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CD40 Ligand (cd40 + ligand)
Kinds of CD40 Ligand Selected AbstractsSeverity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndromePSYCHOPHYSIOLOGY, Issue 4 2010Andrea T. White Abstract Chronic fatigue syndrome (CFS) patients often report symptom flare (SF) for >24 h after moderate exercise (post-ex). We hypothesized that SF is linked to increases in circulating cytokines and CD40 Ligand (CD40L). In 19 CFS patients and 17 controls, mental and physical fatigue and pain symptom ratings were obtained together with serum for 11 cytokines and CD40L before and at 0.5, 8, 24, and 48 h post-ex. Before exercise, CFS had lower CD40L (p<.05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n=11) increased in IL-1,, IL-12, IL-6, IL-8, IL-10, and IL-13 (p<.05) 8 h post-ex. Low SF patients (n=8) showed post-ex decreases in IL-10, IL-13, and CD40L, and controls decreased in IL-10, CD40L, and TNF, (p<.05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings. [source] Clinical Implications of Elevated Serum Interleukin-6, Soluble CD40 Ligand, Metalloproteinase-9, and Tissue Inhibitor of Metalloproteinase-1 in Patients with Acute ST-segment Elevation Myocardial InfarctionCLINICAL CARDIOLOGY, Issue 5 2009Alberto Dominguez-Rodriguez MD, FESC No abstract is available for this article. [source] Increased inflammatory markers in children with familial hypercholesterolaemiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2006T. Ueland Abstract Background, While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high-sensitivity C-reactive protein (hsCRP), and soluble CD40 ligand (sCD40L). Materials and methods, In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH (n = 207) with those in unaffected siblings (n = 84). Furthermore, we investigated the effect of 2-year treatment with pravastatin (20,40 mg qd) or placebo on plasma levels of those markers. Results, Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high-density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group. Conclusion, These findings indicate low-grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti-inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults. [source] Stress-activated dendritic cells interact with CD4+ T cells to elicit homeostatic memoryEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Yufei Wang Abstract Evidence is presented that thermal or oxidizing stress-activated DC interact with CD4+ T cells to induce and maintain a TCR-independent homeostatic memory circuit. Stress-activated DC expressed endogenous intra-cellular and cell surface HSP70. The NF-,B signalling pathway was activated and led to the expression of membrane-associated IL-15 molecules. These interacted with the IL-15 receptor complex on CD4+ T cells, thus activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T-cell proliferation and IFN-, production. CD40 ligand on CD4+ T cells in turn re-activated CD40 molecules on DC, inducing DC maturation and IL-15 expression thereby maintaining the feedback circuit. The proliferating CD4+ T cells were characterized as CD45RA, CD62L+ central memory cells, which underwent homeostatic proliferation. The circuit is independent of antigen and MHC-class-II-TCR interaction as demonstrated by resistance to TCR inhibition by ZAP70 inhibitor or MHC-class II antibodies. These findings suggest that stress can activate a DC-CD4+ T-cell interacting circuit, which may be responsible for maintaining a homeostatic antigen-independent memory. [source] The 21st century renaissance of the basophil?EXPERIMENTAL DERMATOLOGY, Issue 11 2006Current insights into its role in allergic responses, innate immunity Abstract:, Basophils and mast cells express all the three subchains of the high-affinity immunoglobulin E (IgE) receptor Fc,RI and contain preformed histamine in the cytoplasmic granules. However, it is increasingly clear that these cells play distinct roles in allergic inflammatory disease. Despite their presence throughout much of the animal kingdom, the physiological function of basophils remains obscure. As rodent mast cells are more numerous than basophils, and generate an assortment of inflammatory cytokines, basophils have often been regarded as minor players in allergic inflammation. In humans, however, basophils are the prime early producers of interleukin (IL)-4 and IL-13, T helper (Th)2-type cytokines crucial for initiating and maintaining allergic responses. Basophils also express CD40 ligand which, in combination with IL-4 and IL-13, facilitates IgE class switching in B cells. They are the main cellular source for early IL-4 production, which is vital for the development of Th2 responses. The localization of basophils in various tissues affected by allergic inflammation has now been clearly demonstrated by using specific staining techniques and the new research is shedding light on their selective recruitment to the tissues. Finally, recent studies have shown that basophil activation is not restricted to antigen-specific IgE crosslinking, but can be caused in non-sensitized individuals by a growing list of parasitic antigens, lectins and viral superantigens, binding to non-specific IgE antibodies. This, together with novel IgE-independent routes of activation, imparts important new insights into the potential role of basophils in both adaptive and innate immunity. [source] Selective regulation of CD40 expression in murine dendritic cells by thiol antioxidantsIMMUNOLOGY, Issue 2 2003Norifumi Iijima Summary Interaction of CD40 on dendritic cells (DC) with CD40 ligand induces interleukin-12 (IL-12) production by these DC during the antigen presentation. Thus, the level of CD40 expression appears to influence the capability of DC to induce a T helper 1 (Th1) response. However, it is not fully understood how CD40 expression on DC is regulated. In the present study, we examined the effects of the reducing agents, N -acetyl- l -cysteine (NAC) and reduced glutathione (GSH), on tumour necrosis factor-, (TNF-,)-induced phenotypic changes in murine DC. TNF-, markedly increased the expression on DC of major histocompatibility complex (MHC) and the costimulatory molecules, CD40, CD80 and CD86. Both NAC and GSH completely abolished the TNF-,-induced enhancement of CD40 expression, but had no considerable effect on the expression of CD80, CD86 and MHC. The marked decrease of CD40 protein with NAC was also detected by Western blotting, but was not associated with the expression level of CD40 mRNA in DC. Thus, NAC appears to reduce CD40 expression on DC by regulating a post-transcriptional pathway. The inhibitory effect of NAC or GSH on TNF-,-induced CD40 expression was released by simply removing these agents from the culture. In contrast, culture of TNF-,-treated DC with NAC or GSH markedly decreased the expression of CD40 within 12 hr. These results demonstrate that reducing agents selectively, rapidly and reversibly regulate CD40 expression on DC, which may eventually affect the capability of DC for Th1/Th2 polarization. [source] The proportion of CD40+ mucosal macrophages is increased in inflammatory bowel disease whereas CD40 ligand (CD154)+ T cells are relatively decreased, suggesting differential modulation of these costimulatory molecules in human gut lamina propriaINFLAMMATORY BOWEL DISEASES, Issue 11 2006Dr. Hege S. Carlsen MD Abstract Background: Signal transduction through binding of CD40 on antigen-presenting cells and CD40 ligand (CD154) on T cells appears to be crucial for mutual cellular activation. Antibodies aimed at blocking the CD40,CD154 costimulatory pathway dampen the severity of experimental colitis. To elucidate the microanatomical basis for signaling through this costimulatory pathway in human inflammatory bowel disease, we studied in situ the cellular distribution of these 2 molecules on lamina propria macrophages and T cells, respectively. Methods: Colonic specimens from 8 patients with ulcerative colitis and 8 with Crohn's disease, 8 small bowel specimens of Crohn's disease, and histologically normal control samples (6 from colon and 6 from small bowel) were included. Multicolor immunofluorescence in situ staining was performed to determine the percentage of subepithelial macrophages expressing CD40 and that of lamina propria T cells expressing CD154 while avoiding cells in lymphoid aggregates. Results: The proportion of subepithelial CD40highCD68+ macrophages was significantly increased in normal colon compared with normal small bowel and showed further elevation in both colon and small bowel afflicted with inflammatory bowel disease. In addition, on a per-CD68+ -cell basis, CD40 expression was significantly increased in severely inflamed compared with moderately inflamed colonic specimens. Conversely, the proportion of CD154+ T cells was similar in colon and small bowel, and interestingly, it was significantly reduced in colonic inflammatory bowel disease. Conclusions: Our findings suggested that modulation of CD40 expression by subepithelial macrophages and CD154 by lamina propria T cells is inversely modulated in the human gut. [source] Thromboxane and prostacyclin biosynthesis in heart failure of ischemic origin: effects of disease severity and aspirin treatmentJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2010F. SANTILLI Summary.,Background: Thromboembolism is a relatively common complication of chronic heart failure (HF) and the place of antiplatelet therapy is uncertain. Objectives: We characterized the rate of thromboxane and prostacyclin biosynthesis in chronic HF of ischemic origin, with the aim of separating the influence of HF on platelet activation from that of the underlying ischemic heart disease (IHD). Patients and Methods: We compared urinary 11-dehydro-thromboxane (TX)B2, 2,3 dinor 6-keto-PGF1,, 8-iso-prostaglandin (PG)F2,, and plasma N-terminal pro-brain natriuretic peptide (NT-pro-BNP), asymmetric dimethylarginine (ADMA), and soluble CD40 ligand (sCD40L), in 84 patients with HF secondary to IHD, 61 patients with IHD without HF and 42 healthy subjects. Results: HF patients not on aspirin had significantly higher urinary 11-dehydro-TXB2 as compared with healthy subjects (P < 0.0001) and IHD patients not on aspirin (P = 0.028). They also showed significantly higher 8-iso-PGF2, (P =,0.018), NT-pro-BNP (P = 0.021) and ADMA (P < 0.0001) than IHD patients not on aspirin. HF patients on low-dose aspirin had significantly lower 11-dehydro-TXB2 (P < 0.0001), sCD40L (P = 0.007) and 2,3-dinor-6-keto-PGF1, (P = 0.005) than HF patients not treated with aspirin. HF patients in NYHA classes III and IV had significantly higher urinary 11-dehydro-TXB2 than patients in classes I and II, independently of aspirin treatment (P < 0.05). On multiple linear regression analysis, higher NT-pro-BNP levels, lack of aspirin therapy and sCD40L, predicted 11-dehydro-TXB2 excretion rate in HF patients (R2 = 0.771). Conclusions: Persistent platelet activation characterizes HF patients. This phenomenon is related to disease severity and is largely suppressable by low-dose aspirin. The homeostatic increase in prostacyclin biosynthesis is impaired, possibly contributing to enhanced thrombotic risk in this setting. [source] Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: Relationship with thrombosis occurrence and JAK2 V617F allele burden,AMERICAN JOURNAL OF HEMATOLOGY, Issue 2 2009Eduardo Arellano-Rodrigo Patients with essential thrombocythemia (ET) have an increased frequency of thrombosis, but the relationship of both thrombosis and JAK2 V617F allele burden with platelet turnover, acquired activated protein C resistance (aAPCR), and levels of coagulation factors and soluble markers of platelet, and endothelial activation is not well known. In 53 ET patients (26 with a history of thrombosis), reticulated platelets (RP) percentage, aAPCR, platelet tissue factor (TF) expression, and plasma levels of TF, coagulation factors, soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), von Willebrand factor antigen (VWF:Ag), soluble thrombomodulin (sTM), D -dimer and prothrombin fragment 1 + 2 were compared with those in matched healthy individuals and correlated with thrombosis occurrence and JAK2 mutational load. ET patients with thrombosis had significantly higher values for RP percentage, aAPCR, and levels of factors V and VIII, VWF:Ag, sP-selectin, and sCD40L than patients without thrombosis and controls. At multivariate study, RP percentage, factor V levels, and aAPCR were independently associated with an increased risk of thrombosis. Patients with JAK2 mutation had significantly lower levels of free protein S (PS) and higher levels of TF, sP-selectin, sCD40L, VWF:Ag, and sTM than those with wild-type allele. A mutant allele dosage effect (, 12%) was observed for TF, sP-selectin, sCD40L, VWF:Ag, and PS levels. These results support a role for platelet turnover, factor V, and aAPCR in the thrombosis of ET as well as the association between JAK2 V617F allele burden and either decreased free PS or increased TF and soluble markers of platelet and endothelial activation. Am. J. Hematol., 2009. © 2008 Wiley-Liss, Inc. [source] CD40-expressing plasmid induces anti-CD40 antibody and enhances immune responses to DNA vaccinationTHE JOURNAL OF GENE MEDICINE, Issue 1 2010Hanqian Xu Abstract Background Various approaches have been used to improve the efficacy of DNA vaccination, including the incorporation of molecular adjuvants. Because the CD40 ligand,CD40 interaction plays a major role in initiating immune responses, we sought to develop a molecular adjuvant targeting this interaction. Methods and Results We immunized mice with a foot-and-mouth disease virus DNA vaccine, pcD-VP1, together with a CD40-expressing plasmid, pcD-CD40. We found that pcD-CD40 induced anti-CD40 antibodies, which temporally correlated with the augmented production of anti-VP1 antibody. pcD-CD40 similarly augmented the humoral response of another DNA vaccine that targets hepatitis B virus, and passive transfer of anti-CD40 antisera also showed a similar effect. Furthermore, the pcD-CD40-elicited anti-CD40 antibodies were able to activate the CD40 signal pathway in antigen-presenting cells in vitro, which led to the maturation of dendritic cells (DCs) and DC-mediated T cell activation. Thus, pcD-CD40 augments DNA vaccination by inducing anti-CD40 antibodies, which in turn promotes T cell activation. Conclusions This is the first reported ,proadjuvant' that augments DNA vaccination indirectly by eliciting agonistic antibodies. Copyright © 2009 John Wiley & Sons, Ltd. [source] CTLA-4Ig in Combination with Anti-CD40L Prolongs Xenograft Survival and Inhibits Anti-Gal Ab Production in GT-Ko MiceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2002Dengping Yin The generation of GT-Ko mice has provided unique opportunities to study allograft and xenograft rejection in the context of anti-,1,3-Gal antibody (anti-Gal Ab) responses. In this study we used the allotransplantation model of C3H hearts into galactosyltransferase-deficient (GT-Ko) mice and the xenotransplantation model of baby Lewis rat hearts into GT-Ko mice to investigate the ability of CTLA-4Ig in combination with anti-CD40L mAb to control graft rejection and anti-Gal Ab production. Murine CTLA-4Ig or anti-CD40L monotherapy prolonged allograft survival, and the combination of these reagents was most immunosuppressive. However short-term treatment with murine cytotoxic T lymphocyte associated antigen-4 (muCTLA-4Ig) and/or CD40 ligand (CD154) monoclonal antibodies (anti-CD40L mAbs) was unable to induce indefinite allograft survival. CTLA-4-immunoglobulin fusion protein (CTLA-4Ig) or anti-CD40L monotherapy only marginally prolonged xenograft survival; the combination of human CTLA-4Ig and anti-CD40L significantly prolonged xenograft survival (74 days), while the combination of murine CTLA-4Ig and anti-CD40L resulted in graft survival of >,120 days. CTLA-4Ig or anti-CD40L monotherapy or the combination of these agents inhibited the production of alloAbs, including anti-Gal Abs. CTLA-4Ig or anti-CD40L monotherapy partially controlled xenoAb and anti-Gal Ab production, while the combination was more effective. These observations corroborate our previous observations that humoral, including anti-Gal Ab, responses and rejection following allograft or concordant xenograft transplantation in GT-Ko mice are T-cell dependent and can be controlled by costimulation blockade. [source] Heterogeneous requirement of I,B kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: Implications for therapyARTHRITIS & RHEUMATISM, Issue 7 2003Evangelos Andreakos Objective To investigate the potential role of I,B kinase 1 (IKK-1) and IKK-2 in the regulation of nuclear factor ,B (NF-,B) activation and the expression of tumor necrosis factor , (TNF,), as well as interleukin-1, (IL-1,), IL-6, IL-8, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), in rheumatoid arthritis (RA). Methods Recombinant adenoviruses expressing ,-galactosidase, dominant-negative IKK-1 and IKK-2, or I,B, were used to infect ex vivo RA synovial membrane cultures and synovial fibroblasts obtained from patients with RA undergoing joint replacement surgery, or human dermal fibroblasts, human umbilical vein endothelial cells (HUVECs), and monocyte-derived macrophages from healthy volunteers. Then, their effect on the spontaneous or stimulus-induced release of inflammatory cytokines, VEGF, and MMPs from RA synovial membrane cells was examined. Results IKK-2 was not required for lipopolysaccharide (LPS),induced NF-,B activation or TNF,, IL-6, or IL-8 production in macrophages, but was essential for this process in response to CD40 ligand, TNF,, and IL-1. In synovial fibroblasts, dermal fibroblasts, and HUVECs, IKK-2 was also required for LPS-induced NF-,B activation and IL-6 or IL-8 production. In RA synovial membrane cells, IKK-2 inhibition had no effect on spontaneous TNF, production but significantly reduced IL-1,, IL-6, IL-8, VEGF, and MMPs 1, 2, 3, and 13. Conclusion Our study demonstrates that IKK-2 is not essential for TNF, production in RA. However, because IKK-2 regulates the expression of other inflammatory cytokines (IL-1,, IL-6, and IL-8), VEGF, and MMPs 1, 2, 3, and 13, which are involved in the inflammatory, angiogenic, and destructive processes in the RA joint, it may still be a good therapeutic target. [source] A short course of BG9588 (anti,CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritisARTHRITIS & RHEUMATISM, Issue 3 2003Dimitrios T. Boumpas 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. Conclusion 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. [source] CD40L is Critical for Protection from Demyelinating Disease and Development of Spontaneous Remyelination in a Mouse Model of Multiple SclerosisBRAIN PATHOLOGY, Issue 1 2000Kristen M. Drescher Theiler's murine encephalomyelitis virus (TMEV) induces acute neuronal disease followed by chronic demyelination in susceptible strains of mice. In this study we examined the role of a limited immune defect (deletion or blocking of CD40 ligand [CD40L]) on the extent of brain disease, susceptibility to demyelination, and the ability of demyelinated mice to spontaneously remyelinate following TMEV infection. We demonstrated that CD40L-dependent immune responses participate in pathogenesis in the cerebellum and the spinal cord white matter but protect the striatum of susceptible SJL/J mice. In mice on a background resistant to TMEV-induced demyelination (C57BL/6), the lack of CD40L resulted in increased striatal disease and meningeal inflammation. In addition, CD40L was required to maintain resistance to demyelination and clinical deficits in H-2b mice. CD40L-mediated interactions were also necessary for development of protective H-2b -restricted cytotoxic T cell responses directed against the VP2 region of TMEV as well as for spontaneous remyelination of the spinal cord white matter. The data presented here demonstrated the critical role of this molecule in both antibody- and cell-mediated protective immune responses in distinct phases of TMEV-mediated pathology. [source] Infiltrating cells, related cytokines and chemokine receptors in lesional skin of patients with dermatomyositisBRITISH JOURNAL OF DERMATOLOGY, Issue 4 2004M. Caproni Summary Background, There have been only two reports on immunophenotypic characterization in the cutaneous lesions of dermatomyositis (DM) that emphasize the importance of the infiltrating CD4+ T lymphocytes. Objectives, To characterize the immunophenotype of the cells that infiltrate the lesional skin of DM and to evaluate the possible T-helper (Th) polarization Th1/Th2 through detection of specific cytokines, chemokine receptors and markers of cellular activation. Methods, Skin biopsy specimens derived from pathognomonic lesions (Gottron's papules and Gottron's sign) of eight patients with DM were immunostained with a large panel of monoclonal antibodies to CD3, CD4, CD8, myeloperoxidase (MPO), eosinophil cationic protein, tryptase, CD40, CD40 ligand (CD40L), HLA-DR, interleukin (IL)-2, IL-4, IL-5, IL-13, interferon-,, tumour necrosis factor-,, receptor 3 for CXC chemokines (CXCR3) and receptor 3 for CC chemokines, using the alkaline phosphatase,antialkaline phosphatase method. Control specimens were obtained from five healthy subjects and from six patients with discoid lupus erythematosus. Results, Activated CD4+ Th lymphocytes (HLA-DR+ CD40L+) were the principal infiltrating cells in the lesional skin of DM; the CD4/CD8 ratio was approximately 2·5. A mixed Th1/Th2 profile and higher Th1 cytokine production together with significant staining for CXCR3 were detected. Neutrophil granulocytes were the second most abundant population; eosinophil granulocytes were very poorly represented. Conclusions, Activated CD4+ T cells presumably mediate the main pathogenetic mechanisms in pathognomonic skin lesions. The interaction between CD40 and CD40L could be an important mechanism of cellular activation in cutaneous immune-mediated inflammation by induction of secretion of proinflammatory cytokines and chemokines. Neither Th1 nor Th2 clear polarization was found, although there was a slight Th1 prevalence. There was a significant quantity of MPO+ cells (neutrophil granulocytes) in the inflamed tissue, and they might have a role in sustaining the chronic inflammation. [source] Either interleukin-12 or interferon-, can correct the dendritic cell defect induced by transforming growth factor ,1 in patients with myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2004Ross Brown Summary The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44+) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up-regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor ,1 (TGF,1) and interleukin (IL)-10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti-TGF,1. As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up-regulation was reduced in both stage I and stage III. It was demonstrated that both IL-12 and interferon- , neutralized the failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123,) suggesting that there would be a predominantly T-helper cell type response. The addition of IL-12 or interferon- , to future immunotherapy trials involving these patients should be considered. [source] CD40L stimulation enhances the ability of conventional metaphase cytogenetics to detect chromosome aberrations in B-cell chronic lymphocytic leukaemia cellsBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2002Raymund Buhmann Summary. Conventional metaphase cytogenetics underestimates the frequency of specific chromosome aberrations in B-cell chronic lymphocytic leukaemia (B-CLL) as a result of the very low proliferative activity of these cells in vitro. New molecular approaches, such as fluorescence in situ hybridization (FISH) or comparative genomic hybridization (CGH), may circumvent this problem, at least in part, but these techniques are either strongly dependent on the knowledge of candidate regions or detect only unbalanced aberrations. In the present study, we analysed 27 B-CLL peripheral blood samples by metaphase cytogenetics after CD40 ligand (CD40L)-induced cell cycle stimulation. In comparison with the simultaneous use of B-cell mitogens such as 12-O-tetradecanoylphorbol-13-acetate (TPA), lipopolysaccharide (LPS) and pokeweed mitogen (PWM), CD40L stimulation of B-CLL cells induced a threefold increase in metaphases amenable to analysis by conventional cytogenetics. The analysis of these metaphases confirmed all genetic abnormalities detected by FISH. Moreover, CD40L-enhanced cytogenetics revealed complex karyotypic aberrations in 11 out of 27 patients (41%). In one case, a balanced translocation t(11;16)(p15;p13.1), so far unreported in B-CLL, was detected. Taken together, the results of our study show the potential of CD40L-enhanced metaphase cytogenetics to detect more and new chromosome aberrations in B-CLL. [source] Effects of 7,8-dihydro-8-oxo-deoxyguanosine on antigen challenge in ovalbumin-sensitized mice may be mediated by suppression of RacBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2009JY Ro Background and purpose:, Earlier we reported that 7,8-dihydro-8-oxo-deoxyguanosine (8-oxo-dG), an oxidatively modified guanine nucleoside, exerted anti-inflammatory activity through inactivation of the GTP binding protein, Rac. In the present study, the effects of 8-oxo-dG were investigated on responses to antigen challenge in sensitized mice, as Rac is also involved at several steps of the immune process including antigen-induced release of mediators from mast cells. Experimental approach:, Mice were sensitized and challenged with ovalbumin without or with oral administration of 8-oxo-dG during the challenge. Effects of 8-oxo-dG were assessed by measuring lung function, cells and cytokines in broncho-alveolar lavage fluid (BALF) and serum levels of antigen-specific IgE. Rac activity in BALF cells was also measured. Key results:, 8-oxo-dG inhibited the increased airway resistance and decreased lung compliance of sensitized and challenged mice to the levels of non-sensitized control mice and lowered the increased leukocytes particularly, eosinophils, in BALF. Furthermore, 8-oxo-dG suppressed allergy-associated immune responses, such as raised anti- ovalbumin IgE antibody in serum, increased expression of CD40 and CD40 ligand in lung, increased interleukin-4, -5, -13, interferon-, and tumour necrosis factor-, in BALF and mRNA levels of these cytokines in BALF cells, dose-dependently. The corresponding purine, 8-oxo-guanine, showed no effects in the same experiments. Finally, 8-oxo-dG, but not 8-oxo-guanine, inhibited the increased Rac activity in sensitized and challenged mice. Conclusion and implications:, 8-Oxo-dG had anti-allergic actions that might be mediated by Rac inactivation. This compound merits further evaluation of its therapeutic potential in allergic asthma. [source] Increased CD40 ligand in patients with acute anterior uveitisACTA OPHTHALMOLOGICA, Issue 3 2005Carsten Øgard Abstract. Purpose:,The inflammatory response in acute anterior uveitis (AU) is believed to be primarily mediated by autoreactive T-cells. We wanted to evaluate whether the T-cell activation marker CD40 ligand is involved in the AU immunopathogenesis. Methods:,We evaluated the expression of the CD40 ligand on CD4+ T-cells, CD8+ T-cells and CD19+ B-cells on peripheral blood mononuclear cells using flow cytometry in six patients with unilateral AU, six patients with monosymptomatic optic neuritis (ON) as inflammatory controls, and in six healthy controls. The ex vivo induction of the CD40 ligand on T-cells in patients and controls was also studied. Results:,A significantly higher expression of the CD40 ligand on both CD4+ (p < 0.05) and CD8+ (p < 0.05) T-cells in patients with AU compared to ON patients and healthy controls was found. There was a significantly higher induction of the CD40 ligand on CD8+ T-cells in AU patients compared to ON patients and healthy controls (p < 0.01). No differences in the B-cell population were observed between the three groups. Conclusion:,Patients with AU had increased expression of the CD40 ligand on T-cells in the blood and expressed higher levels of the CD40 ligand when stimulated, compared to ophthalmological inflammatory controls and healthy controls. The data suggest that the CD40 ligand is involved in the development of AU. [source] Transfection and ligation of CD40 in human oral keratinocytes affect proliferation, adhesion and migration but not apoptosis in vitroCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 2 2006M. Villarroel Dorrego Summary Aims:, CD40 expression is restricted to Keratinocytes of normal epidermis or stratified squamous epithelium of oral mucosa. Ligation of CD40 inhibits keratinocyte proliferation and apoptosis. The aim of this study was to investigate the functional significance of CD40 in the proliferation, apoptosis, adhesion and migration of human oral keratinocytes in vitro. Methods., The CD40-negative oral keratinocyte line OSC19, its CD40-positive transfected derivative (OSC19T-CD40) and null transfectants (OSC19T-control), with and without stimulation by soluble protein CD40 ligand (sCD40L) or anti-CD40 antibodies were used. Results., OSC19T-CD40 showed significantly (P < 0.001) slower growth than the null transfectants and parent cells. OSC19T-CD40 proliferation was inhibited by ligation with sCD40L and blocking by two anti-CD40 antibodies, but stimulated by a third. Binding of CD40 with ligand or antibody had no effect on keratinocyte apoptosis in any cell line. The capacity of OSC19T-CD40 cells to adhere to CD40L-coated wells was significantly greater (P < 0.001) than that of parent OSC19 and OSC19T-control cells, and the migration rate of OSC19T-CD40 cells was significantly higher than parent OSC19 (P = 0.038 on fibronectin, P = 0.004 on Matrigel) or OSC19T-control (P =0.017 on fibronectin, P = 0.013 on Matrigel) cells. Conclusions., CD40 is an important molecule in keratinocyte homeostasis, and has more than one ligand. The ligand that is bound may be critical in oral epithelial homeostasis, the development of malignancy and the behaviour of the subsequent tumour. [source] Generation of functionally mature dendritic cells from elutriated monocytes using polyinosinic : polycytidylic acid and soluble CD40 ligand for clinical applicationCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2008S. Kim Summary Despite the increasing use of dendritic cell (DC) vaccination in clinical trials, optimal conditions for the generation of functionally mature DCs remain to be established. The current standard DC maturation protocol for clinical trials has been used as an inflammatory cytokine cocktail [tumour necrosis factor (TNF)-,, interleukin (IL)-1,, IL-6 and prostaglandin E2], but this cocktail induced insufficient maturation of DCs derived from elutriated monocytes when cultured in X-VIVO 15. The aim of this study was to define effective combinations of stimulators for generating functionally mature DCs from elutriated monocytes under current good manufacturing practice conditions. We compared the functional capacity of DCs in response to all possible pairwise combinations of four different classes of stimuli: TNF-,, peptidoglycan, polyinosinic : polycytidylic acid [poly(I:C)] and soluble CD40 ligand (CD40L). Maturation status of DCs stimulated with combination of four stimuli was similar to that of the cytokine cocktail as assessed by the cell surface phenotype. However, only the combination of poly(I:C) + CD40L induced complete functional activation of the whole DC population, assessing IL-12p70 production, allostimulatory activity, migratory response to CCL19 and T helper 1-polarizing capacity. Thus, the protocol based on the combination of poly(I:C) and CD40L is more effective for the induction of clinical-grade DCs from elutriated monocytes than the standard cytokine cocktail. [source] Association between serum levels of soluble CD40/CD40 ligand and organ damage in hypertensive patientsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2010Ming Yuan Summary 1.,CD40 and CD40 ligand (CD40L) have a critical role in the pathophysiology and risk prediction of coronary artery syndrome, including atherothrombosis and atherosclerosis. However, the contribution of the CD40/CD40L dyad, especially the soluble form of CD40L (sCD40L), to the pathophysiology of hypertension and associated organ damage remains unknown. 2.,In the present study, serum levels of CD40 and sCD40L were measured in 328 hypertensive patients with varying degrees of organ damage. The data revealed that serum levels of CD40 were significantly greater in patients with severe, but not mild, organ damage compared with patients without any organ damage. There were no significant differences in serum concentrations of sCD40L between patients with no, mild and severe organ damage. Concentrations of soluble CD40 were comparable in patients with mild organ damage that included left ventricular hypertrophy, retinal damage, renal dysfunction and proteinuria. In contrast, concentrations of soluble CD40 were increased significantly in patients with certain forms of severe organ damage, specifically stroke, but not coronary and peripheral artery disease. 3.,Collectively, our data indicate that upregulation of the CD40 system in hypertensive patients with certain forms of severe end-organ damage may contribute to the pro-inflammatory, pro-atherogenic and prothrombotic milieu in hypertension. [source] The kinetics of CD154 (CD40L) expression in peripheral blood mononuclear cells of healthy subjects in liver allograft recipients and X-linked hyper-IgM syndromeCLINICAL TRANSPLANTATION, Issue 6 2000A Bartlett The costimulatory pathways play a key role in T cell activation during allograft rejection (AR). Inhibition of the T cell costimulatory molecule CD154 (CD40 ligand) has been effective in producing long-term allograft survival in rodents and non-human primates. The role of the CD40-CD154 pathway in human orthotopic liver transplantation (OLT) has not been examined. Aim: To describe the patterns of CD154, CD69 and CD152 (CTLA4) expression in OLT recipients and to determine their temporal relationship to AR. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 15 OLT allograft recipients just prior to and for seven consecutive days postoperatively. Gene and protein expression of CD154, CD69 and CD154 were examined by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FC), respectively. Results: FC failed to demonstrate an up-regulation of CD154 and CD152 protein expression during the first postoperative week. Intracellular FC did not increase the sensitivity. There was an increased level of CD3+CD8+ T cells expressing CD69 at the time of rejection compared to that on day 0. RT-PCR demonstrated a sporadic expression of CD154 and CD69 mRNA, with no correlation to episodes of acute cellular rejection. In vitro stimulation of PBMCs revealed an impaired up-regulation of CD154 in patients receiving conventional immunosuppression compared to healthy controls. The assays were validated using positive and negative controls, including a family with X-linked hyper-IgM syndrome. Conclusion: We found no evidence of spontaneous CD154 gene or protein expression in PBMCs associated with acute rejection episodes following OLT. Immunosuppression resulted in impaired responses to ex vivo stimulation. Lymphocyte costimulatory pathways play a critical role in mediating acute allograft rejection. However, we found no evidence of spontaneous CD154 gene or protein expression in PBMCs associated with acute rejection episodes following OLT. Furthermore, stimulation in vitro resulted in less up-regulation of CD154 than for healthy controls. [source] | |||||||||||||||||||||||||||||||