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PubMed1995

Endogenous IL-6 and IL-10 contribute to the differentiation of CD40-activated human B lymphocytes.

This study was initiated to explore the contribution of endogenous cytokines to CD40-induced B cell proliferation and differentiation. First, both CD40 and Ag receptor (AgR) cross-linking induced purified tonsillar human B lymphocytes to secrete the same pattern of cytokines, including IL-1 beta, IL-6, IL-10, granulocyte-macrophage-CSF, and TNF-alpha, whereas IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-7, granulocyte (G)-CSF, or IFN-gamma were not detected. Second, cotriggering of CD40 and AgR resulted in additive secretion of both IL-6 and IL-10. Addition of IL-4 to CD40-activated B cells increased IL-6 levels but decreased IL-10 levels. In contrast, exogenous IL-10 diminished IL-6 levels. Neutralization of IL-6 and IL-10 using blocking Abs did not alter CD40-induced B cell growth. In contrast, IL-6 neutralization markedly inhibited the IL-4-induced IgE secretion (57 +/- 10%) as well as the IgG and IgM production resulting from AgR and CD40 cotriggering (49 +/- 16.5 and 29.5 +/- 4.5%, respectively). Blocking IL-10 inhibited the IgA secretion (25 +/- 2.7%) obtained after CD40 activation and the production of IgG, IgA, and IgM (24.1 +/- 5.6, 25 +/- 8, and 42 +/- 6.5%, respectively) by B lymphocytes undergoing dual ligation of CD40 Ag and AgR. Simultaneous neutralization of both endogenous IL-6 and IL-10 resulted in an increased inhibition of Ig secretion for B cells cotriggered by CD40 Ag and AgR (65-75%). Thus, endogenously produced IL-6 and IL-10 are involved in the differentiation of CD40-activated B cell.

Antigens, CD↗
PubMed1997

Cognate T cell help for CD40-deficient B cells induces c-myc RNA expression, but DNA synthesis requires an additional signal through surface Ig.

To investigate the role of CD40 ligand in the delivery of help to B cells, we examined the Ag-specific interaction of B cells from CD40-deficient mice with a Th2 cell line in vitro. Small resting B cells from normal mice are stimulated to synthesize DNA when they present monovalent Ag (rabbit Fab anti-Ig) to a rabbit Ig-specific Th cell line. This response, which is independent of a signal through the B cell Ag receptor (sIg), is nearly absent in B cells from CD40-deficient mice. The CD40-deficient B cells are not defective in Ag presentation because they induce T cell IL-4 synthesis as well as normal B cells. Also, CD40-deficient B cells respond to T cell help with DNA synthesis almost as well as normal B cells if an additional signal is provided through sIg. In conjunction with a sIg signal, cell contact with helper T cells induces DNA synthesis more effectively than soluble cytokines. CD40-independent T cell help can also be measured as an early increase in c-myc mRNA levels in CD40-deficient B cells presenting Ag to helper T cells, although the levels of c-myc RNA expression are lower than those in normal B cells. However, c-myc RNA induced by noncognate interaction with anti-CD3-activated T cells is completely CD40 dependent. We conclude that early growth signals from activated Th cells are received by CD40-/- B cells, but that CD40 and/or sIg signals are required for efficient induction of DNA synthesis.

Animals↗
PubMed2006

Simvastatin reduces CD40 expression in an experimental model of early arterialization of saphenous vein graft.

BACKGROUND: Saphenous vein graft (VG) failure occurs more frequently compared with arterial grafts, and graft thrombosis represents the main cause of early occlusion. Because CD40-CD40L pathway CD40 represents a culprit link between local inflammation and coagulation cascade, we investigate the role of CD40 and its soluble ligand (sCD40L) in the immediate in vitro response of VG to arterial pressures, and the potential effects of Simvastatin (Merck Sharp&Dohme, White-house Station, NJ) supplementation. METHODS: Samples of saphenous vein and of internal mammary artery (IMA) were obtained from sixteen patients without history of statin therapy. Segments underwent pulsatile pressure distension and culture with or without supplementation of Simvastatin. CD40 and sCD40L were assessed in tissue lysate and in culture supernatant, respectively. sCD40L serum concentrations were also measured. RESULTS: During the course of the experiment, the CD40 expression was significantly lower in IMA samples compared with both distended and not distended VG. Pressure distension up-regulated the production of CD40 in VG segments after 24 and 48 h. Statin supplementation significantly reduced the expression of CD40 in both venous (P < 0.001) and arterial samples (P < 0.001). This effect of Simvastatin was not affected by the treatment with L-NAME, but it was reversed by the addition of mevalonic acid. Mean sCD40L content in culture supernatants increased over time, suggesting that not only platelets but also the vessel wall is a source of CD40 and sCD40L. CONCLUSIONS: Simvastatin treatment modulates endothelial CD40-sCD40L in both venous and arterial grafts, and therefore may represent a useful tool in the pharmacological prevention of graft failure.

Aged↗
PubMedDate not supplied

CD40 signaling and Alzheimer's disease pathogenesis.

The interaction between CD40 and its cognate ligand, CD40 ligand, is a primary regulator of the peripheral immune response, including modulation of T lymphocyte activation, B lymphocyte differentiation and antibody secretion, and innate immune cell activation, maturation, and survival. Recently, we and others have identified CD40 expression on a variety of CNS cells, including endothelial cells, smooth muscle cells, astroglia and microglia, and have found that, on many of these cells, CD40 expression is enhanced by pro-inflammatory stimuli. Importantly, the CD40-CD40 ligand interaction on microglia triggers a series of intracellular signaling events that are discussed, beginning with Src-family kinase activation and culminating in microglial activation as evidenced by tumor necrosis factor-alpha secretion. Based on the involvement of microglial activation and brain inflammation in Alzheimer's disease pathogenesis, we have investigated co-stimulation of microglia, smooth muscle, and endothelial cells with CD40 ligand in the presence of low doses of freshly solubilized amyloid-beta peptides. Data reviewed herein show that CD40 ligand and amyloid-beta act synergistically to promote pro-inflammatory responses by these cells, including secretion of interleukin-1 beta by endothelial cells and tumor necrosis factor-alpha by microglia. As these cytokines have been implicated in neuronal injury, a comprehensive model of pro-inflammatory CD40 ligand and amyloid-beta initiated Alzheimer's disease pathogenesis (mediated by multiple CNS cells) is proposed.

Alzheimer Disease↗
PubMed2001

The clinical course of experimental autoimmune encephalomyelitis and inflammation is controlled by the expression of CD40 within the central nervous system.

Although it is clear that the function of CD40 on peripheral hematopoietic cells is pivotal to the development of autoimmunity, the function of CD40 in autoimmune disease outside this compartment is unresolved. In a model of experimental autoimmune encephalomyelitis (EAE), evidence is presented that CD40-CD154 interactions within the central nervous system (CNS) are critical determinants of disease development and progression. Using bone marrow (BM) chimeric mice, the data suggest that the lack of expression of CD40 by CNS-resident cells diminishes the intensity and duration of myelin oligodendrocyte glycoprotein (MOG)-induced EAE and also reduces the degree of inflammatory cell infiltrates into the CNS. Although CNS inflammation is compromised in the CD40(+/+)-->CD40(-/-) BM chimeric mice, the restricted CD40 expression had no impact on peripheral T cell priming or recall responses. Analysis of RNA expression levels within the CNS demonstrated that encephalitogenic T cells, which entered a CNS environment in which CD40 was absent from parenchymal microglia, could not elicit the expression of chemokines within the CNS. These data provide evidence that CD40 functions outside of the systemic immune compartment to amplify organ-specific autoimmunity.

Animals↗
PubMed2001

CD40 and LMP-1 both signal from lipid rafts but LMP-1 assembles a distinct, more efficient signaling complex.

CD40, a member of the TNFR-1 receptor family, shares several features with LMP-1, an oncoprotein encoded by Epstein-Barr virus. CD40 and LMP-1 activate transcription by binding to TRAFs, JAK3 and/or TRADD. CD40's association with CD40L activates signaling. However, LMP-1 signals independently of a ligand but dependently on self-association. We demonstrate that activated CD40 and LMP-1 co-localize in lipid rafts and recruit TRAF3 there, findings consistent with signals of CD40 and LMP-1 being initiated from lipid rafts. To elucidate their signaling, we compared requirements for their aggregation and subcellular localization. Targeting CD40's monomeric C-terminal signaling domain to lipid rafts activates signaling, as does rendering it trimeric. Addition of both modifications supports signaling more efficiently. Parallel experiments with LMP-1 indicate that targeting the monomeric C-terminal signaling domain of LMP-1 to lipid rafts activates signaling, but trimerizing it does not. Fusing LMP-1's N-terminus and membrane-spanning domains to CD40's C-terminus supports signaling more efficiently than CD40 plus ligand or CD40's trimerized and/or localized derivatives. An activity of LMP-1's N-terminus and membrane-spanning domains other than trimerization must contribute to its efficient signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2002

The effects of malignant transformation on susceptibility of human urothelial cells to CD40-mediated apoptosis.

BACKGROUND: The tumor necrosis factor (TNF) superfamily of ligands and receptors mediates immune cell survival. Some members possess a death domain, a protein motif that functions to transmit apoptotic signals, whereas others, such as CD40, do not. CD40 is expressed by both normal and malignant epithelial cells. To investigate the functional significance of this expression, we studied the effects of ligation of CD40, Fas, and TNF receptors (TNFRs) on the proliferation and survival of normal and malignant human urothelial cells and urothelial cells with disabled p53 function. METHODS: Normal and malignant human urothelial cells were cultured with soluble TNF family agonists (CD40 ligand [CD40L], TNF-alpha, anti-Fas antibody, or cocultured with mouse fibroblasts stably transfected with plasmids that caused the cells to constitutively express CD40L or CD32; cell proliferation was estimated by an [(3)H]thymidine incorporation assay, and apoptosis was determined by Annexin V staining and by a DNA fragmentation assay. Messenger RNA levels for CD40 and potential downstream effector molecules were quantified by polymerase chain reaction-based and ribonuclease protection assays, respectively, and nuclear factor (NF) kappaB nuclear translocation was detected by immunofluorescence. All statistical tests were two-sided. RESULTS: Soluble trimeric CD40L inhibited the growth of normal and malignant urothelial cells but did not induce apoptosis. Cell surface-presented CD40L induced massive apoptosis in CD40-positive transitional cell carcinoma cells but not in normal urothelial cells. Normal cells underwent CD40L-mediated apoptosis only in the presence of other TNFR agonists. An agonistic anti-CD40 antibody presented on the surface of CD32-transfected fibroblasts also induced apoptosis in transitional cell carcinoma cells and in normal urothelial cells. Apoptotic responses of tumor (but not normal) cells to soluble agonists were enhanced by blocking protein synthesis. Karyotypically normal urothelial cells with disabled p53 function underwent apoptosis during coculture with CD40L-expressing fibroblasts alone but were not additionally sensitive to additional TNFR agonists. CONCLUSIONS: Susceptibility to CD40 ligation-induced apoptosis may be a novel mechanism for eliminating neoplastically transformed urothelial cells. Loss of CD40 expression may be an important adaptive mechanism for transitional cell carcinoma development and progression.

Antigens, CD↗
PubMed2003

Monocyte CD40 expression in severe sepsis.

D40 is a cell surface protein belonging to the tumor necrosis factor (TNF) receptor family. Ligation of monocyte CD40 by the T cell-derived CD40 ligand can trigger the production of various mediators, the transcription and activation of enzymes, and the upregulation of costimulatory molecules involved in the pathogenesis of sepsis. To test the hypothesis that CD40 is expressed on the surface of monocytes during sepsis, we measured CD40 expression by flow cytometry on freshly sampled monocytes from 40 patients with severe sepsis, including 15 patients with bacteremia, and from eight healthy volunteers. Plasma concentrations of interleukin (IL) 6, IL-10, and IL-13 were also measured. We detected CD40 only on monocytes from patients with sepsis (mean 6.5 +/- 0.4 median channel fluorescence). There was an inverse correlation between peak CD40 expression and survival (P = 0.05), particularly in the patients with bacteremia (P = 0.019). In the bacteremic group, there was an inverse correlation between CD40 expression and bilirubin levels (r2 = 0.52, P = 0.004) and plasma IL-6 concentrations (r2 = 0.30, P = 0.04). Our results showed that upregulation of CD40 expression on peripheral blood monocytes is a protective phenomenon during severe sepsis. Monocyte deactivation reflected by low CD40 expression may represent impairment of immune function associated with severity of illness and poor outcome. Further studies on monocyte phenotype and function may help to assess the immune status of patients with sepsis and perhaps be useful to guide immunomodulatory strategy in the future.

Adult↗
PubMed2002

CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells.

It was previously demonstrated that p53 status in human multiple myeloma (MM) cells regulates distinct cell cycle responses to CD40 activation. In this study, the production of vascular endothelial growth factor (VEGF) and migration in MM cells triggered by CD40 activation was examined, and the influence of p53 status in regulating this process was determined. Two human MM cell lines that express wild-type p53 at permissive (28 degrees C) and mutant p53 at restrictive (37 degrees C) temperatures were used as a model system. CD40 activation induces a 4-fold (RPMI 8226) and a 6-fold (SV) increase in VEGF transcripts, respectively, under restrictive, but not permissive, temperatures. VEGF expression is significantly induced after CD40 activation in patient MM cells expressing mutant p53. Increased VEGF transcripts result in increased protein and secretion levels, as evidenced by immunoblotting and enzyme-linked immunosorbent assay. In a double-chamber transmigration assay, CD40 activation of MM cells induced a 3-fold (RPMI 8226) and a 5-fold (SV) increase in migration under restrictive, but not permissive, conditions. A 2- to 8-fold induction in migration of patient MM cells expressing mutant p53 was similarly observed. Transduction of MM cells with a luciferase reporter under the control of a human VEGF promoter further indicated that CD40-induced VEGF expression was mediated through a transcriptional control mechanism. Finally, adenovirus-mediated wild-type p53 overexpression down-regulated CD40-induced VEGF expression and transmigration in MM cells expressing mutant p53. These studies demonstrate that CD40 induces VEGF secretion and MM cell migration, suggesting a role for CD40 in regulating MM homing and angiogenesis.

CD40 Antigens↗
PubMed2001

Anti-CD40 antibody induces antitumor and antimetastatic effects: the role of NK cells.

We assessed the effect of the stimulatory anti-CD40 Ab on NK cell activation in vivo and the therapeutic potential of activated NK cells in tumor-bearing mice. Single-dose i.p. injection of the anti-CD40 Ab resulted in production of IL-12 and IFN-gamma in vivo, followed by a dramatic increase in NK cell cytolytic activity in PBLs. NK cell activation by anti-CD40 Ab was also observed in CD40 ligand knockout mice. Because NK cells express CD40 ligand but not CD40, our results suggest that NK activation is mediated by increased cytokine production upon CD40 ligation of APCs. Treatment of tumor-bearing mice with anti-CD40 Ab resulted in substantial antitumor and antimetastatic effects in three tumor models. Depletion of NK cells with anti-asialo GM1 Ab reduced or abrogated the observed antitumor effects in all the tested models. These results indicate that a stimulatory CD40 Ab indirectly activates NK cells, which can produce significant antitumor and antimetastatic effects.

Animals↗
PubMed2001

Lipopolysaccharide modulation of dendritic cells is insufficient to mature dendritic cells to generate CTLs from naive polyclonal CD8+ T cells in vitro, whereas CD40 ligation is essential.

Many cytotoxic CD8+ T cell responses are dependent on the interactions between CD40 ligand on the helper CD4+ T cell and CD40 on the APC. Although CD40 triggering of dendritic cells (DC) has been shown to mature the DC by increasing the level of expression of costimulatory molecules and inducing IL-12 secretion, the precise mechanisms by which CD40-CD40 ligand interactions allow DC to drive CTL responses remain unknown. We have used an in vitro model in which naive polyclonal CD8+ T cells can be activated by bone marrow-derived DC to investigate factor(s) that are responsible for this CD40-dependent generation of CTLs. DC modulated with agonistic anti-CD40 mAb (aCD40) are able to generate Ag-specific CTL responses while DC modulated with the microbial stimulus LPS alone do not. We compared the Ag-presenting capacity, levels of costimulatory molecules, and release of cytokines and chemokines of DC modulated with aCD40 to that of DC modulated by LPS. None of the factors assayed account for the unique capacity of anti-CD40-matured DC to drive CTL but this model provides a simplified system for further investigation. Although we attempted to use an LPS-free system for these studies, we are unable to rule out the possibility that very low levels of endotoxin (<20 pg/ml) may synergize with CD40 ligation in the generation of CTLs.

Adjuvants, Immunologic↗
PubMed1999

Ligation of CD40 induced tumor necrosis factor-alpha in rheumatoid arthritis: a novel mechanism of activation of synoviocytes.

OBJECTIVE: To determine the immunopathological significance of CD40/CD40 ligand (CD40L) interaction in rheumatoid arthritis (RA). METHODS: The expression of CD40 ligand (CD40L) in synovial tissues (ST) from patients with RA was examined by immunohistochemistry. Tumor necrosis factor-alpha (TNF-alpha) was measured by ELISA. Expression of CD40 on ST cells was quantified by anti-CD40 monoclonal antibodies and 125I labelled anti-mouse IgG. RESULTS: Immunohistochemistry showed CD40L+ T cells in RA ST. Ligation of CD40 on RA ST cells significantly increased the production of TNF-alpha in a dose dependent fashion. Adherent, but not non-adherent, fraction of ST cells responded to ligation of CD40 to produce TNF-alpha. Interferon-gamma (IFN-gamma), interleukin 4 (IL-4), or IL-13 acted synergistically with CD40 ligation to enhance TNF-alpha production by ST cells. IL-10 exerted inhibitory effects on both CD40 ligation induced and CD40 ligation plus IFN-gamma induced TNF-alpha production by ST cells. CONCLUSION: These data indicate activated T cells participate in synovial inflammation of RA via CD40L to stimulate the production of TNF-alpha by ST cells. The effect of CD40 ligation is modulated by the presence of several cytokines, e.g., IFN-gamma, IL-4, IL-10, and IL-13.

Arthritis, Rheumatoid↗
PubMed1999

Activation of CD40 favors the growth and vascularization of Kaposi's sarcoma.

Although CD40 is expressed by several tumor lines and is up-regulated in tumor vascular endothelium, its role in tumor biology is still unclear. In the present study, we investigated the role of CD40 in the growth and vascularization of Kaposi's sarcoma (KS). In vitro, stimulation of CD40 induced migration of KS cells and inhibited vincristine-induced apoptosis. Similarly, the CD40 engagement on endothelial cells resulted in cell contraction, migration, and prevention of serum withdrawal-apoptosis. To understand the biological relevance of CD40 in vivo, KS cells were engineered to express and release a soluble form of CD40 (KS-sCD40) able to disrupt CD40-CD154 interaction. SCID mice s.c. injected with KS-sCD40 cells developed tumors that were significantly smaller than those induced by control cells (KS-neo). In addition, KS-sCD40 tumors showed several areas of necrosis, diffuse presence of apoptotic cells, and poor vascularization. In contrast, KS-neo tumors showed few or absent areas of necrosis and apoptosis and intense vascularization. Moreover, anti-CD40 Abs stimulated neo-angiogenesis in a murine model in which s.c. implantation of Matrigel was used as a vehicle for the delivery of mediators. These observations provide demonstration that CD40 supports tumor cell survival, growth, and neo-vascularization of KS.

Animals↗
PubMed1999

Ligation of microglial CD40 results in p44/42 mitogen-activated protein kinase-dependent TNF-alpha production that is opposed by TGF-beta 1 and IL-10.

Recently, it has been demonstrated that the CD40 receptor is constitutively expressed on cultured microglia at low levels. Ligation of CD40 by CD40 ligand on these cells results in microglial activation, as measured by TNF-alpha production and neuronal injury. However, the intracellular events mediating this effect have yet to be investigated. We report that ligation of microglial CD40 triggers activation of p44/42 mitogen-activated protein kinase (MAPK). This effect is evident 30 min posttreatment, and progressively declines thereafter (from 30 to 240 min). Phosphorylated p38 MAPK is not observed in response to ligation of microglial CD40 across the time course examined. Inhibition of the upstream activator of p44/42 MAPK, mitogen-activated protein/extracellular signal-related kinase kinase 1/2, with PD98059, decreases phosphorylation of p44/42 MAPK and significantly reduces TNF-alpha release following ligation of microglial CD40. Furthermore, cotreatment of microglial cells with CD40 ligand and TGF-beta1 or IL-10, or both, inhibits CD40-mediated activation of p44/42 MAPK and production of TNF-alpha in a statistically interactive manner. Taken together, these data show that ligation of microglial CD40 triggers TNF-alpha release through the p44/42 MAPK pathway, an effect that can be opposed by TGF-beta1 and IL-10.

Animals↗
PubMed2001

Interferon-gamma enhances interleukin 12 production in rheumatoid synovial cells via CD40-CD154 dependent and independent pathways.

OBJECTIVE: To determine the role of interferon-gamma (IFN-gamma) in CD40-CD154 dependent production of interleukin 12 (IL-12) by synovial cells of patients with rheumatoid arthritis (RA). METHODS: We examined the effects of IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF) on CD40 expression on CD68+ synovial macrophage-lineage cells (SMC). The effects of IFN-gamma and soluble CD154 (sCD154) on IL-12 production by RA synovial cells were determined by ELISA. RESULTS: CD68+ SMC expressed substantial levels of CD40. IFN-gamma, but not TNF-alpha or GM-CSF, markedly upregulated CD40 expression on CD68+ SMC. IFN-gamma also dose dependently increased IL-12 production by synovial cells. The effects of IFN-gamma on CD40 expression (EC50 = 127.4 U/ml) were observed at a concentration 19 times lower than the effects on IL-12 production (EC50 = 6.8 U/ml). Treatment with IFN-gamma at a concentration low enough to augment CD40 expression but not IL-12 production enhanced spontaneous IL-12 production synergy with sCD 154. The synergistic enhancement of spontaneous IL-12 production was abrogated by CD40-Fc. In contrast, IL-12 production induced by high concentration of IFN-gamma was not neutralized by CD40-Fc. CONCLUSION: IFN-gamma enhanced IL-12 production via both CD40-CD154 dependent and independent pathways in RA synovium. IFN-gamma may play a crucial role in the development of RA synovitis through regulation of IL-12 production.

Antigens, CD↗
PubMed2002

[Inhibition of human glioma cell growth by a soluble recombinant human CD40 ligand].

BACKGROUND & OBJECTIVE: CD40 presents on B cells, monocytes, dendritic cells, and endothelial cells, as well as a variety of neoplastic cell types, including carcinomas. CD40 stimulated by its antibody or CD40 ligand previously had been demonstrated to induce activation-induced cell death in ovarian carcinoma cell lines, colon carcinoma cell lines, breast carcinoma cell lines, and lung carcinoma cell lines and to inhibit their growth in vivo. This study was designed to assess the effects of a recombinant soluble human CD40 ligand (srhCD40L) on human glioma cell lines. METHODS: The specimens of human glioma were examined for CD40 expression by immunohistochemistry. The human glioma cell lines were examined for CD40 expression by flow cytometry. The cell lines were incubated with srhCD40L for 24h and 72h, then the markers of proliferation and apoptosis of these cells were determined, respectively. RESULTS: CD40 expression could be detected in 7/23 human glioma specimens and 1/3 cell line. The srhCD40L inhibited the proliferation of CD40+ human glioma cell line. The viability of these cells was decreased from 98% to 87%. The apoptosis and death of these cells were increased by 17.4%. CONCLUSIONS: CD40 stimulated by its ligand directly inhibits human glioma cell growth in vitro. These results suggest that srhCD40L may be of clinic use to inhibit glioma growth.

Apoptosis↗
PubMed1994

Inhibition of human B-cell lymphoma growth by CD40 stimulation.

CD40 is a molecule present on B lymphocyte lineage cells that is important in B-cell differentiation and activation. Signaling through CD40 has been shown to exert costimulatory signals on normal B cells resulting in proliferative and differentiation responses. Examination of several B-cell lymphomas showed cell-surface expression of the CD40 molecule. Incubation of these lymphomas with anti-CD40 antibodies resulted in significant growth inhibition in vitro. Cross-linking of the CD40 antibodies resulted in even greater inhibition of proliferation. A recombinant soluble human CD40 ligand was also shown to inhibit lymphoma proliferation. When various human B-cell lymphomas were transferred into mice with severe combined immune deficiency, the treatment of the mice with anti-CD40 antibodies resulted in significant increases in survival showing that anti-CD40 is efficacious after in vivo administration. Thus, CD40 stimulation by either the antibody or soluble ligand directly inhibits human B-cell lymphoma growth and therefore, may be of significant clinical use in their treatment.

Animals↗
PubMed1995

The CD40 ligand expressed by human B cells costimulates B cell responses.

The possibility that activated B cells might express a ligand for CD40 that was of functional importance for B cell responses was examined by using highly purified human peripheral blood B cells, as well as a variety of B lymphoblastoid cell lines and hybridomas. Following stimulation with the combination of a calcium ionophore and a phorbol ester, human B cells bound a soluble fusion protein containing the extracellular portion of CD40 and the Fc region of IgG1 (CD40.Ig). A variety of B cell lines and hybridomas also bound CD40.Ig, either constitutively or after activation. In addition, CD40.Ig specifically immunoprecipitated a 33-kDa glycoprotein from surface 125I-labeled activated B cells. The nucleotide sequence of the coding region of the CD40 ligand mRNA amplified by RT-PCR from activated T cells and B cell lines was identical. The CD40 ligand expressed on human B cells was important functionally because homotypic aggregation of CD40 ligand-expressing B cells was inhibited by the CD40.Ig construct. Additionally, RNA and DNA synthesis as well as Ig production by polyclonally activated, highly purified peripheral B cells and a variety of B cell lines were inhibited significantly by the CD40.Ig construct. Finally, B cell lines expressing the CD40 ligand induced Ig production from resting normal B cells in a CD40-dependent manner. These results indicate that human B cells express a ligand for CD40 that is identical with that expressed by activated T cells and that the B cell-expressed CD40 ligand plays an important role in facilitating responses of activated B cells.

Adult↗