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ID PMID Title PublicationDate abstract
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.
16202258 [Treatment of proliferative lupus nephritis with leflunomide and steroid: a prospective mu 2005 Sep OBJECTIVE: Leflunomide (LEF) is a selective inhibitor of de novo pyrimidine synthesis, currently used in the treatment of rheumatoid arthritis. To evaluate the efficacy and safety of LEF in the treatment of proliferative lupus nephritis, a prospective multi-center controlled clinical trial was conducted. METHODS: Patients with biopsy-confirmed proliferative lupus nephritis were recruited. Patients of recent onset who had not used any immunosuppressive drug were given either oral LEF (group A) or IV cyclophosphamide (group B); relapsed patients who had received immunosuppressive therapy 3 months before were given LEF (group C). Efficacy and safety were evaluated at 6 months after treatment. RESULTS: Total 51 patients were enrolled, 4 patients withdrew due to adverse events. For those initial treated patients, total response rate were 80% in group A and 75% in group B, complete remission rate were 40% and 25% respectively, not statistically different. Renal parameters (proteinuria, serum albumin and serum creatinine) and systemic lupus erythematosus disease activity index (SLEDAI) improved similarly in both groups. For 14 relapsed patients, total response rate was 60% and complete remission rate was 6.7%. Major adverse events reported in LEF treated patients were infection and alopecia. Herpes zoster was the most often type among infectious events, and one case of severe lung infection was reported. CONCLUSION: LEF combined with steroid was effective in the induction therapy of proliferative lupus nephritis. LEF was generally well-tolerated, its efficacy in maintenance therapy and long-term safety remains to be clarified.
16086584 Binding of madindoline A to the extracellular domain of gp130. 2005 Aug 16 Elevated levels of IL-6 and IL-11 are associated with multiple myeloma, rheumatoid arthritis, hypercalcemia, cancer cachexia, and Castleman's disease. Madindoline A (MadA), isolated from Streptomyces nitrosporeus K93-0711, specifically inhibits the growth of IL-6- and IL-11-dependent cell lines, most likely by interfering with the homodimerization of gp130. This raises the possibility that MadA can be used as a model compound for the development of novel chemotherapeutic agents. In this report, we demonstrate that the binding of MadA to gp130 is specific and noncovalent, and displays a relatively low affinity. Furthermore, we show that the tricyclic 3a-hydroxytetrahydrofuro[2,3-b]indole (HFI) moiety of MadA alone is not sufficient for binding. Matrix-bound MadA precipitates a protein composed of the extracellular domain of gp130 fused to the Fc region of the immunoglobulin heavy chain. Binding is inhibited in a dose-dependent manner by preincubation with free MadA. The K(D) for binding of MadA to gp130 is 288 microM, as determined by surface plasmon resonance (SPR)-based biosensor analysis. The HFI portion of MadA does not bind to gp130 in either affinity precipitation or SPR analyses. Finally, MadA, but not the HFI portion, inhibits IL-6-dependent Stat3 tyrosine phosphorylation in HepG2 cells.
16026943 Comparison between 60 matched pairs of postmenopausal black and white women: analysis of r 2005 Nov PURPOSE: Osteoporosis is a systemic disease in which bone density is reduced, leading to weakness of the skeleton and increased vulnerability to fractures. The purpose of this study was to compare known or suspected risk factors (medical, gynecological, and lifestyle characteristics) related to bone loss between 60 matched pairs of black and white postmenopausal women. METHODS: The two racial groups were matched one for one on selective anthropometric variables [age (years), standing height (cm), and body weight (kg)] in order to equate age and body size between groups. Information on risk factors was obtained from an orally administered questionnaire and body composition variables (in addition to those used for matching) assessed by anthropometry and total body dual energy X-ray absorptiometry (DXA). Four skinfold sites (chest, triceps, mid-axillary, and abdomen) were measured with Harpendon calipers and four body circumferences (chest, forearm contracted, waist, and gluteal) were assessed with a Gulick tape. DXA radius, spine, femur, and whole body measurements were obtained on a Hologic QDR-2000 with software version 7.20. RESULTS: White women reported significantly higher proportions of alcohol use, family history of broken bones, and a greater utilization of hormones, calcium and vitamins than did black women. Black women reported a greater numbers who had other diseases (i.e., overactive thyroid, diabetes, rheumatoid arthritis, or kidney stones). Although age and body weight were similar in both groups, black women had greater lean tissue and less body fat than white women. Blacks had significantly higher bone mineral density across all body sites with the exception of the mid- and ultra-distal radius. CONCLUSION: On the basis of these data, it was concluded that part of the difference often observed in bone density between black and white postmenopausal women might be due to lifestyle factors.
16010126 Radiation protection in radiosynovectomy of the knee. 2005 Aug Radiosynovectomy is a widely available therapeutic option that involves radiopharmaceutical injections into joints to treat rheumatoid arthritis. However, data on the beta-radiation dose equivalents for the staff performing such treatments are limited. The aim of this study was to determine the personal dose equivalents H(P)(0.07) to the skin of the hands of the treating physician under several exposure scenarios. An activity of 185 MBq (90)Y was used. Thermoluminescence detectors were attached at the finger tip of the thumb, forefinger, and middle finger of the treating physician. Measurements of beta-exposures were made during treatment of 70 knees with (90)Y under the following exposure scenarios: group 1, the radiosynovectomy was performed with syringe shield with Perspex (Plexiglas, Röhm GmbH, Germany) (thickness of 5 mm); group 2, additionally a manipulator was used for fixation of the needle; group 3, radiation-resistant gloves were added to the measures in groups 1 and 2. For group 1, the highest beta doses were measured at the forefinger (22.1 microSv MBq(-1)) (22,100 microrem/27 microCi) and thumb with 16.5 microSv MBq(-1) (16,000 microrem/27 microCi) at the left hand, which holds the needle (right-handed physician). In group 2, the radiation doses were reduced to 0.6 microSv MBq(-1) (60 microrem/27 microCi) at the left forefinger and 0.5 microSv MBq(-1) (50 microrem/27 microCi) at the left thumb. The use of a manipulator and special radiation resistant gloves reduced the radiation dose to 0.4 microSv MBq(-1) (40 microrem/27 microCi) at the left forefinger and to 0.3 microSv MBq(-1) (30 microrem/27 microCi) at the left thumb in group 3. It was concluded that while performing radiosynovectomy without a manipulator for fixation of the needle, the dose measured at the left forefinger could exceed the German limit of 500 mSv (50 rem) per year for the official dosimetry at the skin. Using holding forceps allows compliance with the legal limit and could considerably reduce the beta dose. The use of radiation-resistant gloves reduced the beta dose at the skin only slightly.
15863003 Synthesis, in vitro, and in vivo characterization of an integrin alpha(v)beta(3)-targeted 2005 Jun 1 Integrin alpha(v)beta(3) is a widely-recognized target for the development of targeted molecular probes for imaging pathological conditions. alpha(v)beta(3) is a cell-surface receptor protein that is upregulated in various pathological conditions including osteoporosis, rheumatoid arthritis, macular degeneration, and cancer. The synthesis of an alpha(v)beta(3)-targeted optical probe 7 from compound 1, and its in vitro and in vivo characterization is described. A series of aliphatic carbamate derivatives of the potent non-peptide integrin antagonist 1 was synthesized and the binding affinity to alpha(v)beta(3) was determined in both enzyme linked immunosorbent assay (ELISA) and cell adhesion inhibition assays. The hydrophobic carbamate-linked appendages improved the binding affinity of the parent compound for alpha(v)beta(3) by 2-20 times. A Boc-protected neopentyl derivative in the series is shown to have the best binding affinity to alpha(v)beta(3) (IC(50)=0.72 nM) when compared to compound 1 as well as to c-RGDfV. Optical probe 7 utilizes the neopentyl linker and demonstrates increased binding affinity and significant tumor cell uptake in vitro as well as specific tumor accumulation and retention in vivo. These results illustrate the potential of employing integrin-targeted molecular probes based on 1 to image a multitude of diseases associated with alpha(v)beta(3) overexpression.
15808852 Functional characterization of SDF-1 proximal promoter. 2005 Apr 22 Stromal-cell derived factor 1 (SDF1) is a CXC chemokine that binds and signals through the CXCR4 receptor, playing an essential role in embryonic B lymphopoiesis, myelopoiesis and organogenesis. The CXCR4/SDF1 pathway is associated with several pathologies. CXCR4 serves as a fusion cofactor for lymphotropic strains of human immunodeficiency virus type 1 and SDF1 inhibits viral entry. Moreover, recent works suggest an important role for SDF1 in metastasis progression and autoimmune diseases such as rheumatoid arthritis. To understand the molecular mechanisms that regulate SDF1 expression, we have cloned and functionally analysed its 5' flanking regulatory region. An SDF1-promoter luciferase construct showed high levels of reporter gene activity in transient transfection experiments. DNase I footprinting analysis revealed that the proximal promoter was occupied by six putative Sp1-binding motifs. Binding of Sp1 to the promoter was confirmed by electrophoretic mobility shift assay, and its importance in SDF1 gene expression verified by in vitro mutagenesis. Particularly, mutation of an Sp1 motif located between -57 and -39 upstream of the main transcription start-site resulted in a marked reduction in promoter activity. It has been shown that the SDF1 expression could be induced by mitogenic stimuli, X-ray radiation or treatment with IL1beta, depending on cell environment. We have analysed the effect of these stimuli on SDF1 promoter transactivation in three different cell lines. Phorbol myristated acetate plus ionomycin increased promoter activity in U373 and LC5 but repressed it in MS5 cells. On the contrary, gamma irradiation promoted SDF1 transcription in MS5 cells but not in the other cell lines. Interferon-gamma acted as a transcriptional repressor in U373 and LC5 but not in MS5 cells. Finally, IL1beta functions as mild activator only in U373 cells. The present study demonstrates that these stimuli mediate SDF1 production through promoter activation in a cell-specific manner.
15669946 Prescriptions for cyclooxygenase-2 inhibitors and other nonsteroidal anti-inflammatory age 2005 Jan OBJECTIVE: To determine whether race is a predictor of a patient's likelihood of being prescribed selective cyclooxygenase-2 inhibitors (COX-2s) versus other nonsteroidal anti-inflammatory agents (NSAIDs) in Medicaid managed care plans (MCO). DESIGN: All medical and prescription claims for Medicaid MCO enrollees receiving at least one prescription for a COX-2 or NSAID between January 2000 and June 2002 were retrieved. Selected for study were adults claiming at least one COX-2 prescription or NSAID prescription with a minimum 30 days of supply after June 2000; having 60 total days of supply or more over the study period was also required for study inclusion. The probability of being prescribed a COX-2 was estimated as a logistic function of patient age, gender, race, city/suburban/rural residence, and history of rheumatoid arthritis, osteoarthritis, chronic back pain, acute pains, gastrointestinal problems, use of anticoagulants or corticosteroids, and comorbidities. RESULTS: Of the 16,868 enrollees meeting the selection criteria, 4,005 (24%) were prescribed a COX-2 and 12,863 another NSAID. Half of those studied were African American, three-quarters were female, and a third were 50-64 years old. After adjusting for confounders, odds of a COX-2 prescription were a third less for African Americans and other races compared to Caucasians (OR, 0.67; 95% confidence intervals, 0.62-0.73). CONCLUSION: Patient race is a significant predictor of COX-2 prescriptions in the Medicaid population, even after adjusting for other demographic and clinical variables. Cost to the patient was not a factor, as the patient copayment was 1 US dollar for any prescription.
15647331 Formation, distribution, and elimination of infliximab and anti-infliximab immune complexe 2005 May Infliximab (IFX) is a chimeric IgG1 monoclonal antibody specific for human tumor necrosis factor-alpha that is approved in the United States and Europe for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Approximately 10% of RA and CD patients receiving maintenance treatment with IFX will develop antibodies to IFX. The objective of this study was to develop a model to assess the in vivo formation, distribution, and elimination of immune complexes resulting from a low-level immune response in the presence of the excess concentration of a therapeutic antigen. In this model, cynomolgus monkeys were treated with a single intravenous injection of IFX, followed by injection of either radiolabeled, purified monkey anti-IFX IgG antibody (n = 3, test group) or radiolabeled monkey, nonimmune IgG (n = 3, control group). High-performance liquid chromatography analysis of collected sera revealed a rapid formation of immune complexes comprised of IFX and radiolabeled anti-IFX IgG antibody immune complexes. The terminal half-life of the anti-IFX IgG antibody immune complex was approximately 38 h compared with 86 h for the nonimmune antibody. However, the pharmacokinetic profile of IFX, although slightly lower in concentration over time for the test group, was not notably different relative to the control group. There were no macroscopic or microscopic histological findings in either treatment group. These data confirm that immune complexes between IFX and anti-IFX IgG antibodies can form in vivo and that these immune complexes are eliminated more rapidly than nonimmune antibodies in the presence of excess IFX.
15640830 Expression of aquaporin-5 in and fluid secretion from immortalized human salivary gland du 2005 Mar The aim of the present study was to investigate the possibility that ductal cells, which preferentially survive and/or proliferate in Sjögren's syndrome (SS) salivary glands of patients with SS, could acquire the functional expression of membrane water channel aquaporin-5 (AQP5). Thus, in this study, we demonstrate that an immortalized normal human salivary gland ductal cell (NS-SV-DC) line, lacking the expression of AQP5, acquires AQP5 gene expression in response to treatment with 5-aza-2'-deoxycytidine (5-Aza-CdR), a DNA demethylating agent. Confocal microscopic analysis revealed the localization of AQP5 expression mainly at the apical and lateral sides of the plasma membrane. The expressed AQP5 protein was functionally active because AQP5 expression resulted in a significant increase in the osmotically directed net fluid rate across monolayers of NS-SV-DC cells. By the analysis of bisulfite sequencing of CpG islands in the AQP5 promoter, hypermethylation within the consensus Sp1-binding sites was commonly observed in parental cell clones, whereas demethylation at the CGs, one in the second consensus Sp1 element and the other outside of the third consensus Sp1 element in the AQP5 promoter, was detected in NS-SV-DC cells after treatment with 5-Aza-CdR. By analyzing the luciferase activity of transfected AQP5 promoter vectors, it became evident that demethylation at the CGs cooperatively functions between these two sites to induce AQP5 expression. Our data, therefore, suggest that treatment of ductal cells with 5-Aza-CdR could result in the expression of the AQP5 gene, thereby leading to increased fluid secretion from ductal cells in SS salivary glands.
15882433 Induction of oral tolerance in experimental Sjogren's syndrome autoimmunity. 2005 May Previous studies have showed that immunization with peptides from Ro 60 results in Sjogren's syndrome (SS)-like condition in BALB/c mice. We hypothesized that oral feeding with Ro 60 peptide or Ro 60 would prevent the disease. Four groups (each consisting of 10) of BALB/c mice were used. Group I-III were immunized with Ro 274 peptide. Group IV mice were administered adjuvant only. Group II mice were fed orally with Ro 274 peptide and Group III with Ro 60 for 5 days before immunization. There was a significant reduction in the binding of sera from both Group II and Group III mice to most of the Ro multiple antigenic peptides bound by Group I mice. In Group III mice, salivary flow was maintained above that of the Group I mice (average: 117.5 versus 58.6 microl; t = 2.7; P = 0.02). Salivary infiltrates were drastically decreased in the Ro peptide or Ro 60-fed groups, compared to non-tolerized group. Two of eight mice in Group II and 3/6 mice in Group III had no infiltrates, whereas all eight mice studied in Group I had a significant number of infiltrates. Thus, epitope spreading was prevented, lymphocytic infiltration was blocked and saliva flow was restored by means of oral feeding of either Ro 274 or Ro 60 in this animal model of SS.
16203055 [Immunological abnormalities in myelodysplastic syndromes. Prospective study (series of 40 2005 Oct The association of myelodysplastic syndromes (MDS) with auto-immune diseases and humoral disorders have already been reported. In this prospective study we tried to estimate type and the frequency of immunological associated diseases among patients affected by MDS. PATIENTS-METHODS: In this prospective study, auto-immune disease and humoral immunity disorders were systematically searched during MDS and conversely MDS searched during cytopenia. All MDS secondary to chemotherapy and the children's MDS were excluded. The MDS diagnosis was established according to FAB criteria and patients were classified in two groups A or B according to presence (group A) or not (group B) of dysimmune manifestations. RESULTS: Forty patients(19 males and 21 females, mean age of 56,6 years) with MDS have been enrolled during this period (group A: 20 patients). Associated diseases are following: systemic lupus erythematosus (three), lupus-like syndrome(one), sarcoidisis(one), Sjogrën syndrome(one), polyarthritis (two), chronic liver diseases (three), autoimmune thyroid diseases (two), pyoderma gangrenosum (one), Crohn's disease(one), haemolytic anaemia (one), and pericardial effusion(one). CONCLUSION: A wide spectrum of auto-immune manifestations is frequently reported in myelodysplastic syndromes. Further studies are necessary for discuss the current physiopathological hypothesis with their therapeutic relevance.
15983636 [Efficacy of Carbopol 974P (Siccafluid) in the treatment of severe to moderate keratoconju 2005 Apr OBJECTIVE: To determine efficacy and safety of Carbopol 974P in the treatment of severe to moderate keratoconjunctivitis sicca (KCS) in patients with primary Sjögren's syndrome (SS) not responding to standard treatment with artificial tears. METHODS: 60 patients (57 F, 3 M, mean age 52.5+/-12.0, mean disease duration 12.2+/-7.1 yrs) affected with primary SS diagnosed according to the European Community Study Group criteria were studied. Foregoing medications for SS and artificial tears for KCS have not been changed within 3 and 2 months respectively prior to the study onset. In all cases Carbopol 974P was added because symptoms of KCS were not adequately controlled with traditional lubricants. Schirmer I test, B.U.T. (break up time), rose Bengal-stain, clinical ophthalmological examination (i.e. fluorescein staining, keratis, corneal infiltrates and ulcers) and a questionnaire for dry eye symptoms (range 0-30) were performed at entry (T0) and after 2 (T1) and 12 (T2) weeks. Assessment of global efficacy was obtained by VAS 0-100 at T2 either by patients and by the ophthalmologist. RESULTS: Lachrymal tests significantly improved after 2 and, even more, after 12 weeks. Clinical ophthalmologic picture also ameliorated: a remarkable reduction of fluorescein positive lesions was demonstrated from 71.6% of the cases at T0 to 38.3% at T2. Total score of symptoms (T0: 16.1+/-7.3) dropped to 11.9+/-6.6 (T1) (p=0.000) and then to 6.7+/-5.3 (T2) (p=0.000). Global efficacy expressed by patients and physician was 74.8+/-15.9 and 76.6+/-13.0, respectively. No adverse events (blurred vision, allergy) were reported throughout the study. CONCLUSIONS: Our study seems to demonstrate that addition of Carbopol 974P to the traditional therapeutic armamentarium for moderate to severe KCS is useful and well accepted in patients with primary SS in which management of ocular symptoms is unsatisfactory.
15848146 P2Y2 nucleotide receptor up-regulation in submandibular gland cells from the NOD.B10 mouse 2005 Jun Sjögren's syndrome (SS) is an autoimmune disease that specifically targets exocrine glands, including salivary glands, and results in an impairment of secretory function. P2Y(2) nucleotide receptors for extracellular ATP and UTP are up-regulated in response to stress or injury in a variety of tissues including submandibular glands (SMGs) [Ahn JS, Camden JM, Schrader AM, Redman RS, Turner JT. Reversible regulation of P2Y(2) nucleotide receptor expression in the duct-ligated rat submandibular gland. Am J Physiol Cell Physiol 2000;279:C286-94; Hou M, Malmsjö M, Möller S, Pantev E, Bergdahl A, Zhai X-H, et al. Increase in cardiac P2X(1)- and P2Y(2)-receptor mRNA levels in congestive heart failure. Life Sci 1999;65:1195-206; Kishore BK, Wang Z, Rab H, Haq M, Soleimani M. Upregulation of P2Y(2) purinoceptor during ischemic reperfusion injury (IRI): possible relevance to diuresis of IRI. J Am Soc Nephrol 1998;9:581 (abstract); Koshiba M, Apasov S, Sverdlov V, Chen P, Erb L, Turner JT, et al. Transient up-regulation of P2Y(2) nucleotide receptor mRNA expression is an immediate early gene response in activated thymocytes. Proc Natl Acad Sci U S A 1997;94:831-6; Turner JT, Landon LA, Gibbons SJ, Talamo BR. Salivary gland P2 nucleotide receptors. Crit Rev Oral Biol Med 1999;10:210-24; Seye CI, Gadeau AP, Daret D, Dupuch F, Alzieu P, Capron L, et al. Overexpression of the P2Y(2) purinoceptor in intimal lesions of the rat aorta. Arterioscler Thromb Vasc Biol 1997;17:3602-10; Seye C, Kong Q, Erb L, Garrad RC, Krugh B, Wang M, et al. Functional P2Y(2) nucleotide receptors mediate uridine 5'-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries. Circulation 2002;106:2720-6]. OBJECTIVE: To assess whether P2Y(2) receptor expression is up-regulated in SMGs of the NOD.B10 mouse model of primary SS as compared to SMGs of normal C57BL/6 mice. DESIGN: SMG cells were isolated from normal C57BL/6 and diseased NOD.B10 mice. P2Y(2) receptor mRNA expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization, whereas functional P2Y(2) receptor activity was analyzed by measuring UTP-induced increases in [Ca(2+)](i). RESULTS: In contrast to SMG cells from C57BL/6 mice, SMG cells from 4- to 19-week-old NOD.B10 mice exhibited increased P2Y(2) receptor mRNA localized to both ductal and acinar cell types. The levels of mRNA for other uridine nucleotide receptors, i.e., P2Y(4) and P2Y(6) receptors, showed no significant differences between SMG cells of C57BL/6 and NOD.B10 mice, suggesting that only the P2Y(2) receptor was up-regulated in NOD.B10 mice. Moreover, P2Y(2) receptor activity in SMG cells from NOD.B10 mice increased with age (i.e., disease progression). CONCLUSION: P2Y(2) receptor up-regulation in SMGs is associated with the SS phenotype in NOD.B10 mice, which encourages further attempts to determine the role of this pathway in the development of SS.
15848046 CD4 CD25high regulatory T cells are not impaired in patients with primary Sjögren's syndr 2005 May In animal models of autoimmunity, CD4 CD25high T cells play a key role in the control of the autoimmune process. Few studies have investigated the role of these cells in human autoimmune diseases. We aimed to investigate CD4 CD25high T cells in the peripheral blood of patients with primary Sjogren's syndrome (pSS). The proportion of blood CD4 CD25high T cells was determined by flow cytometry in 21 patients with pSS as determined by the American-European consensus group criteria and two groups of controls (18 patients with lumbar back pain of mechanical origin and 15 healthy blood donors). The suppressive function of CD4 CD25 cells was assessed using co-culture assays. The Vbeta repertoire of CD4 CD25 T cells was examined by flow cytometry. The proportion of CD4 CD25 T cells depended on age in patients and controls. In an age-matched comparison, no significant difference was observed in the proportion of total CD4 CD25low T cells between patients with pSS and controls (P=0.36). In contrast, the pool of CD4 CD25high was significantly increased in patients with pSS (8.5% vs 4.1% in controls, P=0.04). There was a slight but not significant higher proportion of CD4 CD25high cells in patients with a more active disease. CD4 CD25 T cells in patients with pSS effectively suppressed the proliferation of CD4 CD25- autologous responder T cells. The Vbeta repertoire of regulatory T cells from patients with pSS was polyclonal and was not significantly restricted as compared with that in controls. Functional CD4 CD25high regulatory cells are increased in patients with established pSS, through a reactive feedback, despite ongoing autoimmunity. These results suggest that pSS does not occur as a result of reduced level of CD4 CD25high regulatory T cells, nor as a defect of inhibition of proliferation of responder cells.
16891656 Parotid gland biopsy compared with labial biopsy in the diagnosis of patients with primary 2007 Feb OBJECTIVE: To assess the value of the parotid biopsy as a diagnostic tool for primary Sjögren's syndrome (pSS), and to compare the parotid biopsy and the labial biopsy with regard to diagnostic value and biopsy-related morbidity. METHODS: In 15 consecutive patients with pSS and 20 controls, the parotid biopsy was assessed as a diagnostic tool based on the presence of lymphocytic foci, benign lymphoepithelial lesions and lymphoid follicles. These new histological criteria were compared with established diagnostic criteria for the labial biopsy in 35 consecutive patients suspected for pSS who underwent simultaneous biopsies from both sites. In addition, both biopsies were compared for morbidity. RESULTS: The first analysis revealed a focus score of >or=1 or lymphocytic infiltrates (not fulfilling the criterion of a focus score of 1) combined with benign lymphoepithelial lesions as diagnostic criteria for pSS. When comparing the parotid biopsy with the labial biopsy sensitivity and specificity were comparable (sensitivity 78%, specificity 86%). Level of pain was comparable and no loss of motor function was observed. No permanent sensory loss was observed after parotid biopsy, while labial biopsy led to permanent sensory loss in 6% of the patients. Malignant lymphoma was detected in one parotid biopsy by chance, without involvement of the labial salivary gland. CONCLUSION: A parotid biopsy has a diagnostic potential comparable with that of a labial biopsy in the diagnosis of pSS, and may be associated with less morbidity.
16170321 Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumo 2005 Oct Tumor necrosis factor (TNF)-alpha has an important role in the pathogenesis of autoimmune and inflammatory diseases such as rheumatoid and septic arthritis. The biological effects of TNF-alpha are mediated by binding to TNF receptors TNFR1 (also known as P60) or TNFR2 (also known as P80). The pre-ligand assembly domain (PLAD) is a portion of the extracellular region of TNFRs that mediates receptor-chain association essential for signaling. We found that soluble versions of PLAD, especially those derived from P60, block the biochemical effects of TNF-alpha in vitro and potently inhibit arthritis in animal models. Thus, targeting the PLAD may have clinical value in the treatment of human arthritis and other disorders involving receptors of the TNFR superfamily.