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Immunomodulatory Properties (immunomodulatory + property)
Selected AbstractsImmunomodulatory properties of Lactobacillus plantarum and its use as a recombinant vaccine against mite allergyALLERGY, Issue 3 2009P. Rigaux Background:, Selected lactic acid bacteria were reported to prevent atopic dermatitis and experimental asthma but the mechanisms of their immunomodulatory effects are not fully elucidated. In this study, the signaling pathways triggered by Lactobacillus plantarum NCIMB8826 were investigated and the potential use of this strain producing a variant of the mite allergen Der p 1 as live vaccine vehicle was evaluated. Methods:, Mouse bone marrow-derived dendritic cells were stimulated with wild-type or a L. plantarum teichoic acid mutant to evaluate the secretion of cytokines. A recombinant L. plantarum expressing Der p 1 was engineered, its in vitro immunomodulatory properties were characterized and its prophylactic potential was evaluated in a Der p 1-sensitization murine model. Results:, Mouse dendritic cells stimulated by L. plantarum triggered the release of interleukin-10 (IL-10), IL-12 p40, IL-12 p70 and tumor necrosis factor-alpha (TNF-,). IL-12 p40 secretion was dependent on nuclear factor-,B (NF-,B), mitogen-activated protein (MAP) kinases, Toll-like receptor 2 (TLR2), TLR9 and on the bacterial teichoic acid composition. Recombinant L. plantarum producing Der p 1 exhibited similar immunostimulatory properties as wild-type. Prophylactic intranasal pretreatment of mice with this recombinant strain prevented the development of the typical Th2-biased allergic response by a drastic reduction of specific IgE and the induction of protective allergen-specific IgG2a antibodies. Moreover, both wild-type or recombinant L. plantarum reduced airway eosinophilia following aerosolized allergen exposure and IL-5 secretion upon allergen restimulation. Conclusion:, By combining both Th1-type immunostimulatory properties and an efficient allergen delivery capacity, recombinant L. plantarum producing Der p 1 represents a promising vaccine against house dust mite allergy. [source] Immunomodulatory properties of human serum immunoglobulin A: anti-inflammatory and pro-inflammatory activities in human monocytes and peripheral blood mononuclear cellsCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2005K. Olas Summary Our study investigated the immunomodulatory activities of human plasma-derived serum immunoglobulin (Ig)A. Previous findings seem contradictory indicating either pro- or anti-inflammatory activities. We used serum IgA purified from large plasma pools and studied the modulation of the release of cytokines and chemokines from resting and lipopolysaccharide (LPS, endotoxin)-stimulated human adherent monocytes and human peripheral blood mononuclear cells (PBMC). Our results indicate that IgA down-modulates the release of the pro-inflammatory chemokines monocyte chemoattractant protein (MCP) 1, macrophage inflammatory protein (MIP) 1, and MIP1, from LPS-stimulated PBMC and the release of MCP1, MIP1, and MIP1, from LPS-stimulated monocytes. Furthermore, we confirmed previous reports that plasma-derived serum IgA down-modulates the release of the pro-inflammatory cytokines, interleukin (IL)-6 and tumour necrosis factor (TNF)-,, from LPS-stimulated monocytes and PBMC, and up-regulates the release of IL-1 receptor antagonist (IL-1RA) from resting and LPS-stimulated monocytes and resting PBMC. This IgA-mediated up-regulation of IL-1RA is independent of the simultaneous up-regulation of IL-1, release, as shown by blocking the biological activity of IL-1, with a neutralizing antibody. On the other hand, we also found an IgA-induced pro-inflammatory activity, namely IgA-mediated up-regutation of the release of pro-inflammatory IL-1, as well as down-regulation of the anti-inflammatory cytokines IL-10 and IL-12p40 from LPS-stimulated monocytes and PBMC and a down-regulation of transforming growth factor (TGF)-, from resting and LPS-stimulated PBMC. We conclude that human serum IgA has both an anti-inflammatory and a pro-inflammatory capacity and this dual capacity might contribute to the feedback mechanisms maintaining a balance between pro-inflammatory and anti-inflammatory activities. [source] Synergistic activation of interferon-, gene transcription by the viral FLICE inhibitory protein of Kaposi's sarcoma-associated herpesvirus and type,I IFN activatorsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2007Nathalie Cloutier Abstract Expression of Kaposi's sarcoma-associated herpesvirus v-FLIP leads to the spindle-shape morphology of endothelial cells and is essential for the survival of primary effusion lymphoma cells. Activation of the NF-,B transcription factor by v-FLIP is responsible for these effects. Considering that the interferon-, (ifn- ,) gene is regulated partly through NF-,B, we sought to determine whether v-FLIP would activate the expression of the ifn -, gene. Our results indicate that when v-FLIP is expressed by itself it has no effect on ifn -, gene activation but when it is combined with known IFN-, inducers, a synergistic activation of the ifn -, gene occurs. This effect is strictly dependent on NF-,B and is mediated through the positive regulatory domain,II of the IFN-, promoter. Furthermore, we report that protection from Fas-induced cell-death by v-FLIP is observed whether or not the type,I IFN signaling pathway is activated. Our work therefore contributes to increase our knowledge on v-FLIP, highlighting the complex immunomodulatory properties of this anti-apoptotic viral protein. [source] A comparative study of the preventative effects exerted by three probiotics, Bifidobacterium lactis, Lactobacillus casei and Lactobacillus acidophilus, in the TNBS model of rat colitisJOURNAL OF APPLIED MICROBIOLOGY, Issue 4 2007L. Peran Abstract Aims:, The intestinal anti-inflammatory effects of three probiotics with immunomodulatory properties, Lactobacillus casei, Lactobacillus acidophilus and Bifidobacterium lactis, were evaluated and compared in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. Methods and Results:, Colitis was induced in rats by intracolonic administration of 10 mg of TNBS dissolved in 0·25 ml of 50% ethanol. Each probiotic was administered orally (5 × 108 CFU suspended in 0·5 ml of skimmed milk) for 3 weeks, starting 2 weeks before the administration of TNBS. Colonic damage was evaluated histologically and biochemically 1 week after TNBS instillation. The results obtained revealed that all probiotics assayed showed intestinal anti-inflammatory effects, macroscopically evidenced by a significant reduction in the colonic weight/length ratio. Only B. lactis showed a lower incidence of diarrhoea in comparison with untreated rats. Biochemically, all probiotics restored colonic glutathione levels, depleted as a consequence of the oxidative stress of the inflammatory process. Bifidobacterium lactis treatment reduced colonic tumour necrosis factor (TNF)-, production, and inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) expression; L. acidophilus administration reduced colonic leukotriene B4 production and iNOS expression and L. casei intake was associated with a decrease in colonic COX-2 expression. Conclusion:, The three probiotics assayed have shown intestinal anti-inflammatory activity in the TNBS model of rat colitis, although each probiotic shows its own anti-inflammatory profile. Significance and Impact of the Study:, These probiotics could be considered as potential adjuvants in the treatment of inflammatory bowel disease, although more studies are required in order to demonstrate their efficacy in humans. [source] Morphine and HIV-Tat increase microglial-free radical production and oxidative stress: possible role in cytokine regulationJOURNAL OF NEUROCHEMISTRY, Issue 1 2009Jadwiga Turchan-Cholewo Abstract Opiate abuse alters the progression of human immunodeficiency virus and may increase the risk of neuroAIDS. As neuroAIDS is associated with altered microglial reactivity, the combined effects of human immunodeficiency virus-Tat and morphine were determined in cultured microglia. Specifically, experiments determined the effects of Tat and morphine on microglial-free radical production and oxidative stress, and on cytokine release. Data show that combined Tat and morphine cause early and synergistic increases in reactive oxygen species, with concomitant increases in protein oxidation. Furthermore, combined Tat and morphine, but not Tat or morphine alone, cause reversible decreases in proteasome activity. The effects of morphine on free radical production and oxidative stress are prevented by pre-treatment with naloxone, illustrating the important role of opioid receptor activation in these phenomena. While Tat is well known to induce cytokine release from cultured microglia, morphine decreases Tat-induced release of the cytokines tumor necrosis factor-, and interleukin-6, as well as the chemokine monocyte chemoattractant protein-1 (MCP-1). Finally, experiments using the reversible proteasome inhibitor MG115 show that temporary, non-cytotoxic decreases in proteasome activity increase protein oxidation and decrease tumor necrosis factor-,, interleukin-6, and MCP-1 release from microglia. Taken together, these data suggest that oxidative stress and proteasome inhibition may be involved in the immunomodulatory properties of opioid receptor activation in microglia. [source] Omega-3 fatty acids inhibit an increase of proinflammatory cytokines in patients with active Crohn's disease compared with omega-6 fatty acidsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 11-12 2005A. A. NIELSEN Summary Background :,Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract. Polyunsaturated omega-3 fatty acids given orally may reduce the secretion of proinflammatory cytokines and hereby downregulate the inflammatory process. Aim :,To assess the effects of enteral fatty acids, in the form of Impact Powder (Novartis, Switzerland), as adjuvant therapy to corticosteroid treatment on the proinflammatory and anti-inflammatory cytokine profiles in patients with active Crohn's disease. Methods :,The proinflammatory and anti-inflammatory cytokines were measured in plasma from 31 patients with active Crohn's disease. Patients were randomized for oral intake of omega-3 fatty acid (3-Impact Powder) or omega-6 fatty acids (6-Impact Powder). Clinical and biochemical markers of inflammation were studied at baseline and after 5 and 9 weeks. Results :,Within the 3-Impact Powder group, no significant changes in concentrations of interleukin-6, interferon- ,, monocyte chemoattractant protein-1, interleukin-2, interleukin-5 and interleukin-10, whereas a significant differences in concentration of interleukin-1, and interleukin-4 were observed during therapy. Within the 6-Impact Powder group a significant changes in concentrations of interleukin-1,, interleukin-6, interferon- ,, monocyte chemoattractant protein-1, interleukin-2, interleukin-4, interleukin-5 and interleukin-10 were observed. Conclusions :,The 3-Impact Powder showed immunomodulatory properties and might inhibit an increase of proinflammatory cytokines in contrast to the 6-Impact Powder. [source] Long-term reduction in local inflammation by a lipid raft molecule in atopic dermatitisALLERGY, Issue 9 2010S. Dölle To cite this article: Dölle S, Hoser D, Rasche C, Loddenkemper C, Maurer M, Zuberbier T, Worm M. Long-term reduction in local inflammation by a lipid raft molecule in atopic dermatitis. Allergy 2010; 65: 1158,1165. Abstract Background:, The complex pathogenesis of atopic dermatitis (AD) is guided by cell surface receptor-mediated signal transduction regulated in lipid rafts. Miltefosine is a raft-modulating molecule targeting cell membranes. With this controlled clinical study, the clinical and immunomodulatory efficacy of miltefosine was investigated in patients with AD in comparison with a topical corticosteroid treatment. Methods:, Sixteen patients with AD were treated topically with miltefosine and hydrocortisone localized on representative AD target lesions for 3 weeks. To assess the clinical efficacy, the three item severity (TIS) score was evaluated before, during and after treatment as well as after 4-week-follow-up period. To study the anti-inflammatory effect of miltefosine on the cellular T cell pattern, skin biopsies were analysed before and after treatment. Results:, The TIS score dropped in both groups significantly after treatment. A carry-over effect was exclusively seen for miltefosine after discontinuing the treatment. These findings were substantiated by thermographic imaging with a significant decrease in the maximum temperature (Tmax) after miltefosine application (P = 0.034, ,Tmax = 1.7°C [2.1,3.9]). Immunohistochemically, a reduction in lesional CD4+ -infiltrating T cells was observed in both treatments. Moreover, increased FoxP3+ cells were present in the skin after miltefosine treatment (before 5.4% [1.9,9.8], after 6.2% [3.5,9.5]). Conclusion:, We demonstrate that miltefosine is locally active in patients with AD and led to a sustained clinical improvement in local skin inflammation. Moreover, the increased frequency of FoxP3+ cells in the skin of patients with AD suggests its immunomodulatory properties. [source] Immunomodulatory properties of Lactobacillus plantarum and its use as a recombinant vaccine against mite allergyALLERGY, Issue 3 2009P. Rigaux Background:, Selected lactic acid bacteria were reported to prevent atopic dermatitis and experimental asthma but the mechanisms of their immunomodulatory effects are not fully elucidated. In this study, the signaling pathways triggered by Lactobacillus plantarum NCIMB8826 were investigated and the potential use of this strain producing a variant of the mite allergen Der p 1 as live vaccine vehicle was evaluated. Methods:, Mouse bone marrow-derived dendritic cells were stimulated with wild-type or a L. plantarum teichoic acid mutant to evaluate the secretion of cytokines. A recombinant L. plantarum expressing Der p 1 was engineered, its in vitro immunomodulatory properties were characterized and its prophylactic potential was evaluated in a Der p 1-sensitization murine model. Results:, Mouse dendritic cells stimulated by L. plantarum triggered the release of interleukin-10 (IL-10), IL-12 p40, IL-12 p70 and tumor necrosis factor-alpha (TNF-,). IL-12 p40 secretion was dependent on nuclear factor-,B (NF-,B), mitogen-activated protein (MAP) kinases, Toll-like receptor 2 (TLR2), TLR9 and on the bacterial teichoic acid composition. Recombinant L. plantarum producing Der p 1 exhibited similar immunostimulatory properties as wild-type. Prophylactic intranasal pretreatment of mice with this recombinant strain prevented the development of the typical Th2-biased allergic response by a drastic reduction of specific IgE and the induction of protective allergen-specific IgG2a antibodies. Moreover, both wild-type or recombinant L. plantarum reduced airway eosinophilia following aerosolized allergen exposure and IL-5 secretion upon allergen restimulation. Conclusion:, By combining both Th1-type immunostimulatory properties and an efficient allergen delivery capacity, recombinant L. plantarum producing Der p 1 represents a promising vaccine against house dust mite allergy. [source] Mesenchymal stem cells: Immunobiology and therapeutic potential in kidney disease (Review Article)NEPHROLOGY, Issue 1 2007STEVEN J MCTAGGART SUMMARY: Mesenchymal stem cells (MSC) are non-haematopoietic cells that are prevalent in the adult bone marrow but can also be isolated from a variety of other postnatal tissues. MSC are non-immunogenic and are immunosuppressive, with the ability to inhibit maturation of dendritic cells and suppress the function of naïve and memory T cells, B cells and NK cells. In addition to their immunomodulatory properties, MSC are capable of differentiating into various tissues of mesenchymal and non-mesenchymal origin and migrating to sites of tissue injury and inflammation to participate in tissue repair. A number of studies in animal models of cardiac injury, stroke and ischaemic renal injury have demonstrated the clinical potential of MSC in tissue regeneration and repair. MSC are currently being evaluated in various preclinical and clinical studies in humans and offer significant potential as a novel cellular therapy for tissue regeneration and immunological conditions. The present review focuses on the unique immunomodulatory and regenerative properties of MSC and their potential role in the treatment of kidney disease. [source] HYPOTHESIS: Sjögren's syndrome: a possible pathogenetic mechanism involving somatostatinORAL DISEASES, Issue 5 2000L Baccaglini Sjögren's syndrome is a chronic systemic disease that primarily affects the salivary and lacrimal glands. The pathogenesis of Sjögren's syndrome is unknown. We hypothesize that reduced somatostatin activity is an important factor in promoting immune dysregulation in patients affected by Sjögren's syndrome. Somatostatin is a multifunctional peptide with potent immunomodulatory properties. Its effects include reduced lymphocytic activity, reduced gastric and intestinal secretions, activation of the hypothalamic-pituitary axis, and anti-inflammatory action, all opposite to the general presentation in Sjögren's syndrome. We suggest that the activity of somatostatin is low in patients affected by this disease, and this contributes significantly to the pathology observed. [source] Dissecting Ascaris glycosphingolipids for immunomodulatory moieties , the use of synthetic structural glycosphingolipid analoguesPARASITE IMMUNOLOGY, Issue 3 2006D. E. KEAN SUMMARY We have previously shown glycosphingolipids of Ascaris suum to have phosphorylcholine (PC) and non-PC immunomodulatory moieties. In the present study we further investigated the nature of the immunomodulatory moieties by employing three synthetic glycosphingolipids each possessing features of the original molecule to examine effects on macrophage and dendritic cell (DC) cytokine production and surface co-stimulatory molecule expression. Compound 2, which lacked PC but contained ceramide, had no effect on either macrophages or DCs. Surprisingly however, Compound 1, which contained PC and hence arguably most resembled the native material, had, with the exception of a small increase in surface antigen expression, no immunomodulatory properties. Conversely, Compound 3, which contained PC but was otherwise least like the native molecule, demonstrated a number of effects on both macrophages and DCs, including induction of Th-1/pro-inflammatory cytokines, inhibition of such cytokines induced by IFN-,/LPS and increased expression of co-stimulatory molecules. Taken together these results indicate: (i) that although PC is an immunomodulatory component of the native molecule other structural feature are necessary to allow it to act; (ii) that carbohydrate rather than ceramide is likely to represent a non-PC immunomodulatory moiety; and (iii) that synthetic PC-containing molecules have the potential to act as immunomodulatory drugs. [source] Metabolism of the major Echinacea alkylamide N -isobutyldodeca-2E,4E,8Z,10Z -tetraenamide by human recombinant cytochrome P450 enzymes and human liver microsomesPHYTOTHERAPY RESEARCH, Issue 8 2010F. Toselli Abstract Echinacea preparations are used for the treatment and prevention of upper respiratory tract infections. The phytochemicals believed responsible for the immunomodulatory properties are the alkylamides found in ethanolic extracts, with one of the most abundant being the N -isobutyldodeca-2E,4E,8Z,10Z -tetraenamide (1). In this study, we evaluated the human cytochrome P450 enzymes involved in the metabolism of this alkylamide using recombinant P450s, human liver microsomes and pure synthetic compound. Epoxidation, N -dealkylation and hydroxylation products were detected, with different relative amounts produced by recombinant P450s and microsomes. The major forms showing activity toward the metabolism of 1 were CYP1A1, CYP1A2 (both producing the same epoxide and N -dealkylation product), CYP2A13 (producing two epoxides), and CYP2D6 (producing two epoxides and an hydroxylated metabolite). Several other forms showed less activity. In incubations with human liver microsomes and selective inhibitors, CYP2E1 was found to be principally responsible for producing the dominant, hydroxylation product, whereas CYP2C9 was the principal source of the epoxides and CYP1A2 was responsible for the dealkylation product. In summary, in this study the relative impacts of the main human xenobiotic-metabolizing cytochrome P450s on the metabolism of a major Echinacea alkylamide have been established and the metabolites formed have been identified. Copyright © 2010 John Wiley & Sons, Ltd. [source] Isolation and immunomodulatory properties of a flavonoid, casticin from Vitex agnus-castusPHYTOTHERAPY RESEARCH, Issue 11 2009M. Ahmed Mesaik Abstract Casticin (1), a flavonoid isolated from the aerial parts of Vitex agnus-castus, was found to be a potent immunomodulatory and cytotoxic compound. The activity was tested in vitro for chemiluminescence, chemotaxis, T-cell proliferation and cytotoxicity. Casticin (1) exhibited a significant inhibitory effect on monocyte oxidative burst in a dose dependent manner. It was found to have a significant suppressive effect on the chemotaxic action at higher concentrations on fMLP (10,8m) stimulated neutrophils. It also showed a potent suppressive effect on PHA stimulated T-cell (PMBC). Copyright © 2009 John Wiley & Sons, Ltd. [source] Influence of Cyclooxygenase-2 (COX-2) Gene Promoter Polymorphism ,765 on Graft Loss After Renal TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009C. Courivaud A G,C polymorphism has been identified in the human cyclooxygenase-2 (COX-2) gene promoter at position ,765 with C allele leading to a decreased promoter activity with low prostaglandin E2 (PGE2) production. PGE2 has strong immunomodulatory properties that could influence graft survival. We studied the association between this polymorphism and allograft failure in two independent cohorts of renal transplant recipients (RTRs) including a total of 603 patients. The functional effect of COX-2 gene promoter polymorphism was analyzed by measuring serum levels of PGE2. Median follow-up was 8.7 and 7.9 years for the first and second cohort, respectively. Analysis of 603 patients identified 20 CC (3.3%), 179 GC (29.7%) and 404 GG (67%) carriers. Patients with the GG genotype had significantly higher serum PGE2 concentrations than patients with the C allele. Carriers with a C allele have an independent increased risk of graft loss (hazard ratio (HR) 2.43 [95% CI 1.19,4.97], p = 0.015 for cohort 1; HR 1.72 [95% CI 0.99,3.77], p = 0.051 for cohort 2) compared to GG patients. COX-2 gene promoter polymorphism at position ,765 (G,C) is associated with a higher rate of graft loss in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management. [source] Interferon-,,dependent inhibition of B cell activation by bone marrow,derived mesenchymal stem cells in a murine model of systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 9 2010Francesca Schena Objective Bone marrow,derived mesenchymal stem cells (BM-MSCs) are multipotent cells characterized by immunomodulatory properties and are therefore considered a promising tool for the treatment of immune-mediated diseases. This study was undertaken to assess the influence of murine BM-MSCs on the activation of B cells in (NZB × NZW)F1 mice as an animal model of systemic lupus erythematosus (SLE). Methods We evaluated the in vitro effects of BM-MSCs on the proliferation and differentiation to plasma cells of splenic mature B cell subsets, namely follicular and marginal zone B cells isolated from (NZB × NZW)F1 mice. Lupus mice were also treated with BM-MSCs, and serum autoantibodies, proteinuria, histologic changes in the kidney, and survival rates were monitored. Results BM-MSCs inhibited antigen-dependent proliferation and differentiation to plasma cells of follicular and marginal zone B cells in vitro. This inhibitory effect was dependent on interferon-, (IFN,) and was mediated by cell-to-cell contact, involving the programmed death 1 (PD-1)/PD ligand pathway. In vivo treatment with BM-MSCs did not affect the levels of anti,double-stranded DNA antibodies or proteinuria. However, a reduction in glomerular immune complex deposition, lymphocytic infiltration, and glomerular proliferation was observed. Conclusion Our findings indicate that BM-MSCs affect B cell receptor,dependent activation of both follicular and marginal zone B cells from lupus mice. This inhibitory effect is IFN,-dependent and cell contact,dependent. MSCs in vivo do not affect the production of autoantibodies, the level of proteinuria, or the mortality rates. Nonetheless, the significant improvement in histologic findings in the kidney supports the potential role of MSCs in the prevention of glomerular damage. [source] Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon productionARTHRITIS & RHEUMATISM, Issue 7 2010Hideki Amuro Objective Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs. Methods We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFN, production, and intracellular signaling. Results Statins inhibited IFN, production profoundly and tumor necrosis factor , production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFN, production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFN, production by PDCs from SLE patients and SLE serum,induced IFN, production. Conclusion Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE. [source] Indoleamine 2,3 dioxygenase,mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 5 2009Gabriel Criado Objective Indoleamine 2,3 dioxygenase (IDO) is a catabolic enzyme that initiates the kynurenine pathway of tryptophan degradation and has immunomodulatory properties. The aim of this study was to investigate the regulation of collagen-induced arthritis by tryptophan catabolism mediated by IDO. Methods Arthritis was induced by immunization with type II collagen. After induction of arthritis, the expression of IDO was analyzed by quantitative reverse transcription,polymerase chain reaction. The effect of IDO deficiency on collagen-induced arthritis was assessed in vivo by administration of 1-methyltryptophan and clinical and histologic evaluation of IDO-deficient mice. The requirement for IDO activation was bypassed by administration of L -kynurenine. Results IDO was induced in lymph node dendritic cells after collagen immunization. Systemic inhibition of tryptophan catabolism during active arthritis increased disease severity. Conversely, bypassing the requirement for tryptophan degradation by the administration of L -kynurenine resulted in amelioration of arthritis. Furthermore, IDO-deficient mice showed a higher incidence of arthritis and exacerbated disease severity compared with IDO-competent mice. Such increased disease activity in IDO-deficient mice correlated early with increased production of the proinflammatory cytokines interferon-, and interleukin-17 by lymph node T cells and later with increased infiltration of Th1 and Th17 cells in the inflamed joints. Conclusion Our data indicate that the induction of IDO controls the accumulation of Th1 and Th17 pathogenic T cells at the site of inflammation during collagen-induced arthritis. Therefore, manipulation of the kynurenine pathway of tryptophan degradation provides the potential for therapeutic intervention in rheumatoid arthritis. [source] Phase II study of lenalidomide in patients with metastatic renal cell carcinomaCANCER, Issue 11 2006Toni K. Choueiri MD Abstract BACKGROUND. Lenalidomide (LEN) is a structural and functional analogue of thalidomide that has demonstrated enhanced immunomodulatory properties and a more favorable toxicity profile. A Phase II, open-label study of LEN in patients with metastatic renal cell carcinoma (RCC) was conducted to determine its safety and clinical activity. METHODS. Patients with metastatic RCC received LEN orally at a dose of 25 mg daily for the first 21 days of a 28-day cycle. The primary endpoint was the objective response rate. Time to treatment failure, safety, and survival were secondary endpoints. RESULTS. In total, 28 patients participated in the trial and were included in the current analysis. Three of 28 patients (11%) demonstrated partial responses and continued to be progression-free for >15 months. Eleven patients (39%) had stable disease that lasted >3 months, including 8 patients who had tumor shrinkage. In total, 6 patients (21%) remained on the trial, and 5 additional patients continued to be followed for survival. The median follow-up for those 11 patients was 13.5 months (range, 8.3,17.0 months). The median survival had not been reached at the time of the current report. Serious adverse events included fatigue (11%), skin toxicity (11%), and neutropenia (36%). CONCLUSIONS. LEN demonstrated an antitumor effect in metastatic RCC, as evidenced by durable partial responses. LEN toxicities were manageable. Further studies will be required to assess the overall activity of LEN in patients with metastatic RCC. Cancer 2006. © 2006 American Cancer Society. [source] G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus -induced suppression of TNF production in macrophagesCELLULAR MICROBIOLOGY, Issue 12 2006Sung O. Kim Summary Lactobacillus rhamnosus is a human commensal with known immunomodulatory properties. To date the mechanism of these immunomodulatory effects is not well understood. To unravel the immunomodulatory signalling mechanism, we investigated the effects of two strains of L. rhamnosus, L. rhamnosus GG and GR-1, in modulating production of tumour necrosis factor-, (TNF) in human monocytic cell line THP-1 and mouse macrophages. Live L. rhamnosus GG and GR-1 or their spent culture supernatant induced minuscule amounts of TNF production but large quantities of granulocyte-colony stimulating factor (G-CSF) in macrophages compared with those induced by pathogenic Escherichia coli GR-12 and Enterococcus faecalis. By using neutralizing antibodies and G-CSF receptor knockout mice, we demonstrated that G-CSF secreted from L. rhamnosus GG- and GR-1-exposed macrophages suppressed TNF production induced by E. coli - or lipopolysaccharide-activated macrophages through a paracrine route. The suppression of TNF production by G-CSF was mediated through activation of STAT3 and subsequent inhibition of c-Jun-N-terminal kinases (JNKs). The inhibition of JNK activation required STAT3,-mediated de novo protein synthesis. This demonstrates a novel role of G-CSF in L. rhamnosus -triggered anti-inflammatory effects and its mechanism in the suppression of TNF production in macrophages. [source] Glycodelin: a novel serum anti-inflammatory marker in type 1 diabetic retinopathy during pregnancyACTA OPHTHALMOLOGICA, Issue 1 2007Sirpa Loukovaara Abstract. Purpose:, Inflammation may play a role in the development of diabetic retinopathy during pregnancy. Glycodelin is a glycoprotein whose secretion from the endometrial glands increases during pregnancy. Glycodelin has immunosuppressive properties thought to play a role in the protection of the fetoplacental unit. We studied the role of glycodelin in the development and progression of retinopathy in type 1 diabetes during pregnancy. Methods:, Retinopathy was graded from fundus photographs in 45 diabetes subjects and nine non-diabetes subjects prospectively during pregnancy. Serum glycodelin concentration was measured by an immunofluorometric assay. Results:, In women with diabetes with progression of retinopathy, serum glycodelin concentration was 263 ng/ml (range 116,505 ng/ml) during the first trimester, 61 ng/ml (range 30,106 ng/ml) during the second trimester, and 29 ng/ml (range 13,53 ng/ml) during the third trimester, compared with values of 595 ng/ml (range 376,870 ng/ml), 104 ng/ml (range 75,228 ng/ml) and 45 ng/ml (range 32,74 ng/ml), respectively, in diabetes subjects without progression (p = 0.005 between the groups). Low glycodelin concentration was associated with progression of diabetic retinopathy in multiple regression analysis. Serum glycodelin concentration was similar in women with and without diabetes throughout pregnancy (p = 0.63 by repeated measures anova). Conclusions:, Low glycodelin concentration is associated with progression of retinopathy in pregnant women with diabetes. A possible causal relationship between low glycodelin levels and progression of retinopathy may be mediated by the immunomodulatory properties of glycodelin. [source] Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune toleranceCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2010K. J. Lee Summary Statins are potent inhibitors of hydroxyl-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, and have emerged as potential anti-cancer agents based on preclinical evidence. In particular, compelling evidence suggests that statins have a wide range of immunomodulatory properties. However, little is known about the role of statins in tumour immune tolerance. Tumour immune tolerance involves the production of immunosuppressive molecules, such as interleukin (IL)-10, transforming growth factor (TGF)-, and indoleamine-2,3-dioxygenase (IDO) by tumours, which induce a regulatory T cell (Treg) response. In this study, we investigated the effect of simvastatin on the production of IL-10, TGF-, and IDO production and the proliferation of Tregs using several cancer cell lines, and Lewis lung cancer (3LL) cells-inoculated mouse tumour model. Simvastatin treatment resulted in a decrease in the number of cancer cells (3LL, A549 and NCI-H292). The production of the immune regulatory markers IL-10, TGF-, in 3LL and NCI-H292 cells increased after treatment with simvastatin. The expression of IDO and forkhead box P3 (FoxP3) transcription factor was also increased in the presence of simvastatin. In a murine 3LL model, there were no significant differences in tumour growth rate between untreated and simvastatin-treated mice groups. Therefore, while simvastatin had an anti-proliferative effect, it also exhibited immune tolerance-promoting properties during tumour development. Thus, due to these opposing actions, simvastatin had no net effect on tumour growth. [source] Differential immunomodulatory properties of Bifidobacterium logum strains: relevance to probiotic selection and clinical applicationsCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2007M. Medina Summary Modulation of host immunity is one of the proposed benefits of the consumption of probiotics. Nonetheless, comparative studies on the immunological properties that support the selection of strains of the same species for specific health benefits are limited. In this study, the ability of different strains of Bifidobacterium longum to induce cytokine production by peripheral blood mononuclear cells (PBMCs) has been evaluated. Live cells of all B. longum strains greatly stimulated regulatory cytokine interleukin (IL)-10 and proinflammatory cytokine tumour necrosis factor (TNF)-, production. Strains of the same species also induced specific cytokine patterns, suggesting that they could drive immune responses in different directions. The probiotic strain B. longum W11 stimulated strongly the production of T helper 1 (Th1) cytokines while B. longum NCIMB 8809 and BIF53 induced low levels of Th1 cytokines and high levels of IL-10. The effects of cell-surface components obtained by sonication of B. longum strains overall confirm the effects detected by stimulation of PBMCs with live cells, indicating that these components are important determinants of the immunomodulatory activity of B. longum. Genomic DNA of some strains stimulated the production of the Th1 and pro-inflammatory cytokines, interferon (IFN)-, and TNF-,, but not that of IL-10. None of the cell-free culture supernatants of the studied strains was able to induce TNF-, production, suggesting that the proinflammatory component of these strains is associated mainly with structural cell molecules. The results suggest that despite sharing certain features, some strains can perform a better functional role than others and their careful selection for therapeutic use is desirable. [source] Interferon-,2a is sufficient for promoting dendritic cell immunogenicityCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2005A. Tamir Summary Type I interferons (IFNs) are widely used therapeutically. IFN-,2a in particular is used as an antiviral agent, but its immunomodulatory properties are poorly understood. Dendritic cells (DCs) are the only antigen-presenting cells able to prime naive T cells and therefore play a crucial role in initiating the adaptive phase of the immune response. We studied the effects of IFN-,2a on DC maturation and its role in determining Th1/Th2 equilibrium. We found that IFN-,2a induced phenotypic maturation of DCs and increased their allostimulatory capacity. When dendritic cells were stimulated simultaneously by CD40 ligation and IFN-,2a, the production of interleukin (IL)-10 and IL-12 was increased. In contrast, lipopolysaccharide (LPS) stimulation in the presence of IFN-,2a mainly induced IL-10 release. The production of IFN-, and IL-5 by the responder naive T cells was also amplified in response to IFN-,2a-treated DCs. Furthermore, IL-12 production by IFN-,2a-treated DCs was enhanced further in the presence of anti-IL-10 antibody. Different results were obtained when DCs were treated simultaneously with IFN-,2a and other maturation factors, in particular LPS, and then stimulated by CD40 ligation 36 h later. Under these circumstances, IFN-,2a did not modify the DC phenotype, and the production of IL-10/IL-12 and IFN-,/IL-5 by DCs and by DC-stimulated naive T cells, respectively, was inhibited compared to the effects on DCs treated with maturation factors alone. Altogether, this work suggests that IFN-,2a in isolation is sufficient to promote DC activation, however, other concomitant events, such as exposure to LPS during a bacterial infection, can inhibit its effects. These results clarify some of the in vivo findings obtained with IFN-,2a and have direct implications for the design of IFN-,-based vaccines for immunotherapy. [source] | |||||||||||||