CD40LG - CD40 ligand
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Publication
Journal: Cell
April/11/2001
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Publication
Journal: Journal of Leukocyte Biology
February/8/2000
Abstract
CD40 is a cell surface receptor that belongs to the tumor necrosis factor-R (TNF-R) family, and that was first identified and functionally characterized on B lymphocytes. Its critical role in T cell-dependent humoral immune responses was demonstrated by patients with the hyper-IgM syndrome, as well as by gene targeting in mice. However, in recent years it has become clear that CD40 is expressed much more broadly, including expression on monocytes, dendritic cells, endothelial cells, and epithelial cells. In addition, the CD40-ligand (CD40-L/CD154), a member of the TNF family, is also expressed more widely than activated CD4+ T cells only. Therefore it is now thought that CD40-CD40-L interactions play a more general role in immune regulation. Collectively these studies have culminated in pre-clinical and clinical studies that are in progress. This article reviews recent developments in this field of research, with main emphasis on (1) structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function of CD40 on different cell types; and (4) in vivo functions of CD40/CD40-L interactions.
Publication
Journal: Nature
March/1/1998
Abstract
CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, was originally identified on stimulated CD4+ T cells, and later on stimulated mast cells and basophils. Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system. CD40 is not only constitutively present on B cells, but it is also found on monocytes, macrophages and endothelial cells, suggesting that CD40L has a broader function in vivo. We now report that platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo. Like TNF-alpha and interleukin-1, CD40L on platelets induces endothelial cells to secrete chemokines and to express adhesion molecules, thereby generating signals for the recruitment and extravasation of leukocytes at the site of injury. Our results indicate that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.
Publication
Journal: Nature
May/31/1992
Abstract
The CD40 surface molecule is a 277-amino-acid glycoprotein expressed on B lymphocytes, epithelial cells and some carcinoma cell lines. Monoclonal antibodies against CD40 mediate a variety of effects on B lymphocytes, including induction of intercellular adhesion, short- and long-term proliferation, differentiation and enhanced tyrosine phosphorylation of proteins. In addition, germinal centre centrocytes are prevented from undergoing apoptosis by activation through CD40 and receptor for antigen. These data indicate that CD40 could be a receptor for an unknown ligand with important functions in B-cell development and activation. This hypothesis is strengthened by the homology of the extracellular region of the CD40 molecule with a family of cell-surface glycoproteins that includes the receptors for nerve growth factor and tumour necrosis factor. Here we report the cloning of a ligand for CD40 that is expressed on the cell surface of activated T cells and mediates B-cell proliferation in the absence of co-stimulus, as well as IgE production in the presence of interleukin-4.
Publication
Journal: Immunity
May/12/2008
Abstract
Costimulatory signals are critical to T cell activation, but how their effects are mediated remains incompletely characterized. Here, we demonstrate that locally produced C5a and C3a anaphylatoxins interacting with their G protein-coupled receptors (GPCRs), C5aR and C3aR, on APCs and T cells both upstream and downstream of CD28 and CD40L signaling are integrally involved in T cell proliferation and differentiation. Disabling these interactions reduced MHC class II and costimulatory-molecule expression and dramatically diminished T cell responses. Importantly, impaired T cell activation by Cd80-/-Cd86-/- and Cd40-/- APCs was reconstituted by added C5a or C3a. C5aR and C3aR mediated their effects via PI-3 kinase-gamma-dependent AKT phosphorylation, providing a link between GPCR signaling, CD28 costimulation, and T cell survival. These local paracrine and autocrine interactions thus operate constitutively in naive T cells to maintain viability, and their amplification by cognate APC partners thus is critical to T cell costimulation.
Publication
Journal: Immunity
April/12/1995
Abstract
To study the potential roles of CD40L in immune responses, we generated CD40L-deficient mice by gene targeting. Similar to the effects of CD40L mutations in humans (hyper-IgM syndrome), CD40L-deficient mice have a decreased IgM response to thymus-dependent antigens, fail altogether to produce an antigen-specific IgG1 response following immunization, yet respond normally to a T-independent antigen, TNP-Ficoll. Moreover, these mice do not develop germinal centers in response to thymus-dependent antigens, suggesting an inability to develop memory B cell responses. Although CD40L-deficient mice have low levels of most circulating immunoglobulin isotypes, they do not exhibit the spontaneous hyper-IgM syndrome seen in humans, at least up to 12 weeks of age. In summary, our study confirms the important role of CD40-CD40L interactions in thymus-dependent humoral immune responses and germinal center formation.
Publication
Journal: Science
March/21/1993
Abstract
The ligand for CD40 (CD40L) is a membrane glycoprotein on activated T cells that induces B cell proliferation and immunoglobulin secretion. Abnormalities in the CD40L gene were associated with an X-linked immunodeficiency in humans [hyper-IgM (immunoglobulin M) syndrome]. This disease is characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. CD40L complementary DNAs from three of four patients with this syndrome contained distinct point mutations. Recombinant expression of two of the mutant CD40L complementary DNAs resulted in proteins incapable of binding to CD40 and unable to induce proliferation or IgE secretion from normal B cells. Activated T cells from the four affected patients failed to express wild-type CD40L, although their B cells responded normally to wild-type CD40L. Thus, these CD40L defects lead to a T cell abnormality that results in the failure of patient B cells to undergo immunoglobulin class switching.
Publication
Journal: Cell
March/1/1993
Abstract
The prominent role of the CD40 receptor in B cell responses led us to investigate the role of the gp39-CD40 interaction in a group of primary immunodeficient patients with defective antibody production. Here we report that patients with hyper-IgM syndrome (HIM) have a defective gp39-CD40 interaction. B cells from HIM patients express functional CD40, but their T cells do not bind CD40-Ig. These patients expressed normal levels of gp39 mRNA, but these mRNAs encode defective gp39 proteins owing to mutations in the extracellular domain of gp39. Soluble recombinant forms of gp39 containing these mutations were unable to bind CD40 and drive normal B cell proliferation. The gene encoding gp39 was mapped to Xq26, the X chromosome region where the gene responsible for HIM had previously been mapped. These data suggest that a defect in gp39 is the basis of X-linked HIM.
Publication
Journal: Journal of Experimental Medicine
September/2/2004
Abstract
Dendritic cell (DC) maturation is an innate response that leads to adaptive immunity to coadministered proteins. To begin to identify underlying mechanisms in intact lymphoid tissues, we studied alpha-galactosylceramide. This glycolipid activates innate Valpha14(+) natural killer T cell (NKT) lymphocytes, which drive DC maturation and T cell responses to ovalbumin antigen. Hours after giving glycolipid i.v., tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were released primarily by DCs. These cytokines induced rapid surface remodeling of DCs, including increased CD80/86 costimulatory molecules. Surprisingly, DCs from CD40(-/-) and CD40L(-/-) mice did not elicit CD4(+) and CD8(+) T cell immunity, even though the DCs exhibited presented ovalbumin on major histocompatibility complex class I and II products and expressed high levels of CD80/86. Likewise, an injection of TNF-alpha up-regulated CD80/86 on DCs, but CD40 was required for immunity. CD40 was needed for DC interleukin (IL)-12 production, but IL-12p40(-/-) mice generated normal ovalbumin-specific responses. Therefore, the link between innate and adaptive immunity via splenic DCs and innate NKT cells has several components under distinct controls: antigen presentation in the steady state, increases in costimulatory molecules dependent on inflammatory cytokines, and a distinct CD40/CD40L signal that functions together with antigen presentation ("signal one") and costimulation ("signal two") to generate functioning CD4(+) T helper cell 1 and CD8(+) cytolytic T lymphocytes.
Publication
Journal: Nature
March/10/1993
Abstract
X chromosome-linked immunodeficiency with hyper-IgM (HIGM1, MIM number 308230) is a rare disorder characterized by recurrent bacterial infections, very low or absent IgG, IgA and IgE, and normal to increased IgM and IgD serum levels. HIGM1 has been suggested to result from ineffective T-cell help for B cells. We and others have identified a novel, TNF-related activation protein (TRAP) that is exclusively expressed on the surface of stimulated T cells. TRAP, a type II transmembrane protein of M(r) 33,000, is the physiological ligand for CD40 (refs 5-8). Crosslinking of CD40 on B cells induces, in the presence of lymphokines, immunoglobulin class switching from IgM to IgG, IgA or IgE. Mapping of the TRAP gene to the X-chromosomal location q26.3-q27.1 (ref. 6) suggested a causal relationship to HIGM1, which had previously been assigned to Xq26 (refs 12-14). Here we present evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with HIGM1. The resultant failure of TRAP to interact with CD40 on functionally intact B cells is responsible for the observed immunoglobulin isotype defect in HIGM1.
Publication
Journal: Nature
July/26/1998
Abstract
Increasing amounts of evidence support the involvement of inflammation and immunity in atherogenesis, but mediators of communication between the major cell types in atherosclerotic plaques are poorly defined. Cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand CD40L (also known as CD154 or gp39). The interaction of CD40 with CD40L figures prominently in both humoral and cell-mediated immune responses. CD40L-positive T cells accumulate in atheroma, and, by virtue of their early appearance, persistence and localization at sites of lesion growth and complication, activated T cells may coordinate important aspects of atherogenesis. Interruption of CD40L-CD40 signalling by administration of an anti-CD40L antibody limits experimental autoimmune diseases such as collagen-induced arthritis, lupus nephritis, acute or chronic graft-versus-host disease, multiple sclerosis and thyroiditis. Ligation of CD40 on atheroma-associated cells in vitro activates functions related to atherogenesis, including induction of proinflammatory cytokines, matrix metalloproteinases, adhesion molecules and tissue factor. However, the role of CD40 signalling in atherogenesis in vivo remains unknown. Here we determine whether interruption of CD40 signalling influences atherogenesis in vivo in hyperlipidaemic mice. Treatment with antibody against mouse CD40L limited atherosclerosis in mice lacking the receptor for low-density lipoprotein that had been fed a high-cholesterol diet for 12 weeks. This antibody reduces the size of aortic atherosclerotic lesions by 59% and their lipid content by 79%. Furthermore, atheroma of mice treated with anti-CD40L antibody contained significantly fewer macrophages (64%) and T lymphocytes (70%), and exhibited decreased expression of vascular cell adhesion molecule-1. These data support the involvement of inflammatory pathways in atherosclerosis and indicate a role for CD40 signalling during atherogenesis in hyperlipidaemic mice.
Publication
Journal: Journal of Immunology
February/17/2004
Abstract
Modification in the function of dendritic cells (DC), such as that achieved by microbial stimuli or T cell help, plays a critical role in determining the quality and size of adaptive responses to Ag. NKT cells bearing an invariant TCR (iNKT cells) restricted by nonpolymorphic CD1d molecules may constitute a readily available source of help for DC. We therefore examined T cell responses to i.v. injection of soluble Ag in the presence or the absence of iNKT cell stimulation with the CD1d-binding glycolipid alpha-galactosylceramide (alpha-GalCer). Considerably enhanced CD4(+) and CD8(+) T cell responses were observed when alpha-GalCer was administered at the same time as or close to OVA injection. This enhancement was dependent on the involvement of iNKT cells and CD1d molecules and required CD40 signaling. Studies in IFN-gammaR(-/-) mice indicated that IFN-gamma was not required for the adjuvant effect of alpha-GalCer. Consistent with this result, enhanced T cell responses were observed using OCH, an analog of alpha-GalCer with a truncated sphingosine chain and a reduced capacity to induce IFN-gamma. Splenic DC from alpha-GalCer-treated animals expressed high levels of costimulatory molecules, suggesting maturation in response to iNKT cell activation. Furthermore, studies with cultured DC indicated that potentiation of T cell responses required presentation of specific peptide and alpha-GalCer by the same DC, implying conditioning of DC by iNKT cells. The iNKT-enhanced T cell responses resisted challenge with OVA-expressing tumors, whereas responses induced in the absence of iNKT stimulation did not. Thus, iNKT cells exert a significant influence on the efficacy of immune responses to soluble Ag by modulating DC function.
Publication
Journal: Nature
March/10/1993
Abstract
Signalling for the B-cell immunoglobulin isotype switch requires T-cell-derived cytokines and T-B cell interaction, which operates primarily through the CD40 molecule on B cells with its ligand (CD40L) on activated T cells (reviewed in ref. 1). The CD40L is a type II membrane protein with homology to tumour necrosis factor-alpha and -beta, and has important functions in B-cell activation and differentiation. Human CD40L maps on Xq26.3-27.1 (ref. 3), the region where a primary immunodeficiency characterized by an immunoglobulin isotype switch defect (the hyper-IgM immunodeficiency syndrome, HIGM1) has been localized. The hypothesis that HIGM1 involves an abnormality of the CD40L has been tested. We report here the lack of CD40L expression in four unrelated male children with the hyper-IgM syndrome. CD40L transcripts in these patients showed either deletions or point mutations clustered within a limited region of the CD40L extracellular domain. These genetic alterations with abnormal CD40L expression provide a molecular basis for immunoglobulin isotype switch defects observed in this immunodeficiency.
Publication
Journal: Journal of Experimental Medicine
July/12/2009
Abstract
The relationship of T follicular helper (TFH) cells to other T helper (Th) subsets is controversial. We find that after helminth infection, or immunization with helminth antigens, reactive lymphoid organs of 4get IL-4/GFP reporter mice contain populations of IL-4/GFP-expressing CD4(+) T cells that display the TFH markers CXCR5, PD-1, and ICOS. These TFH cells express the canonical TFH markers BCL6 and IL-21, but also GATA3, the master regulator of Th2 cell differentiation. Consistent with a relationship between Th2 and TFH cells, IL-4 protein production, reported by expression of huCD2 in IL-4 dual reporter (4get/KN2) mice, was a robust marker of TFH cells in LNs responding to helminth antigens. Moreover, the majority of huCD2/IL-4-producing Th cells were found within B cell follicles, consistent with their definition as TFH cells. TFH cell development after immunization failed to occur in mice lacking B cells or CD154. The relationship of TFH cells to the Th2 lineage was confirmed when TFH cells were found to develop from CXCR5(-) PD-1(-) IL-4/GFP(+) CD4(+) T cells after their transfer into naive mice and antigen challenge in vivo.
Publication
Journal: Immunity
October/15/2008
Abstract
Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens. However, signals underlying mTEC development remain largely unclear. Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-kappaB (RANK) and CD40 signals. Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment. Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappaB inducing kinase (NIK)-, and IkappaB kinase beta (IKKbeta)-dependent manner. These results show that developmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance.
Publication
Journal: Nature Medicine
April/4/2002
Abstract
CD40L, a member of the tumor necrosis factor family of ligands, plays a major role in immune responses via its receptor, CD40. Recently, CD40L has been detected on the surfaces of activated platelets and shown to activate endothelium. Here we further addressed the function of platelet CD40L. We show that absence of CD40L affects the stability of arterial thrombi and delays arterial occlusion in vivo. Infusion of recombinant soluble (rs)CD40L restored normal thrombosis, whereas rsCD40L lacking the KGD integrin-recognition sequence did not. CD40-deficient mice exhibited normal thrombogenesis. rsCD40L specifically bound to purified integrin alphaIIbbeta3 and to activated platelets in a beta3-dependent manner and induced platelet spreading. In addition, rsCD40L promoted the aggregation of either human or mouse platelets under high shear rates. Thus, CD40L appears to be an alphaIIbbeta3 ligand, a platelet agonist, and necessary for stability of arterial thrombi.
Publication
Journal: Blood
June/4/2007
Abstract
Bone homeostasis is regulated by a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclastogenesis is controlled by the ratio of receptor activator of NF-kappaB ligand (RANKL) relative to its decoy receptor, osteoprotegerin (OPG). The source of OPG has historically been attributed to osteoblasts (OBs). While activated lymphocytes play established roles in pathological bone destruction, no role for lymphocytes in basal bone homeostasis in vivo has been described. Using immunomagnetic isolation of bone marrow (BM) B cells and B-cell precursor populations and quantitation of their OPG production by enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), cells of the B lineage were found to be responsible for 64% of total BM OPG production, with 45% derived from mature B cells. Consistently B-cell knockout (KO) mice were found to be osteoporotic and deficient in BM OPG, phenomena rescued by B-cell reconstitution. Furthermore, T cells, through CD40 ligand (CD40L) to CD40 costimulation, promote OPG production by B cells in vivo. Consequently, T-cell-deficient nude mice, CD40 KO mice, and CD40L KO mice display osteoporosis and diminished BM OPG production. Our data suggest that lymphocytes are essential stabilizers of basal bone turnover and critical regulators of peak bone mass in vivo.
Publication
Journal: Immunity
September/7/2010
Abstract
Effective humoral immunity depends on the support of B cell responses by T follicular helper (Tfh) cells. Although it has been proposed that Tfh cell differentiation requires T-B interactions, the relative contribution of specific populations of Ag-presenting cells remains unknown. We employed three independent strategies that compromised interactions between CD4(+) T cells and activated B cells in vivo. Whereas the expansion of CD4(+) T cells was relatively unaffected, Tfh cell differentiation was completely blocked in all scenarios. Surprisingly, augmenting antigen presentation by non-B cells rescued Tfh cell differentiation, as determined by surface phenotype, gene expression, and germinal center localization. We conclude that although Ag presentation by responding B cells is typically required for the generation of Tfh cells, this does not result from the provision of a unique B cell-derived signal, but rather because responding B cells rapidly become the primary source of antigen.
Publication
Journal: Journal of Immunology
August/2/2000
Abstract
A model of Leishmania major infection in C57BL/6 mice has been established that combines two main features of natural transmission: low dose (100 metacyclic promastigotes) and inoculation into a dermal site (the ear dermis). The evolution of the dermal lesion could be dissociated into two distinct phases. The initial "silent" phase, lasting 4-5 wk, favored establishment of the peak load of parasites in the dermis in the absence of lesion formation or any overt histopathologic changes in the site. The second phase corresponds to the development of a lesion associated with an acute infiltration of neutrophils, macrophages, and eosinophils into the dermis and was coincident with the killing of parasites in the site. The onset of immunity/pathology was correlated with the appearance of cells staining for IL-12p40 and IFN-gamma in the epidermal compartment, and an expansion of T cells capable of producing IFN-gamma in the draining lymph node. Parasite growth was not enhanced over the first 4.5 wk in anti-CD4-treated mice, SCID mice, or C57BL/6 mice deficient in IL-12p40, IFN-gamma, CD40 ligand, or inducible NO synthase. These mice all failed to ultimately control infection in the site, but in some cases (anti-CD4 treated, IL-12p40-/-, CD40 ligand-/-, and SCID) high dermal parasite loads were associated with little or no pathology. These results extend to a natural infection model a role for Th1 cells in both acquired resistance and lesion formation, and document the remarkable avoidance of this response during a prolonged phase of parasite amplification in the skin.
Publication
Journal: Blood
January/3/2007
Abstract
Despite the importance of thymic stromal cells to T-cell development, relatively little is known about their biology. Here, we use single-cell analysis of stromal cells to analyze extensive changes in the number and composition of thymic stroma throughout life, revealing a surprisingly dynamic population. Phenotypic progression of thymic epithelial subsets was assessed at high resolution in young mice to provide a developmental framework. The cellular and molecular requirements of adult epithelium were studied, using various mutant mice to demonstrate new cross talk checkpoints dependent on RelB in the cortex and CD40 in the medulla. With the use of Ki67 and BrdU labeling, the turnover of thymic epithelium was found to be rapid, but then diminished on thymic involution. The various defects in stromal turnover and composition that accompanied involution were rapidly reversed following sex steroid ablation. Unexpectedly, mature cortical and medullary epithelium showed a potent capacity to stimulate naive T cells, comparable to that of thymic dendritic cells. Overall, these studies show that the thymic stroma is a surprisingly dynamic population and may have a more direct role in negative selection than previously thought.
Publication
Journal: Journal of Clinical Investigation
December/29/2008
Abstract
Infection with influenza A virus (IAV) presents a substantial threat to public health worldwide, with young, elderly, and immunodeficient individuals being particularly susceptible. Inflammatory responses play an important role in the fatal outcome of IAV infection, but the mechanism remains unclear. We demonstrate here that the absence of invariant NKT (iNKT) cells in mice during IAV infection resulted in the expansion of myeloid-derived suppressor cells (MDSCs), which suppressed IAV-specific immune responses through the expression of both arginase and NOS, resulting in high IAV titer and increased mortality. Adoptive transfer of iNKT cells abolished the suppressive activity of MDSCs, restored IAV-specific immune responses, reduced IAV titer, and increased survival rate. The crosstalk between iNKT and MDSCs was CD1d- and CD40-dependent. Furthermore, IAV infection and exposure to TLR agonists relieved the suppressive activity of MDSCs. Finally, we extended these results to humans by demonstrating the presence of myeloid cells with suppressive activity in the PBLs of individuals infected with IAV and showed that their suppressive activity is substantially reduced by iNKT cell activation. These findings identify what we believe to be a novel immunomodulatory role of iNKT cells, which we suggest could be harnessed to abolish the immunosuppressive activity of MDSCs during IAV infection.
Publication
Journal: Journal of Experimental Medicine
November/30/1994
Abstract
Individuals with X-linked hyper-IgM syndrome fail to express functional CD40 ligand (CD40L) and, as a consequence, are incapable of mounting protective antibody responses to opportunistic bacterial infections. To address the role of CD40L in humoral immunity, we created, through homologous recombination, mice deficient in CD40L expression. These mice exhibited no gross developmental deficiencies or health abnormalities and contained normal percentages of B and T cell subpopulations. CD40L-deficient mice did display selective deficiencies in humoral immunity; basal serum isotype levels were significantly lower than observed in normal mice, and IgE was undetectable. Furthermore, the CD40L-deficient mice failed to mount secondary antigen-specific responses to immunization with a thymus-dependent antigen, trinitrophenol-conjugated keyhole limpet hemocyanin (TNP-KLH). By contrast, the CD40L-deficient mice produced antigen-specific antibody of all isotypes except IgE in response to the thymus-independent antigen, DNP-Ficoll. These results underscore the requirement of CD40L for T cell-dependent antibody responses. Moreover, Ig class switching to isotypes other than IgE can occur in vivo in the absence of CD40L, supporting the notion that alternative B cell signaling pathways regulate responses to thymus-independent antigens.
Publication
Journal: Journal of Immunology
December/5/2007
Abstract
Why systemic lupus erythematosus primarily affects women is unknown. Recent evidence indicates that human lupus is an epigenetic disease characterized by impaired T cell DNA methylation. Women have two X chromosomes; one is inactivated by mechanisms including DNA methylation. We hypothesized that demethylation of sequences on the inactive X may cause gene overexpression uniquely in women, predisposing them to lupus. We therefore compared expression and methylation of CD40LG, a B cell costimulatory molecule encoded on the X chromosome, in experimentally demethylated T cells from men and women and in men and women with lupus. Controls included TNFSF7, a methylation-sensitive autosomal B cell costimulatory molecule known to be demethylated and overexpressed in lupus. Bisulfite sequencing revealed that CD40LG is unmethylated in men, while women have one methylated and one unmethylated gene. 5-Azacytidine, a DNA methyltransferase inhibitor, demethylated CD40LG and doubled its expression on CD4(+) T cells from women but not men, while increasing TNFSF7 expression equally between sexes. Similar studies demonstrated that CD40LG demethylates in CD4(+) T cells from women with lupus, and that women but not men with lupus overexpress CD40LG on CD4(+) T cells, while both overexpress TNFSF7. These studies demonstrate that regulatory sequences on the inactive X chromosome demethylate in T cells from women with lupus, contributing to CD40LG overexpression uniquely in women. Demethylation of CD40LG and perhaps other genes on the inactive X may contribute to the striking female predilection of this disease.
Publication
Journal: Arthritis and rheumatism
March/24/2003
Abstract
OBJECTIVE
CD40-CD40 ligand (CD40L) interactions play a significant role in the production of autoantibodies and tissue injury in lupus nephritis. We performed an open-label, multiple-dose study to evaluate the safety, efficacy, and pharmacokinetics of BG9588, a humanized anti-CD40L antibody, in patients with proliferative lupus nephritis. The primary outcome measure was 50% reduction in proteinuria without worsening of renal function.
METHODS
Twenty-eight patients with active proliferative lupus nephritis were scheduled to receive 20 mg/kg of BG9588 at biweekly intervals for the first 3 doses and at monthly intervals for 4 additional doses. Safety evaluations were performed on all patients. Eighteen patients receiving at least 3 doses were evaluated for efficacy.
RESULTS
The study was terminated prematurely because of thromboembolic events occurring in patients in this and other BG9588 protocols (2 myocardial infarctions in this study). Of the 18 patients for whom efficacy could be evaluated, 2 had a 50% reduction in proteinuria without worsening of renal function. Mean reductions of 38.9% (P < 0.005), 50.1% (P < 0.005), and 25.3% (P < 0.05) in anti-double-stranded DNA (anti-dsDNA) antibody titers were observed at 1, 2, and 3 months, respectively, after the last treatment. There was a significant increase in serum C3 concentrations at 1 month after the last dose (P < 0.005), and hematuria disappeared in all 5 patients with significant hematuria at baseline. There were no statistically significant reductions in lymphocyte count or serum immunoglobulin, anticardiolipin antibody, or rubella IgG antibody concentrations after therapy.
CONCLUSIONS
A short course of BG9588 treatment in patients with proliferative lupus nephritis reduces anti-dsDNA antibodies, increases C3 concentrations, and decreases hematuria, suggesting that the drug has immunomodulatory action. Additional studies will be needed to evaluate its long-term effects.
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