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ID PMID Title PublicationDate abstract
18433878 Evaluation of the use of anti-TNF-alpha in an LPS-induced murine model. 2008 Jul OBJECTIVE: Tumor necrosis factor alpha (TNF-alpha) may play a critical role in inflammatory-mediated preterm labor. Medications blocking the activity of TNF-alpha have been shown to be effective in the treatment of conditions such as rheumatoid arthritis; however, the use of these medications for an event like preterm birth or fetal death is unknown. We hypothesized that treatment with anti-TNF-alpha may decrease the rate of fetal death and preterm birth in a LPS-induced murine model. METHODS: Pregnant C57BL/6J mice received intraperitoneal (IP) injections of either vehicle or 2mg anti-TNF-alpha. After 24h, 10 microg of LPS was administered IP. Mice were sacrificed 24h later and outcomes between groups were assessed. A second set of experiments utilizing RT-PCR was performed to determine the influence of anti-TNF-alpha on production of inflammatory cytokines in response to LPS. RESULTS: There were 72 resultant pups in the LPS+saline group, and 91 in the group receiving LPS+anti-TNF-alpha. Pretreatment with anti-TNF-alpha reduced the rate of fetal death and preterm birth after LPS administration (p<0.01). Expression of IL-6, IL-1beta, TLR-2, CD14 and COX-1 were found to be significantly reduced in mice treated with anti-TNF-alpha and LPS compared to LPS alone. CONCLUSION: The use of anti-TNF-alpha decreased fetal deaths and preterm deliveries in an LPS-induced model of preterm birth. In addition, there were critical gene expression alterations in the group receiving anti-TNF-alpha. Further evaluation of TNF-alpha blockade as a potential treatment for preterm labor is warranted.
18336138 [Systemic AA amyloidosis induced by benign neoplasms]. 2008 Amyloidosis is a systemic disorder characterized by the extracellular tissue deposition of insoluble, toxic aggregates in bundles of beta-sheet fibrillar proteins. These deposits are typically identified on the bases of their apple-green birrefringence under a polarized light microscope after staining with Congo red, and by the presence of rigid, nonbranching fibrils 8 to 10 nm in diameter on electron microscopy. The type of amyloid fibril unit can be further defined by immunohistology or by immunoelectron microscopy. It has been described at least 25 different human protein precursors of amyloid fibrils, which will describe its corresponding amyloid disease. The most common types of amyloidosis are AL (primary) and AA (secondary) types; the former, is the most frequent and is due to deposition of proteins derived from immunoglobulin light chain fragments, occurring alone or in association with multiple myeloma. The later (AA), is caused by deposition of fibrils composed of fragments of the acute phase reactant serum amyloid A (SAA) and complicates chronic diseases with ongoing or recurring inflammation, namely; rheumatoid arthritis (RA), juvenile chronic polyarthritis, ankylosing spondylitis, familial periodic fever syndromes (Familial Mediterranean Fever), chronic infections and furthermore, some neoplasms (mainly renal cell carcinoma and Hodgkin's disease). Despite its less frequent association, some benign neoplasms can subsequently complicate to AA amyloidosis, therefore, an early diagnose and successful treatment may lead indeed, to regression of the amyloid disease. Herein, we present two cases of AA amyloidosis, both of them caused by 2 different benign neoplasms: 1. A 34 year-old woman, after chronic oral contraceptive use, developed an hepatic adenoma (fig. 1) which finally lead to AA amyloidosis with primary kidney presentation (pure nephrotic syndrome) (table 1). Post-surgical complications yield to acute renal failure from which unfortunately could not be recovered. After being on hemodialysis therapy during 10 months she received a first renal allograft without any complication. 2. A 20 year old woman, was diagnosed of AA amyloidosis after a renal biopsy (fig. 2) because of nephrotic syndrome (table 1). Further investigation lead to the finding of a hialyne-vascular type Castleman's disease located in the retroperitoneum (fig. 2). Despite surgical resection and medical treatment (colchicine) she developed progressive renal failure requiring initialization of hemodialysis therapy. After 6 years being on hemodialysis, she received a first renal allograft which is currently functioning after one year of follow- up. Although other chronic inflammatory diseases complicate more frequently to AA amyloidosis, benign tumors have to be taken into account as a potential ethiological cause for secondary amyloidosis.
18285424 Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis 2008 Jun BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.
18239242 Infection in primary total knee replacement. 2008 Feb OBJECTIVES: To determine the infection rate and identify the risk factors of primary total knee replacement in a general hospital and discuss possible preventive measure. DESIGN: Retrospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: All cases of primary total knee replacement performed between the period July 1997 and June 2006 were reviewed. MAIN OUTCOME MEASURES: Infection rate of primary total knee replacement and its relationship to risk factors. RESULTS: In the defined period, 479 total knee replacements were performed in 353 patients (291 female and 62 male); 105 women and 21 men had bilateral replacements. The mean patient age was 69 (range, 40-88) years. In all, 447 knees had osteoarthritis, and 32 had rheumatoid arthritis. The mean follow-up period was 46 (range, 1-107) months; 345 knees were followed up longer than 24 months, but seven had no postoperative follow-up. Wound infection was defined by clinical, bacteriological, and/or histological examination. Primary total knee replacement was invariably performed in a theatre with vertical laminar flow, under prophylactic antibiotic cover, and body exhaust suits, water impermeable gowns, and double gloves were always used. The overall infection rate was 3.0% (14/472); the acute deep infection rate (within 4 weeks) was 0.2% (1/472), the delayed deep infection rate (4 weeks-2 years) was 0.6% (2/345). The superficial infection rate was 1.9% (9/472) and the late deep infection rate (after 2 years) was 0.6% (2/345). Diabetic patients had a three-fold higher risk of infection than non-diabetic patients, though this difference did not attain statistical significance (P=0.077). CONCLUSIONS: Our infection rates for primary total knee replacement were comparable to those encountered internationally.
18157119 In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanopartic 2008 Jan We describe biocompatible and nontoxic nanoparticles for in vivo tumor targeting and detection based on pegylated gold nanoparticles and surface-enhanced Raman scattering (SERS). Colloidal gold has been safely used to treat rheumatoid arthritis for 50 years, and has recently been found to amplify the efficiency of Raman scattering by 14-15 orders of magnitude. Here we show that large optical enhancements can be achieved under in vivo conditions for tumor detection in live animals. An important finding is that small-molecule Raman reporters such as organic dyes were not displaced but were stabilized by thiol-modified polyethylene glycols. These pegylated SERS nanoparticles were considerably brighter than semiconductor quantum dots with light emission in the near-infrared window. When conjugated to tumor-targeting ligands such as single-chain variable fragment (ScFv) antibodies, the conjugated nanoparticles were able to target tumor biomarkers such as epidermal growth factor receptors on human cancer cells and in xenograft tumor models.
18065872 [Dental care and joint prostheses]. 2007 Oct PURPOSE OF THE STUDY: Infectious dental foci and oral dental care constitute one of the leading causes of arthroplasty infection after infections involving the skin and the urinary tract. There is however no formal evidence confirming the relationship between oral or dental care and arthroplasty infection. MATERIAL AND METHODS: We reviewed 44 cases of arthroplasty infection secondary to dental infections and searched for data in the literature. In our series, no risk factor could be identified for 24 cases. The median disease-free interval was five years and mean time from the oral-dental procedure to the first signs of prosthesis infection was one month. Tooth extraction was the most common oral-dental procedure involved (n=19). Most of the infections were caused by a single agent, predominantly Streptococci sp. (n=24) and Staphylococci sp. (n=12). DISCUSSION: It is well known that dental-related bacteriemia is a spontaneous daily event even without dental procedures. It is also probable that spontaneous bacteriemia induced by daily activities is much more frequent than dental-care induced bacteriemia. The presence of foreign material diminishes local antibacterial defense systems increasing the risk of hematogeneous contamination of the joint prosthesis after dental care. The oral flora is also modified in immunodepressed subjects, particularly carriage of Staphylococcus aureus in the oral cavity which is significantly more frequent in patients with rheumatoid arthritis. These changes increase the risk of contamination after dental care. For arthroplasty infection, the pathogenic power of Staphylococci sp. is certainly greater than that of Streptococci sp. even if the inoculum is less abundant. Antibiotic prophylaxis during dental care in patients with an arthroplasty remains a controversial subject and the most appropriate antibiotic remains to be defined. Successive episodes of spontaneous bacteriemia arising from an oral-dental foci are probably the main cause of arthroplasty infections, more so than bacteriemia triggered by dental care. CONCLUSION: Antibiotic therapy is not indicated for routine dental care in the majority of patients but is recommended whenever there is a high risk of arthroplasty contamination. In the event of oral-dental infection, antibiotic therapy is necessary. The recommendations proposed by the ADA and the AAOS were revised in 2003. The most important point is to obtain and maintain a good state of oral hygiene. For prevention, awareness of the risk is essential, for the patient, the orthopedic surgeon and the primary care physician alike. Regular dental visits are necessary.
17480064 Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 2007 May 31 A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK-2) for the treatment of rheumatoid arthritis has been prepared and evaluated. These inhibitors have IC50 values as low as 10 nM against the target and have good selectivity profiles against a number of kinases including CDK2, ERK, JNK, and p38. These MK-2 inhibitors have been shown to suppress TNFalpha production in U397 cells and to be efficacious in an acute inflammation model. The structure-activity relationships of this series, the selectivity for MK-2 and their activity in both in vitro and in vivo models are discussed. The observed selectivity is discussed with the aid of an MK-2/inhibitor crystal structure.
17391989 A rat pharmacokinetic/pharmacodynamic model for assessment of lipopolysaccharide-induced t 2007 Jul INTRODUCTION: Tumor necrosis factor-alpha (TNFalpha) participates in many inflammatory processes. TNFalpha modulators show beneficial effects for the treatment of many diseases including rheumatoid arthritis. The purpose of this study was to validate a rat pharmacokinetic/pharmacodynamic (PK/PD) model for rapid assessment of drug candidates that intended to interrupt TNFalpha synthesis or release. METHODS: Rats received intravenous (IV) or oral administrations of test article or dose vehicle, followed by LPS challenge. Plasma levels of test article and TNFalpha were determined. The areas under the concentration-time curves (AUC(drug) and AUC(TNFalpha)) were calculated. The overall percentage of inhibition on TNFalpha release in vivo was calculated by comparing AUC(TNFalpha) of the test article treated group against that for the vehicle control group. RESULTS: The dosing vehicles tested in this study did not increase plasma TNFalpha level. At IV dose of up to 100 microg/kg, LPS did not alter the pharmacokinetics of the compound tested. Using a selective TNFalpha converting enzyme (TACE) inhibitor as model compound, this PK/PD model demonstrated its ability to correlate plasma test article concentration with its biological activity of lowering the LPS-induced TNFalpha plasma levels in vivo. DISCUSSION: A rat PK/PD model for evaluation of the effect of drug candidates on LPS-induced TNFalpha synthesis and/or release has been investigated. This model provides integrated information on pharmacokinetics and in vivo potency of the test articles.
17244502 [Carpal bones and joints: roentgenographic measurements in 20- to 70-year-old healthy Mexi 2006 Nov BACKGROUND: We undertook this study to identify normal radiographic anthropometry reference values of the carpal bones and joints in healthy Mexicans between 20 and 70 years old. METHODS: The study was comprised of 112 subjects without diabetes mellitus, rheumatoid arthritis, congenital and/or traumatic diseases in upper limbs. Roentgenograms in postero-anterior and lateral views of carpal bones and joints were performed using standardized techniques. Measurements were done by two blinded observers. Statistical analysis was done applying Kolmogorov-Smirnov-Lilliefors test [K-S-L] (p >0.05), Student's t-test, intraclass correlation coefficient [ICC], Kappa test and Pearson correlation coefficient (p <0.05). RESULTS: The study sample showed homogeneity in the K-S-L test (p >0.05), ICC (0.93-0.99). The carpal height in men was 34.6 +/- 4.4 mm [2 SD] (29-40 mm), in women 32.0 +/- 3.3 mm [2 SD] (22-41 mm) p = 0.001. The alternative carpal height ratio was 1.45 +/- 0.1 [2SD]. The scapholunate angle was 49.25 +/- 20.46 degrees [2 SD] (28.5-90 degrees ). The inter-observer congruence agreement percentage of the Gilula's arches in first arch was 68.70% and 98.20% in the third; Kappa values were 0.55 and 0.66, respectively. CONCLUSIONS: The 31.3% disagreement in the first and second Gilula's arches demonstrated its poor utility for evaluating inter-carpal instability and incongruence. Anthropometric values by sex and age reported here will allow the study of the associations with pathologies such as carpal tunnel disease, DISI and VISI. This contributes to the identification of normal reference parameters.
17237603 Crosslinking of the CD69 molecule enhances S100A9 production in activated neutrophils. 2007 Expression of CD69 on neutrophils and generation of anti-CD69 autoantibodies in patients with rheumatoid arthritis (RA) have been reported. Thus natural ligands for CD69 not yet identified and/or the anti-CD69 autoantibodies possibly affect neutrophils by evoking CD69 signaling, which may further affect joint-composing cells in RA. However, the effect of the CD69 signaling in neutrophils remains largely unclear. To elucidate the issue, we tried to identify proteins affected by the crosslinking of CD69 on neutrophils using a proteomic approach. Specifically, CD69 on granulocyte-macrophage colony stimulating factor (GM-CSF)-activated neutrophils was crosslinked by anti-CD69 monoclonal antibodies, and then intracellular proteins were detected using 2-dimensional electrophoresis and further identified by mass spectrometry and subsequent protein database searching. As a result, we successfully identified multiple proteins that increased their production by the CD69 signaling. Among the proteins, we focused on one of the up-regulated proteins, S100A9 calcium binding protein (S100A9), and investigated proteome changes brought by a recombinant S100A9 in a human synovial sarcoma cell line (SW982), a human chondrosarcoma cell line (OUMS-27), and a human T leukemia cell line (Jurkat). This revealed that the recombinant S100A9 altered proteomes of SW982 and OUMS-27, and to a lesser extent, that of the Jurkat cells. Further, S100A9 induced IL-1beta production from neutrophils and the SW982 cells. These data suggest that unidentified natural ligands for CD69 and/or the anti-CD69 autoantibodies possibly affect joint-composing cell types through the increased production of S100A9 in neutrophils, providing a new insight into functions of CD69 on neutrophils in RA.
17191033 Does renal function influence plasma levels of advanced glycation and oxidation protein pr 2007 BACKGROUND: The aim of the study was to assess the contribution of carbonyl and oxidative stresses to the development of amyloidosis in patients suffering from chronic rheumatic diseases, and the potential influence of renal function to their concentrations was considered. METHODS: We investigated 17 patients with chronic rheumatological diseases and histologically proven diagnosis of AA amyloidosis (group AA-RA), 26 patients suffering from rheumatoid arthritis without any signs of AA amyloidosis (group nonAA-RA) and 20 healthy volunteers (Co). In all patients, advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), pregnancy-associated plasma protein A (PAPP-A) and other selected proinflammatory markers were measured. RESULTS: An increase in serum levels of AOPP and AGEs was found in the AA-RA group in comparison with nonAA-RA patients and also with Co (p < 0.001 for all comparisons). AGEs positively correlated with serum creatinine (r = 0.67, p = 0.004) and negatively with glomerular filtration rate (r = -0.54, p = 0.027). We did not find a correlation between AOPP and any other assessed parameters including proteins and renal parameters. PAPP-A levels were not significantly increased in any group of patients (AA-RA, nonAA-RA) in comparison with Co. CONCLUSIONS: Increased plasma levels of AGEs and AOPP in the group of patients with AA-RA may have been partly explained by the diminished renal clearance. However, the increase in AOPP levels was higher than what is expected in this degree of renal failure (glomerular filtration rate in the AA-RA group corresponding to chronic kidney disease stage III).
16836843 [Overview of clinical occurrence of primary immunodeficiency disorders in children]. 2006 Jun OBJECTIVE: More than one hundred primary immunodeficiency disorders have been discovered so far. But the incidence of these disorders in our country is still not clear, so we analyzed the clinical data of 93 children with primary immunodeficiency disorders seen in our hospital in recent 30 years to understand the occurrence of primary immunodeficiency disorders in children, to promote the clinicians to become familiar with these disorders, to improve the nationwide registry system and to establish the basis for the treatment and prevention in future. METHODS: To analyze the constituent ratio of the 93 children with primary immunodeficiency disorders seen in our hospital from 1974 to 2003, diagnostic and classification criteria were set by taking the proposal by International Union of Immunological Societies (IUIS) PID classification committee in 2003 into account. All the data were analyzed retrospectively. RESULTS: In the 93 children with primary immunodeficiency disorders, antibody deficiencies were the most frequent (39.8%) finding, followed by combined immunodeficiency, combined T- and B-cell disorders (22.6%), and T lymphocytic deficiencies alone (14.0%). Immunodeficiency with other major defects accounted for 12.9%, phagocytic disorders 9.7%, and complement deficiencies 1.1%. Thus, there seemed to be a tendency that the incidence increased with time. The incidence of these disorders has increased significantly as shown by 50 diagnosed cases in children with these disorders since 1996. Sixteen children died, with the highest mortality occurred with combined immunodeficiency. Seven children developed bronchiectasis. Two children suffered from persistent diarrhea while one of the two was complicated with persistent intestinal fistula. One child developed juvenile rheumatoid arthritis, another one with granulocytopenia and iridocyclitis, and the other with allergic purpura. The boys: girls ratio for all disorders was 3:1. The age of onset ranged from 10 days to 37 years of age. CONCLUSIONS: There are vast variety of primary immunodeficiency disorders in our area and antibody deficiency is the most common abnormality. Combined immunodeficiency has early onset age and high mortality rate. With the great improvement of the diagnostic techniques, these disorders have become a group of important disorders and all the clinicians should pay great attention to these disorders.
16698671 Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. 2006 Mar Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.
16571608 Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor 2006 Oct OBJECTIVES: Despite recent major advances in the understanding of the pathogenesis of rheumatoid arthritis, with tumour necrosis factor-alpha (TNFalpha) established as a major therapeutic target, comparatively little is known about the mediators involved in the destructive and inflammatory pathways in osteoarthritis (OA). Recently, it has become appreciated that an inflammatory synovitis contributes not only to the signs and symptoms of osteoarthritis, but also to disease progression. Here, we use high-efficiency adenoviral gene transfer to investigate the role of the transcription factor nuclear factor-kappaB (NFkappaB) in regulating inflammatory and destructive mediators in the late stage OA synovium. METHODS: Infection with reporter adenoviruses transferring the beta-galactosidase or green fluorescent protein genes verified that OA synovial cells could be infected (>95%). Adenovirus transferring the inhibitory subunit IkappaBalpha inhibited NFkappaB. The production of a whole array of pro- and anti-inflammatory cytokines and mediators, and several matrix metalloproteinases and their main inhibitor, was measured by enzyme-linked immunosorbent assay. RESULTS: The spontaneous production of macrophage-produced pro-inflammatory cytokines varied: TNFalpha was modestly inhibited by IkappaBalpha overexpression, but interleukin (IL)-1 was unaffected. Both IL-6 and IL-8 were potently inhibited, as were granulocyte-macrophage colony stimulating factor and oncostatin M. Anti-inflammatory mediators like IL-10, the IL-1 receptor antagonist and the p55 soluble TNF receptor were unaffected. Matrix metalloproteinases 1, 3, 9 and 13 were potently inhibited by IkappaBalpha overexpression, but not their main inhibitor tissue inhibitor of metalloproteinase-1. CONCLUSIONS: The OA synovium is a highly inflammatory environment, with spontaneous production of many cytokines and matrix metalloproteinases. Inhibition of NFkappaB may have a beneficial effect on the balance between pro-inflammatory cytokines and anti-inflammatory mediators, and between destructive metalloproteinases and their main inhibitor.
16505807 Noble metals strip peptides from class II MHC proteins. 2006 Apr Class II major histocompatibility complex (MHC) proteins are essential for normal immune system function but also drive many autoimmune responses. They bind peptide antigens in endosomes and present them on the cell surface for recognition by CD4(+) T cells. A small molecule could potentially block an autoimmune response by disrupting MHC-peptide interactions, but this has proven difficult because peptides bind tightly and dissociate slowly from MHC proteins. Using a high-throughput screening assay we discovered a class of noble metal complexes that strip peptides from human class II MHC proteins by an allosteric mechanism. Biochemical experiments indicate the metal-bound MHC protein adopts a 'peptide-empty' conformation that resembles the transition state of peptide loading. Furthermore, these metal inhibitors block the ability of antigen-presenting cells to activate T cells. This previously unknown allosteric mechanism may help resolve how gold(I) drugs affect the progress of rheumatoid arthritis and may provide a basis for developing a new class of anti-autoimmune drugs.
16454763 New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 2006 The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-alpha monoclonal antibody), Adalimumab (recombinant human anti-human TNF-alpha monoclonal antibody) and Anakinra (recombinant form of human interleukin 1beta (IL-1) receptor antagonist). The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1alpha and TNF-alpha to be validated targets. However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1beta and TNF-alpha signalling network at both the transcriptional and translational level. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.
16418799 CD166 expression, characterization, and localization in salivary epithelium: implications 2006 Jan CD166 is an Ig superfamily molecule that binds homotypically to itself and heterotypically to CD6. Interactions between CD6 and CD166 are important during immune development and in alloreactivity. CD166 is expressed at increased levels in selected cancers and in rheumatoid arthritis synovium. Knowledge that CD166 was expressed in normal human salivary epithelium led to these studies of CD166 and CD6 in diseased mouse salivary glands, that resemble pathology seen in the human disease, Sjögren's syndrome. We showed that in mouse salivary epithelium CD166 was expressed but that expression of CD166 did not necessarily predict its function. Recombinant soluble CD6-Ig bound to CD6 ligands (CD6L) on transformed and freshly isolated salivary epithelial cells. Cross-blocking studies showed that binding of CD6-Ig to salivary epithelium was in part dependent on CD166, but that CD6-Ig binding may also involve additional CD6L. Binding of CD6-Ig was sensitive to trypsin digestion but resistant to digestion by collagenase and sialidase. Anti-CD166 ab precipitated CD166 from salivary epithelium pre- and post-treatment with the pro-inflammatory cytokine IFN-gamma. In contrast CD6-Ig only precipitated CD166 from IFN-gamma treated cells. More extensive colocalization between CD166 and the actin cytoskeleton was observed in sialoadenitis epithelium compared to control. We conclude that during sialoadenitis, CD166 undergoes a gain of function, resulting in closer association with the actin cytoskeleton and increased capacity to bind CD6. We suggest that altered CD166 function may contribute to the pro-inflammatory milieu during sialoadenitis seen in Sjögren's syndrome.
20641472 (111)In-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-L 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the development of (111)In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-Lys) ((111)In-DOTA-E-c(RGDfK)) for imaging α(v)β(3) receptors in nude mice bearing ovarian carcinoma tumors.
17393395 Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients 2007 Apr OBJECTIVE: To identify the cells that produce BAFF in the salivary glands of patients with primary Sjögren's syndrome (SS), and to analyze BAFF receptor expression by local T and B lymphocytes. METHODS: We used 3 methods to identify the source of BAFF: in situ hybridization of the transcripts for BAFF combined with staining of membrane markers, regular and real-time reverse transcription-polymerase chain reaction (RT-PCR) of cultured epithelial cells, and RT-PCR of sorted single-cell T and B lymphocytes eluted from salivary glands. Cells expressing TACI, BCMA, and B lymphocyte stimulator receptor 3 (BR-3) were disclosed by combining each specific staining of the receptors with each specific staining of the cells. The function of BAFF generated by epithelial cells on B lymphocytes was determined in short-term cocultures. RESULTS: Transcripts for BAFF were seen in epithelial cells and infiltrating T lymphocytes and, for the first time, were detected in local B cells. It is interesting that BR-3 was present on these B cells but not on T cells. In contrast, TACI and, to a lesser degree, BCMA were observed on transitional B lymphocytes, whereas T lymphocytes were devoid of receptors for BAFF. Furthermore, this cytokine was shown to be functional, in that epithelial cell-bound BAFF extended the survival of normal B cells, but cell-free BAFF released in the supernatants did not. CONCLUSION: These experiments establish that in primary SS, BAFF is produced not only by epithelial cells and T cells but also by B cells. The expression of receptors for BAFF would thus allow these receptors to participate in an autocrine pattern of self-stimulation.
17599739 Human chorionic gonadotropin prevents Sjögren's syndrome-like exocrinopathy in mice. 2007 Jul OBJECTIVE: Results of recent studies suggest that human chorionic gonadotropin (HCG), a placental glycoprotein hormone required for the maintenance of pregnancy, may have immunomodulatory properties. Primary Sjögren's syndrome (SS), a chronic autoimmune disorder of unknown etiology, affects multiple exocrine glands including the salivary and lacrimal glands. The purpose of the present study was to determine whether HCG could prevent the development of salivary gland exocrinopathy in NOD mice, an experimental model of Sjögren's-like syndrome. METHODS: Female NOD mice were treated with HCG from 6 weeks of age to 12 weeks of age. At 14 weeks, tissue samples were evaluated for inflammatory lesions and cytokine messenger RNA by real-time polymerase chain reaction. At 18 weeks, the salivary flow rate was measured. RESULTS: Treatment with HCG resulted in a significant decrease in lymphocyte infiltration and parenchymal cell damage in the submandibular salivary glands. Messenger RNA levels of interferon-gamma, tumor necrosis factor alpha, interleukin-1beta, and interleukin-10, as well as inducible nitric oxide synthase and matrix metalloproteinase 9, were significantly decreased. Function studies revealed a marked increase in the salivary flow rate in HCG-treated mice compared with that in phosphate buffered saline-treated mice. CONCLUSION: In NOD mice, HCG acts as an immune modulator and prevents the development of salivary gland exocrinopathy. These findings suggest that HCG, a naturally occurring reproductive hormone, may be useful in the treatment of Sjögren's syndrome and other human autoimmune diseases.