of freshly purified GC B cells expressed receptors for IL-4 and IL-5. Anti-CD40 mAb sustained the viability of GC B cells and IL-4 co-operated with anti-CD40 mAb for further enhancement of the cell viability. Anti-CD40 mAb and IL-4 were essential for inducing differentiation of GC B cells into antigen-specific IgG1-AFC and IL-5 efficiently enhanced their differentiation. GC B cells with the xid mutation responded for proliferation to CD40 ligation to a lesser extent and for the IgG1-AFC response to anti-CD40 mAb together with IL-4, but they showed impaired responsiveness to IL-5, regardless of enhanced expression of IL-5R in response to anti-CD40 mAb and IL-4. These results suggest that anti-CD40 mAb, IL-4 and IL-5 play a critical role in the differentiation of mouse GC B cells. The GC B cells from XID mice show a functional defect with respect to IL-5-mediated differentiation. 相似文献
8.
C Johnson-Léger JR Christenson M Holman GG Klaus 《Canadian Metallurgical Quarterly》1998,161(9):4618-4626
The interaction of CD40 on B cells with the CD40 ligand (CD40L) on preactivated CD4 T cells is critical for the initiation of T-dependent Ab responses. It is believed that signals via CD40 synergize with cytokines (e.g., IL-4 and IL-5) to drive B cell activation. However, primary T cells preactivated via CD3 alone cannot induce B cell proliferation; we have shown previously that costimulation of T cells via CD3 and CD28 stabilizes the expression of the CD40L, which we propose contributes to their capacity to act as competent helper-effector cells. Here we show that an additional, critical reason why CD3-stimulated CD40L-bearing T cells are incompetent helper cells is because they secrete insufficient IL-2. In contrast, CD28/CD3-activated T cells induce B cells to become IL-2 responsive via a combination of CD40L and IL-2-mediated signals, and these two stimuli subsequently drive B cell proliferation and IgM secretion. We therefore propose that T cells must first encounter Ag in conjunction with CD80/86 on APCs. This leads to the stable expression of CD40L and maximal secretion of IL-2, which together render primary T cells competent to activate B cells in an IL-2-dependent fashion. 相似文献
9.
Costimulatory signals provided by T cells are required for B cells to produce specific antibody to T-dependent antigen. We have investigated the suitability of using the CD40 culture system for the proliferation and differentiation of Ag-specific human B cells using cytomegalovirus (CMV) or tetanus toxoid (TT) as antigen. We modified the CD40 culture system (CD32-transfected L cells, anti-CD40, and IL-4) by applying a sequential cytokine stimulation and compared total B-cell cultures with antigen-specific B cells preselected by panning. The detection of specific antibody became possible when antigen-selected B cells were cultured for 7 days in the CD40 system to induce clonal expansion, followed by the addition of IL-2 and IL-10 for an additional 7 days to induce plasma-cell differentiation. We conclude that our initial inability to detect specific antibody in the CD40 system is due to overgrowth of nonspecific B-cell clones and that selection of antigen-specific B cells by panning overcomes this problem. Induction of antigen-specific antibody production was found to be optimal when the initial contact with antigen during panning was limited to between 1 to 24 hours. 相似文献
10.
IL-10 is a well-documented immunosuppressant that inhibits macrophage-dependent Ag presentation and CD4+ T cell proliferation in vitro. We report that IL-10 inhibits alloantigen-specific proliferative responses and induces a long lasting anergic state in human purified CD8+ T cells when added concomitantly with the Ag in the presence of APC. Moreover, the generation of allospecific cytotoxic activity is inhibited by IL-10. These effects are indirect and are mediated through inhibition of the costimulatory functions of APC. In contrast, IL-10 has no direct inhibitory effects on the proliferation of purified CD8+ T cells activated by anti-CD3 mAb and promotes the growth of activated CD8+ T cells in combination with low doses of IL-2. Taken together, these results indicate that IL-10 has differential effects on CD8+ T cells depending on their state of activation, which may explain both the enhancing and inhibitory effects observed after IL-10 treatment in different in vivo experimental models. 相似文献
11.
X Peng JE Remacle A Kasran D Huylebroeck JL Ceuppens 《Canadian Metallurgical Quarterly》1998,160(3):1166-1172
IL-12 is a heterodimeric cytokine produced by APC that promotes the development of CD4+ Th1 cells and their IFN-gamma production after TCR/CD3 triggering. We here investigated the capacity of IL-12 to modify the expression on T cells of CD40 ligand (CD40L or CD154), a molecule transiently expressed on activated T cells and known to be of utmost importance for cognate interaction with B cells and for activation of dendritic cells and macrophages. Our data demonstrate that IL-12 up-regulates CD40L expression on anti-CD3-activated human peripheral blood T cells. For optimal induction of CD40L, IL-12 synergizes with IL-2 as well as with other costimulatory interactions, such as B7/CD28. The effect of IL-12 was observed at both the protein and the mRNA level. T cells costimulated by IL-12 provided more efficient help for IL-4-dependent B cell proliferation and for IgG production than when activated in the absence of IL-12. This helper activity was blocked by an mAb against CD40L, indicating that the effect of IL-12 on B cells is mediated indirectly through CD40L. The data thus suggest that the effects of IL-12 on cellular and humoral immune responses are partly mediated through CD40L induction. 相似文献
12.
V Friman LA Hanson JM Bridon A Tarkowski J Banchereau F Brière 《Canadian Metallurgical Quarterly》1996,104(3):432-438
In search for a possible explanation of the phenotypic heterogeneity in IgA deficiency, we studied the function of B cells from IgA-deficient (IgAd) individuals. Two groups of IgAd individuals, one frequently infected and one clinically apparently healthy, as well as normal controls, were studied. Peripheral blood mononuclear cells (PBMC) and B cells from IgAd individuals and controls were cultured with Staphylococcus aureus Cowan I strain and with anti-CD40 MoAb presented on the CD32-transfected fibroblast cell line in the presence of IL-10. In this experimental system PBMC and B cells from the infection-prone IgAd individuals produced only minute amounts of IgA. In contrast, PBMC and B cells from healthy IgAd subjects secreted significantly more IgA1 and IgA2 in comparison with infection-prone IgAd patients (P < 0.05). These data suggest that the abnormalities of B cell differentiation in IgAd could be of heterogeneous origin. Thus, whereas in healthy IgAd subjects IgA production may be efficiently up-regulated in vitro by addition of IL-10 to CD40-activated B cell culture, the corresponding B cell differentiation does not occur in infection-prone IgAd patients. These observations provide a conceptual framework for phenotypic heterogeneity in IgAd subjects. 相似文献
13.
T Yoshimoto N Nagai K Ohkusu H Ueda H Okamura K Nakanishi 《Canadian Metallurgical Quarterly》1998,161(3):1483-1492
SJL mice are known for their poor IgE production upon helminth infection. In this study, we have demonstrated that SJL standard B cells (85% IgM+ or B220+), prepared by complement-mediated T cell lysis, failed to proliferate and to produce IgE and IgG1 in response to LPS plus IL-4 in vitro. This diminished IgE production was restored by anti-IL-12 and enhanced by additional treatment with anti-IL-18, suggesting active suppression by the cells that produce IL-12 and IL-18. Indeed, SJL standard B cells were contaminated with Mac-1+ cells. Therefore, we removed macrophages by passing standard B cells through a Sephadex G-10 column (G10). Resultant cells (95% IgM+), designated as G10-B cells, responded to LPS and IL-4 by their proliferation and differentiation. G-10 treatment markedly diminished the proportion of B220- cells and Mac-1+ cells in SJL standard B cells. Furthermore, addition of SJL B220- cells dose dependently and MHC independently inhibited LPS plus IL-4-induced B cell growth and IgE production in SJL and BALB/c B cells. B220- cells in SJL standard B cells contained Mac-1+ cells (51%) and Fas ligand+ CD4-CD8- double-negative CD3intIL-2R beta+ T cells (26%). Thus, IL-12 and IL-18 produced by LPS-stimulated Mac-1+ cells stimulate this unique subpopulation of T cells to produce IFN-gamma, which in combination with Fas ligand, inhibits IgE production from the B cells. Our present results indicate that Mac-1+ cells and double-negative CD3intIL-2R beta+ T cells, uniquely abundant in the spleens of SJL mice, inhibit IgE production, indicating their new role in IgE response. 相似文献
14.
No reliable culture system exists for B-lineage acute lymphoblastic leukaemia (ALL). Recently we found that many different mature B-cell malignancies proliferate upon stimulation via the CD40 antigen, and this led us to investigate whether a similar CD40 activation on ALL cells could also induce proliferation. First, we measured CD40 expression in 21 ALL cases; all were CD40+, although mostly weak. Next, we triggered the CD40 antigen by anti-CD40 antibodies and by a CD40 ligand-expressing cell line. In addition, we measured the influence of IL-3, IL-4 and IL-7 with and without these stimuli. In 8/10 cases proliferation, measured by 3H-thymidine incorporation, could be induced after CD40 crosslinking, especially in the presence of IL-3. Stimulation via the CD40 ligand was more successful than using crosslinked anti-CD40 antibodies. IL-4 inhibited the spontaneous proliferation found in three cases, but stimulated proliferation after CD40 crosslinking. IL-7 did not contribute to proliferation. Morphology, immunophenotyping and surface marker analysis, combined with DNA flow cytometry confirmed that the proliferation found could be ascribed to the ALL cells. In conclusion, B-lineage ALL cases are CD40+, and many can be cultured using CD40 stimulation and IL-3. 相似文献
15.
T Yoshimoto K Takeda T Tanaka K Ohkusu S Kashiwamura H Okamura S Akira K Nakanishi 《Canadian Metallurgical Quarterly》1998,161(7):3400-3407
IL-18 is a product of macrophages and with IL-12 strikingly induces IFN-gamma production from T, B, and NK cells. Furthermore, IL-18 and 1L-12 synergize for IFN-gamma production from Th1 cells, although this combination fails to affect Th2 cells. In this study, we show that IL-12 and IL-18 promptly and synergistically induce T and B cells to develop into IFN-gamma-producing cells without engaging their Ag receptors. We also studied the mechanism underlying differences in IL-18 responsiveness between Th1 and Th2 cells. Pretreatment of T or B cells with IL-12 rendered them responsive to IL-18, which induces cell proliferation and IFN-gamma production. These IL-12-stimulated cells had both high and low affinity IL-18R and an increased IL-18R mRNA expression. In particular, IL-12-stimulated T cells strongly and continuously expressed IL-18R mRNA. However, when T cells developed into Th1 cells after stimulation with anti-CD3 and IL-12, they lowered this IL-12-induced-IL-18R mRNA expression. Then, such T cells showed a dominant response to anti-CD3 by IFN-gamma production when they were subsequently stimulated with anti-CD3 and IL-18. In contrast, Th2 cells did not express IL-18R mRNA and failed to produce IFN-gamma in response to anti-CD3 and IL-18, although they produced a substantial amount of IFN-gamma in response to anti-CD3 and IL-12. However, when Th1 and Th2 cells were stimulated with anti-CD3, IL-12, and IL-18, only the Th1 cells markedly augmented IFN-gamma production in response to IL-18, suggesting that IL-18 responsiveness between Th1 and Th2 cells resulted from their differential expression of IL-18R. 相似文献
16.
L Lagneaux A Delforge D Bron M Massy M Bernier P Stryckmans 《Canadian Metallurgical Quarterly》1997,97(3):612-620
We investigated the potential role of transforming growth factor-beta (TGF-beta) on spontaneous and cytokine-induced proliferation of B-cell chronic lymphocytic leukaemia (B-CLL) cells in vitro. Purified B lymphocytes from 21 B-CLL patients were cultured for 5 d in the presence of medium alone, IL-2 and/or IL-10, in the presence or absence of TGF-beta, and proliferation was measured by 3H-thymidine incorporation. TGF-beta inhibited B-cell proliferation in the majority of patients (15/21) but no inhibition was detected in 6/21 patients whatever the type of stimulant used. Addition of neutralizing antibodies to TGF-beta increased spontaneous and cytokine-induced proliferation; this effect was dose dependent and specific because addition of an irrelevant chicken IgG had no effect on B-CLL proliferation. In resistant patients, neutralizing antibodies to TGF-beta did not increase the proliferation. The expression of TGF-beta receptors on B-CLL cells was significantly lower than the one observed on normal CD5+ B lymphocytes for which the sensitivity to TGF-beta inhibition was more marked than in CLL. In addition, we found a strong correlation between the response of leukaemic B cells to TGF-beta inhibitory action and the expression of TGF-beta receptors on these cells. In summary, TGF-beta appears to function in CLL as a negative regulator of B lymphocytes but loss of responsiveness to this factor accompanied by a decrease of TGF-beta receptor expression, might provide a selective advantage to B-CLL lymphocytes. 相似文献
17.
RS de Brito AI Monteiro LT Aguila RP Timóteo BC Enders RM Germano FV Oliveira 《Canadian Metallurgical Quarterly》1995,48(1):26-32
Superantigens have been used to study peripheral tolerance in CD4+ T cells. The superantigen SEB induces T cell anergy by promoting the differentiation of SEB-activated virgin T cells into anergic memory T cells. Memory T cells from SEB or antigen-primed mice do not proliferate when they are cultured with SEB. The present studies were performed to determine whether memory T cells fail to interact with SEB antigen-presenting cells or whether SEB promotes incomplete or negative signals in memory T cells. When murine virgin and memory T cells were separated on the basis of CD45RB expression and cultured with SEB-pulsed B cells, SEB induced the expression of CD25, which then mediated proliferation when IL-2 was added to the cultures. In addition, SEB promoted the expression of the CD40L, which is required for T helper cell function. Finally, PMA induced a costimulatory signal leading to the proliferation of these cells. Surprisingly, the agents, i.e., IL-2 and PMA, which induced TM cell proliferation in conjunction with SEB failed to induce lymphokine secretion. However, in the presence of IL-4 plus IL-5, the T memory cells induced the SEB-pulsed B cells to secrete IgM and IgG. These results suggest that memory T cells are not simply unresponsive to SEB but are actively anergized. 相似文献
18.
Neonatal T cells are poor promoters of Ig secretion by neonatal B cells. Since IL-10 has been shown to play a role in B cell differentiation, we investigated the relationship of IL-10 production by neonatal T cells and their ability to provide B cell help. Neonatal CD4+(CD8-) T cells and adult naive CD4+ (CD8-/CD45RO-) T cells activated with immobilized anti-CD3 produced consistently less IL-10 than adult memory CD4+(CD8-/CD45RA-) T cells. Production of IL-10 by adult and neonatal T cells was dependent on IL-2, but was unaffected by supplemental IL-4. Despite diminished IL-10 production, supplemental IL-10 increased neonatal T cell-dependent Ig secretion only modestly, but did not increase Ig heavy chain isotype switching. This contrasted with the ability of IL-10 to enhance the secretion of all Ig isotypes by adult B cells stimulated in the presence of either IL-2 or IL-4. These results suggest that IL-10 can promote T cell-dependent Ig secretion but not Ig heavy chain isotype switching by neonatal B cells. However, deficient IL-10 production alone does not account for the poor ability of neonatal T cells to support neonatal B cell Ig production. 相似文献
19.
To understand the molecular events for the proliferation of B cells, we studied the induction of telomerase activity in vitro after stimulation to B-cell antigen receptor (BCR) on human peripheral B cells. Although unstimulated purified B cells of tonsils and peripheral blood from healthy volunteers do not express detectable telomerase activity, anti-IgM beads induce telomerase activity in these B cells. Soluble anti-IgM antibody (Ab) alone does not induce telomerase activity, but the second signal, given by either one of the cytokines of interleukin-2 (IL-2), IL-4, and IL-13 or by anti-CD40 monoclonal Ab (MoAb), is effective as the costimulation for the induction of the activity. Stimulation with anti-IgM Ab and anti-CD40 MoAb induces telomerase activity in most mature B cells of the tonsils and peripheral blood. The stimuli to both IgM and IgD receptors similarly induce the activity. Induction of telomerase activity is accompanied with the proliferation of B cells, but is not absolutely correlated with the extent of B-cell growth. Phorbol dibutylate (PDB) plus calcium (Ca) ionophore (PDB/Ca), which replace the activation through BCR and the costimulatory molecules, also induce telomerase activity. Moreover, it is suggested that phosphoinositide (PI) 3-kinase plays a role for the induction of telomerase activity in B cells stimulated with anti-IgM Ab and anti-CD40 MoAb. These results suggest that telomerase activity is induced in the B-cell activation of the antigen specific immune response. 相似文献