Immunomodulatory Role (immunomodulatory + role)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

An Immunomodulatory Role for Follistatin-Like 1 in Heart Allograft Transplantation

J. B. Le Luduec
Donor-specific tolerance to heart allografts in the rat can be achieved by donor-specific blood transfusions (DST) before transplantation. We have previously reported that this tolerance is associated with strong leukocyte infiltration, and that host CD8+ T cells and TGF, are required. In order to identify new molecules involved in the induction phase of tolerance, we compared tolerated and rejected heart allografts (suppressive subtractive hybridization) 5 days after transplantation. We identified overexpression of Follistatin-like 1 (FSTL1) transcript in tolerated allografts compared to rejected allografts or syngeneic grafts. We show that FSTL1 is overexpressed during both the induction and maintenance phase of tolerance, and appears to be specific to the tolerance model induced by DST. Analysis of graft-infiltrating cells revealed predominant expression of FSTL1 in CD8+ T cells from tolerated grafts, and depletion of these cells prior to transplantation abrogated FSTL1 expression and heart allograft survival. Moreover, overexpression of FSTL1 by adenovirus gene transfer in vivo significantly prolonged allograft survival in association with inhibition of the proinflammatory cytokines, IL6, IL17 A and IFN,. Taken together, these results suggest that FSTL1 could be an active component of the mechanisms mediating heart allograft tolerance. [source]

Neutrophil gelatinase-associated lipocalin is a marker for dysregulated keratinocyte differentiation in human skin

Lotus Mallbris
Abstract: Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein initially isolated from the specific granules of human neutrophils. It is a member of the highly heterogeneous lipocalin protein family, which shares a common tertiary structure. Its synthesis is induced in gastrointestinal epithelium in association with inflammation and malignancy. To gain insight into its potential role in other epithelia we have investigated the expression of NGAL in human skin embryonic development, in normal adult skin, and in skin associated with inflammation and neoplastic transformation. In the present study we report that the embryonic expression of NGAL appears to be regulated in a spatio-temporal pattern. It was induced in the interfollicular epidermis at 20,24 weeks of gestational age but thereafter progressively receded towards the hair follicles. In normal adult skin, NGAL was detected solely in association with hair follicles. However, strong induction of NGAL in the epidermis was seen in a variety of skin disorders characterized by dysregulated epithelial differentiation such as psoriasis, pityriasis rubra and squamous cell carcinoma. In these tissues production of NGAL was confined to spatially distinct subpopulations of keratinocytes underlying areas of parakeratosis, whereas skin samples lacking parakeratotic epithelium such as lichen ruber planus, acute contact eczema and basal cell carcinoma were negative for NGAL. Consistent with being a marker for disturbed terminal differentiation, NGAL immunoreactivity showed an inverse pattern when compared with that of the differentiation marker filaggrin. The biologic functions of NGAL in epithelia are not fully known, although an immunomodulatory role in host defense has been proposed. In addition, the transient interfollicular NGAL expression during skin embryogenesis along with the induction of NGAL in adult parakeratotic epidermis suggests it play a role in epithelial differentiation pathways. [source]

Adenosine receptors: promising targets for the development of novel therapeutics and diagnostics for asthma

Cristina Russo
Abstract Interest in the role of adenosine in asthma has escalated considerably since the early observation of its powerful bronchoconstrictor effects in asthmatic but not normal airways. A growing body of evidence has emerged in support of a proinflammatory and immunomodulatory role for the purine nucleoside adenosine in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma. The fact that adenosine enhances mast cell allergen-dependent activation, that elevated levels of adenosine are present in chronically inflamed airways, and that adenosine given by inhalation cause dose-dependent bronchoconstriction in subjects with asthma emphasizes the importance of adenosine in the initiation, persistence and progression of these common inflammatory disorders of the airways. These distinctive features of adenosine have been recently exploited in the clinical and research setting to identify innovative diagnostic applications for asthma. In addition, because adenosine exerts its multiple biological activities by interacting with four adenosine receptor subtypes, selective activation or blockade of these receptors may lead to the development of novel therapies for asthma. [source]

Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodies

IMMUNOLOGY, Issue 4 2008
Tyler R. Hall
Summary Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b9611) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b9611 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b9611 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b9611 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne. [source]

Microarray analysis of transcription factor gene expression in melatonin-treated human peripheral blood mononuclear cells

Eunyoung Ha
Abstract:, The existence of specific melatonin-binding sites in lymphoid cells led to the discovery of signal transduction pathway for melatonin in human lymphocytes and immunomodulatory role of melatonin in immune cells. In recent years, transcriptional regulation of melatonin on various transcription factors has been demonstrated. Therefore, this study was designed to assess by cDNA microarray analysis the regulatory effects of melatonin on transcription factors in human peripheral blood mononuclear cells (PBMCs). Forty-six genes were upregulated and 23 were downregulated more than twofold in melatonin-treated PBMCs. Of the more than twofold upregulated transcription factor genes, homeo box A4 (HOXA4), forkhead box O1A (FOXO1A), transcription elongation factor B (SIII), polypeptide 3 (TCEB3), and peroxisome proliferative activated receptor delta (PPARD) were identified. Of the more than twofold downregulated genes, PHD finger protein 15 (PHF15) and zinc finger protein 33a (ZNF33A) were identified. In summary, identification of these genes by cDNA microarray analysis in response to melatonin administration may provide a foundation for further studies on the function of melatonin in human PBMCs. [source]

Phosphorylcholine mimics the effects of ES-62 on macrophages and dendritic cells

SUMMARY Modulation of macrophage/dendritic cell (DC) cytokine production by the filarial nematode phosphorylcholine (PC)-containing product, ES-62, is mediated by Toll-like receptor (TLR) 4 and signal transduction depends on the TLR adaptor MyD88. Intriguingly, comparison of TLR4 knock-out (ko) mice with TLR4 mutant C3H/HeJ mice indicates that ES-62 cytokine responses are not dependent on the Pro712 residue of TLR4, which is crucial for the response to bacterial lipopolysaccharide (LPS). Because other immunomodulatory effects of ES-62 have been attributed to PC we have now investigated, using PC conjugated to ovalbumin (PC-Ova), whether PC is responsible for the interaction of ES-62 with TLR4. PC-Ova mimicked the modulation of interleukin (IL)-12 production by ES-62 in a TLR4- and MyD88-dependent manner and as with native ES-62, PC-Ova effects were not dependent on Pro712. Furthermore, both native ES-62 and PC-Ova suppressed Akt phosphorylation, whereas neither altered the activation of p38 or Erk MAP kinases. To rule out any role for the ES-62 protein component, we tested a PC-free recombinant ES-62 (rES-62) generated in the yeast Pichia pastoris. Surprisingly, rES-62 also modulated IL-12 production, but in a TLR4/MyD88-independent manner. Furthermore, rES-62 strongly activated both the p38 and Erk MAP kinases and Akt. However, recent biophysical analysis suggests there are differences in folding/shape between native and rES-62 and hence data obtained with the latter should be treated with caution. Nevertheless, although our study indicates that PC is likely to be primarily responsible for the modulation of cytokine production observed with native ES-62, an immunomodulatory role for the protein component cannot be ruled out. [source]

Stress mitigating and immunomodulatory effect of dietary pyridoxine in Labeo rohita (Hamilton) fingerlings

Mohammad Shahbaz Akhtar
Abstract A 60-day experiment was carried out to delineate stress mitigating and immunomodulatory role of dietary pyridoxine (PN) in Labeo rohita fingerlings exposed to endosulfan. Two hundred and seventy fingerlings were randomly distributed into six treatments in triplicates. Five iso-caloric and iso-nitrogenous purified diets were prepared with graded levels of pyridoxine. Six treatment groups were T0 (10 mg PN+without endosulfan), T1 (0 mg PN+endosulfan), T2 (10 mg PN+endosulfan), T3 (50 mg PN+endosulfan), T4 (100 mg PN+endosulfan) and T5 (200 mg PN+endosulfan). The role of pyridoxine on stress mitigation and immunomodulation was assessed by biochemical and haemato-immunological parameters like aspartate aminotransaminase, alanine aminotransaminase, lactate dehydrogenase, malate dehydrogenase, superoxide dismutase and catalase were significantly (P<0.05) lower while acetylcholinesterase was significantly (P<0.05) higher in pyridoxine-fed groups. Erythrocytes count, haemoglobin content and total serum protein, albumin, globulin, nitroblue tetrazolium and lysozyme activity were significantly (P<0.05) higher while cortisol and blood glucose were decreased significantly (P<0.05) in pyridoxine-fed groups. Percentage survival after challenge with Aeromonas hydrophila was highest in T0 group. The results obtained in present study indicate that dietary pyridoxine supplementation at 100 mg PN kg,1 diet reduces the endosulfan-induced stress and triggers immune response in L. rohita fingerlings. [source]

Cloning, expression, purification, crystallization and preliminary X-ray crystallographic analysis of interleukin-4-inducing principle from Schistosoma mansoni eggs (IPSE/alpha-1)

Hubert Mayerhofer
The interleukin-4-inducing principle from Schistosoma mansoni eggs (IPSE/alpha-1) triggers the release of large amounts of interleukin-4 from human blood basophils, thus presumably playing an immunomodulatory role during schistosome infection. IPSE/alpha-1 was crystallized and a native X-ray data set was collected to 1.66, resolution from a single crystal at 100,K using synchrotron radiation. The crystal belonged to space group P61 or P65, with one molecule per asymmetric unit. [source]

Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human ,-defensin 1 (HBD-1) expression in the intestinal epithelial cells

Krishnendu Chakraborty
Summary Cathelicidin (hCAP-18/LL-37) and ,-defensin 1 (HBD-1) are human antimicrobial peptides (AMPs) with high basal expression levels, which form the first line of host defence against infections over the epithelial surfaces. The antimicrobial functions owe to their direct microbicidal effects as well as the immunomodulatory role. Pathogenic microorganisms have developed multiple modalities including transcriptional repression to combat this arm of the host immune response. The precise mechanisms and the pathogen-derived molecules responsible for transcriptional downregulation remain unknown. Here, we have shown that enteric pathogens suppress LL-37 and HBD-1 expression in the intestinal epithelial cells (IECs) with Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) exerting the most dramatic effects. Cholera toxin (CT) and labile toxin (LT), the major virulence proteins of V. cholerae and ETEC, respectively, are predominantly responsible for these effects, both in vitro and in vivo. CT transcriptionally downregulates the AMPs by activating several intracellular signalling pathways involving protein kinase A (PKA), ERK MAPKinase and Cox-2 downstream of cAMP accumulation and inducible cAMP early repressor (ICER) may mediate this role of CT, at least in part. This is the first report to show transcriptional repression of the AMPs through the activation of cellular signal transduction pathways by well-known virulence proteins of pathogenic microorganisms. [source]

Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation

K L Wright
The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB1 receptor activation. However, the presence and function of the CB2 receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB2 receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain. CB2 receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and many of its symptoms. CB2 receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction. British Journal of Pharmacology (2008) 153, 263,270; doi:10.1038/sj.bjp.0707486; published online 1 October 2007 [source]