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ID PMID Title PublicationDate abstract
16870089 Identification of health problems in patients with acute inflammatory arthritis, using the 2006 May OBJECTIVES: To identify the most common health problems experienced by patients with acute inflammatory arthritis using the International Classification of Functioning, Disability and Health (ICF), and to provide empirical data for the development of an ICF Core Set for acute inflammatory arthritis. METHODS: Cross-sectional survey of patients with acute inflammatory arthritis of two or more joints requiring admission to an acute hospital. The second level categories of the ICF were used to collect information on patients' health problems. Relative frequencies of impairments, limitations and restrictions in the study population were reported for the ICF components Body Functions, Body Structures, and Activities and Participations. For the component Environmental Factors absolute and relative frequencies of perceived barriers or facilitators were reported. RESULTS: In total, 130 patients were included in the survey. The mean age of the population was 59.9 years (median age 63.0 years), 75% of the patients were female. Most had rheumatoid arthritis (57%) or early inflammatory polyarthritis (22%). Fifty-four second-level ICF categories had a prevalence of 30% or more: 3 (8%) belonged to the component Body Structures and 10 (13%) to the component Body Functions. Most categories were identified in the components Activities and Participation (19; 23%) and Environmental Factors (22; 56%). CONCLUSION: Patients with acute inflammatory arthritis can be well described by ICF categories and components. This study is the first step towards the development of an ICF Core Set for patients with acute inflammatory arthritis.
17994628 Glycosylation profiling of immunoglobulin G (IgG) subclasses from human serum. 2007 Nov All four subclasses of human serum IgG contain a single N-glycosylation site in the constant region of their heavy chain, which is occupied by biantennary, largely core-fucosylated and partially truncated oligosaccharides, that may carry a bisecting N-acetylglucosamine and sialic acid residues. IgG glycosylation has been shown to be altered under various physiological and pathological circumstances. IgG N-glycan profiles vary with age, and galactosylation for example is enhanced during pregnancy. Several diseases including rheumatoid arthritis are associated with a reduction in galactosylation of the IgG N-glycans. Here, we describe a robust method for the isolation of IgG subclasses using protein A (binds IgG1, IgG2, and IgG4) and protein G (binds additionally IgG3) at the 96-well plate level, which is suitable for automation. Isolated IgGs were digested with trypsin, and obtained glycopeptides were analyzed by nano-LC-MS. Glycopeptides were characterized by CID as well as electron transfer dissociation (ETD). The method provided glycosylation profiles for IgG1, IgG2, IgG3, and IgG4 and revealed distinct differences in N-glycosylation between the four IgG subclasses. The changes in galactosylation associated with rheumatoid arthritis could readily be monitored. This method is suitable for the subclass-specific analysis of IgG glycosylation from clinical samples.
17299446 Drug insight: the mechanism of action of rituximab in autoimmune disease--the immune compl 2007 Feb Inflammatory responses to cell-associated or tissue-associated immune complexes are key elements in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and immune thrombocytopenic purpura. Effector cells, such as monocytes, macrophages and neutrophils, bind immune complexes in a process mediated by Fcgamma receptors, and these cells then initiate inflammatory reactions that lead to tissue destruction. Rituximab is an anti-CD20 monoclonal antibody that suppresses inflammation effectively in autoimmune diseases. It was initially approved by the FDA for the treatment of B-cell lymphomas and later for rheumatoid arthritis refractory to anti-tumor necrosis factor therapies. Rituximab is hypothesized to suppress disease injury in autoimmune diseases by promoting rapid and long-term elimination of circulating and possibly lymphoid-tissue-associated B cells. We suggest, however, that a different mechanism may underlie much of the therapeutic action of rituximab in autoimmune diseases: binding of tens of thousands of rituximab-IgG molecules to B cells generates decoy sacrificial cellular immune complexes that efficiently attract and bind Fcgamma receptor-expressing effector cells, which diminishes recruitment of these effector cells at sites of immune complex deposition and, therefore, reduces inflammation and tissue damage.
17187508 Pharmacogenetic study of methylenetetrahydrofolate reductase and thymidylate synthase in J 2007 Jan OBJECTIVES: We investigated the four polymorphisms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS) genes that are related to the pharmacologically active sites of methotrexate for the treatment of rheumatoid arthritis in 102 healthy Japanese adults and assessed the possibility of ethnic and gender differences. METHODS: Polymorphisms of MTHFR C677T, A1298C, the two or three 28-bp tandem repeats in the TYMS 5'-untranslated regions (UTR), and the 6-bp deletion/insertion in the TYMS 3'-UTR were measured using polymerase chain reaction with restriction fragment length polymorphism method. Published data on allelic frequencies by ethnic group and gender were collected from Medline. RESULTS: Allelic frequencies in healthy Japanese adults were: MTHFR 677T allele 41%, MTHFR 1298C allele 22%, TYMS 5'-UTR 3R allele 84%, and TYMS 3'-UTR-6-bp allele 59%. Significant differences were found in the distribution of MTHFR C677T between black and Japanese populations, of TYMS 5'-UTR alleles between Caucasian or black and Japanese populations, and of TYMS 3'-UTR alleles between Caucasian and Japanese populations (p < 0.001). Moreover, a gender difference was found in TYMS 3'-UTR allelic frequency in Japanese (p = 0.015). CONCLUSION: Ethnic and gender variations in the distribution of these allelic frequencies may associate with the difference in the effects of methotrexate in rheumatoid arthritis patients.
16762152 Leflunomide in rheumatoid arthritis in daily practice: treatment discontinuation rates in 2006 Mar OBJECTIVE: To evaluate the treatment discontinuation rate of leflunomide in rheumatoid arthritis (RA) in comparison with the discontinuation of other disease modifying anti-rheumatic drugs (DMARDs), in daily practice, in a single center and during the same period of time. STUDY DESIGN: 3-year, retrospective, monocenter. PATIENTS: RA patients for whom leflunomide or another DMARD was initiated between 1998 and 2001 (several DMARDs could be initiated for a given patient during this period). Collected data: For each patient, demographic and disease data. For each treatment course, date of initiation, if relevant date of discontinuation and reason for discontinuation. ANALYSIS: Percentage of patients discontinuing treatment over time (life table method; Kaplan-Meier), comparison between leflunomide and the "any other DMARD" or methotrexate groups using the Log-Rank test. RESULTS: During the study period, 515 DMARDs were initiated in 285 patients. Leflunomide was initiated in 161 patients who were older and had a longer disease duration than the other treated patients (59 +/- 13 years and 14 +/- 9 years versus 54 +/- 15 years and 11 +/- 10 years in the leflunomide group and other DMARDs group respectively). Discontinuation rate of leflunomide after 1 year was 56.7%, mainly because of adverse drug reactions (41.6%). The discontinuation rate whatever the reason and for toxicity was higher for leflunomide than for other DMARDs studied. However discontinuation for inefficacy was similar in both groups. CONCLUSION: This study conducted in conditions of daily practice when leflunomide was first available suggests a higher discontinuation rate of leflunomide because of adverse events when compared to other DMARDs.
19578469 The Development of Novel Therapies for Rheumatoid Arthritis. 2008 Jul BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease that affects approximately 0.5 to 1 percent of the adults worldwide and commonly results in joint destruction and significant impairment in the quality of life. RA is considered as an autoimmune disease with unknown etiology. Many pathogenic pathways of RA have been revealed recently, which led to development of various novel therapies. OBJECTIVE: The current treatments of RA include 4 categories: non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, non-biologic disease-modifying anti-rheumatic drugs (DMARDs) and biologic DMARDs. In this review, we will discuss some of the most recent development in antirheumatic therapies. METHODS: Using SciFinder Scholar and PubMed as main searching tools, we evaluated various newly developed therapies for RA. Under each drug category, emphases are placed on the mode of action, limitation of the drugs and new drug candidates from the patents search. Those well-established therapies will only be reviewed briefly. CONCLUSION: During the past 20 years, most of the development of new therapies is in DMARDs, especially biological DMARDs. With the discovery of new pathways and the application of drug delivery strategies, more growth is anticipated in this research field.
19054824 Effects of Porphyromonas gingivalis on cell cycle progression and apoptosis of primary hum 2009 Dec BACKGROUND: It has been suggested that bacterial infections have a role in the pathogenesis of rheumatoid arthritis (RA). P gingivalis, a Gram-negative, anaerobic rod, is one of the major pathogens associated with periodontal disease. OBJECTIVE: To examine P gingivalis infection and its effects on cell cycle progression and apoptosis of human articular chondrocytes. METHODS: Primary human chondrocytes cultured in monolayers were challenged with P gingivalis. Infection and invasion of P gingivalis into chondrocytes was analysed by scanning electron microscopy, double immunofluorescence and by antibiotic protection and invasion assay. Cell cycle progression of infected chondrocytes was evaluated by flow cytometry. Also, cell apoptosis was visualised by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) of DNA strand breaks and by western blot analysis. RESULTS: Data showed that P gingivalis could adhere and infect primary human chondrocytes. After chondrocyte infection, intracellular localisation of P gingivalis was noted. Flow cytometry analyses demonstrated affected cell cycle progression, with an increase of the G(1) phase and a significant decrease of the G(2) phase after infection. In addition, increased apoptosis of P gingivalis-infected chondrocytes was visualised by TUNEL assay and by upregulation of caspase-3 protein expression. CONCLUSION: These data demonstrate that P gingivalis infects primary human chondrocytes and affects cellular responses, which might contribute to the tissue damage seen in the pathogenesis of rheumatoid arthritis.
21794528 [Is the DAS28 Score the Most Adequate Method to Estimate Activity in Rheumatoid Arthritis? 2008 Sep INTRODUCTION: The DAS28 score has now consolidated as a fundamental variable for the assessment of rheumatoid arthritis activity and is the main parameter used to establish therapeutic decisions in this disease, including the start and change of biologic therapies. OBJECTIVES: We have studied the clinimetric properties of DAS28, including ceiling and floor effects and its behavior in several clinical scenarios. MATERIAL AND METHOD: Individualized study of the variables included in the DAS28 formula along its possible range. Sensitivity analysis of the results of the DAS28 of 4 variables in four theoretical scenarios corresponding to low (DAS28=2.43), fair (DAS28=4.05), high (DAS28=6.32) or very high (DAS28=8.40) clinical activity. RESULTS: Tender joint count (NAD) and erithrosedimentation rate (ESR) have a weight of 35- 40% each on the total DAS28 score, while swollen join count (SJC) and global health assessed by the patient (GH) only contribute with 15% each. As tender joints weights double than swollen joints, in the simulation models having one swollen joint needed just 3 tender joints to get the DAS28 above the non remission level (DAS28>2.6), while having one tender joint needed 5 swollen joints to be above remission. Given its logarithmic calculation in the DAS28 formula, ESR contribution is much higher in its lower range, and thus small variations of ESR in the normal range can influence decisively in the final DAS28 score. CONCLUSIONS: The asymmetric weight of each component in the complex DAS28 formula must be taken into account when interpreting changes in the DAS28 lower range as they influence the estimation of clinical remission and thus can be relevant when taking therapeutic decisions.
21794441 [Reduction in time until first treatment with disease modifying treatment in patients with 2007 Nov OBJECTIVE: To analyze changes in the lag time to first disease modifying antirheumatic drug (DMARD) prescription since onset of symptoms of rheumatoid arthritis (RA) over the last 2 decades in Spain. PATIENTS AND METHOD: Review of medical records of 865 patients diagnosed with RA living in Spain and attended in specialty care settings of the National Health System. The principal variable was the lag time between the onset of symptoms of RA and the date of first DMARD therapy prescription. Analyses were performed by year and five-year periods and differences between groups were assessed by χ(2) test, Student t test and analysis of variance. RESULTS: Sociodemographic and clinical characteristics corresponded to a typical cross-sectional population of patients diagnosed with RA. The median lag time between symptom onset and first DMARD therapy was 14 months (6-36) for the whole group. However, a significant shortening of time to first DMARD was observed over the last two decades (-4.59±0.2 months by year; P<001). Shortening of time to first DMARD was mainly due to a shortening of time to first visit with specialists since onset of symptoms with a smaller decrease in time from first visit to first prescription of a DMARD agent. CONCLUSIONS: A significant shortening in the lag time to first DMARD therapy was observed over the last 2 decades in Spain, being a significant reduction in the time to first visit with a specialists its major cause.
16785717 Beta-glucan derived from zymosan acts as an adjuvant for collagen-induced arthritis. 2006 Collagen-induced arthritis (CIA) is an experimental model of rheumatoid arthritis (RA) and has helped researchers to analyze the pathogenesis of inflammatory joint disease. In classical CIA, Freund's complete adjuvant (FCA), which contains heat-killed Mycobacterium tuberculosis, is used as an adjuvant. In our previous study, we reported that particles of beta-glucan, OX-CA, derived from Candida albicans, acted as a proper adjuvant in the CIA model. In this study, to establish pure beta-glucan as an adjuvant for CIA, we tested a commercially available preparation of Zymosan A (ZYM) and modified its products. beta-Glucan fractions of ZYM were prepared by oxidation with various concentrations of NaClO. The oxidized ZYM (OX-ZYM) was mainly composed of beta-glucan. In this study, we examined its effect as an adjuvant for CIA. DBA/1 mice injected with CII and OX-CA developed arthritis 7-10 days after receiving booster injections; the OX-ZYM fractions induced arthritis with the same time course. 0.01% OX-ZYM (oxidized with a 0.01% NaClO solution) caused arthritis faster than 0.1% OX-ZYM or 0.5% OX-ZYM. In conclusion, beta-glucan derived from ZYM by brief oxidation with NaClO is a suitable adjuvant for a CIA model with anti-CII antibody production.
17119970 Effects of pravastatin in murine collagen-induced arthritis. 2007 May Here we evaluated whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have beneficial effects for collagen-induced arthritis (CIA). DBA/1 mice were immunized with bovine type-II collagen and administered 100 mg/kg of pravastatin interperitoneally. We measured the effects of pravastatin for CIA including infiltration of macrophages at the synovial membrane and production of anti-type-II collagen antibodies and cytokines. Adverse reactions of pravastatin were also measured. The pravastatin-treated mice had delayed onset of CIA compared with the controls. The involvement of inflammatory cells in the synovial membrane and the expression of monocyte chemotactic protein-1 (MCP-1) mRNA in the joint were reduced. Moreover, some cytokines (TNF-alpha, IL-6, IFN-gamma) and MCP-1 levels in the supernatants of spleen cells cultured with pravastatin decreased. Meanwhile, adverse reactions of pravastatin, such as peritonitis, were not detected. Pravastatin may have good prospects for treating some anti-inflammatory effects on human rheumatoid arthritis.
17963168 A recent onset inflammatory polyarthritis register in Spain: factors that predict remissio 2007 Sep OBJECTIVE: To identify baseline variables that predict remission at 1 year in patients with recent onset inflammatory polyarthritis (IP). METHODS: We prospectively studied 167 patients aged >or=16 years with a 4-week to 12-month history of swelling of >or=2 joints. At baseline, no patient had previously received corticosteroids or disease-modifying anti-rheumatic drugs (DMARDs). To adjust for differences in baseline variables associated with the type of treatment given (a surrogate marker of disease severity), we used regression analysis. The classification probability of treatment thus obtained was entered, along with other significant baseline variables, in a second separate regression analysis to identify variables that predicted remission (no swollen joints). RESULTS: Frequency of remission was 50.9% at 1 year. In the first regression analysis, variables associated with treatment with DMARDs or DMARDs and corticosteroids versus corticosteroids alone included age, morning stiffness, swollen joint count (SJC), disease severity according to the patient, and rheumatoid factor (RF) level; the strongest association was for higher SJC. In the second regression analysis, the model that best predicted remission (correct in 70.1% of cases) included age, tender joint count (TJC), erythrocyte sedimentation rate (ESR), RF, total Sharp score, disease severity according to the physician, and the 1987 American Rheumatism Association (ARA) criteria for rheumatoid arthritis (RA); the strongest association was for failure to meet these criteria. The model's sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve were 70.6%, 70.9%, and 75.4%, respectively. CONCLUSION: Although we identified some predictors of remission, no model accurately predicted remission at 1 year in this cohort.
17481560 Time-dependent expression of leukotriene B4 receptors in rat collagen-induced arthritis. 2007 May Leukotriene B4 acts through its receptors, BLT(1) and BLT(2), however, their expression in rheumatoid arthritis is unknown. In this experiment, BLT(1) and BLT(2) mRNA expressions in the synovium of rats with collagen-induced arthritis (CIA) at days 1, 3, 7 and 14 after CIA onset were analyzed by RT-PCR. The expression of two immunological and inflammatory factors, S100A8 and S100A9, in the synovium of the arthritic rats was also determined at the indicated time. At d14, the differential expressions of BLT(1) and BLT(2) in the synovium, spleen, peripheral blood mononuclear cells (PBMC) and thymus of CIA rats were analyzed. The results showed that, in the synovium of the arthritic rats, the BLT(1) mRNA expression increased after CIA onset, reached the highest value between d1 and d3, and declined afterwards while the BLT(2) expression increased with time and reached its peak at d14. Both S100A8 and S100A9 expression reached the peak levels between d1 and d3, and decreased to lower levels between d7 and d14. For the analyzed tissues from CIA rats at d14, BLT(1) mRNA was expressed in the thymus with the highest level, followed by the spleen, PBMC and synovium. BLT(2) mRNA was expressed in the thymus the highest as well, but followed by the synovium, spleen and PBMC. Since BLT(1) and BLT(2) play distinct roles during CIA, this study may provide basis for new therapies targeting BLT(1) and BLT(2), respectively, for the treatment of arthritic inflammation at different stages.
17056575 Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced 2006 Nov 1 TNF-like weak inducer of apoptosis (TWEAK) is a type II membrane protein belonging to the TNF family that regulates apoptotic cell death, cellular proliferation, angiogenesis, and inflammation. However, the role of TWEAK in the pathogenesis of rheumatoid arthritis (RA) remains unclear. In this study, we have investigated the effect of neutralizing anti-TWEAK mAb on the development of collagen-induced arthritis (CIA), a well-established murine model of RA. Administration of anti-TWEAK mAb significantly ameliorated paw swelling, synovial hyperplasia, and infiltration of inflammatory cells. The levels of proinflammatory chemokines such as MCP-1 and MIP-2 in serum and knee joints were reduced by this treatment. Consistently, recombinant TWEAK enhanced the proliferation of MCP-1 and MIP-2 production by synovial cells from CIA mice in vitro. Histological examination also revealed that the treatment with anti-TWEAK mAb suppressed the development of small vessels in synovial tissues. These results indicated anti-inflammatory and antiangiogenic effects of the TWEAK blockade in CIA, which may be also beneficial for the treatment of RA.
18692362 Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-d 2008 Sep The occurrence of other autoimmune diseases in celiac disease families has not been previously reported in a North American population. We investigated the familial aggregation of rheumatoid arthritis (RA), juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA), hypothyroidism, insulin dependent diabetes mellitus (IDDM), and alopecia areata (AA) among individuals in families with celiac disease (CD). Family history information, obtained from questionnaires from the University of California Irvine Celiac Disease study, was reviewed for reports of RA, JRA/JIA, hypothyroidism, IDDM, and AA in celiac disease cases and their first-degree relatives. Reports of disease were compared with prevalence data from the literature and analyzed by calculating the standardized ratio (SR) with 95% confidence limits. We analyzed: (1) subjects with confirmed celiac disease or dermatitis herpetiformis (205 probands and 203 affected first-degree relatives) and (2) first-degree relatives of celiac disease cases (n=1272). We found a significantly increased number of cases, relative to the expected number, of IDDM in both groups and hypothyroidism among subjects with celiac disease. JRA/JIA was increased among first-degree relatives of celiacs. These results indicate that the presence of IDDM within our celiac disease families may be due to shared genetic susceptibility predisposing to these diseases or autoimmune diseases in general.
17910039 Glucocorticoid-induced leucine zipper (GILZ) mediates glucocorticoid action and inhibits i 2008 Apr 15 Cyclooxygenase-2 (COX-2) plays an important role in rheumatoid arthritis and therefore, has been a major target for anti-arthritis therapies. The expression of COX-2 is induced by inflammatory cytokines such as TNF-alpha and IL-1beta, and inhibited by glucocorticoids. However, the molecular mechanisms underlying the anti-inflammatory and immune suppressive actions of glucocorticoids are not well defined. Here we report that glucocorticoid-induced leucine zipper (GILZ) mimics glucocorticoid action and inhibits inflammatory cytokine-induced COX-2 expression in bone marrow mesenchymal stem cells, the cells that have been recently implicated in the pathogenesis and progression of rheumatoid arthritis. Using a retrovirus-mediated gene expression approach we demonstrate that overexpression of GILZ inhibits TNF-alpha and IL-1beta-induced COX-2 mRNA and protein expression, and knockdown of GILZ by shRNA reduces glucocorticoid inhibition of cytokine-induced COX-2 expression. Consistent to these results, overexpression of GILZ also inhibits NF-kappaB-mediated COX-2 promoter activity. Finally, we show that GILZ inhibits COX-2 expression by blocking NF-kappaB nuclear translocation. Our results suggest that GILZ is a key glucocorticoid effect mediator and that GILZ may have therapeutic value for novel anti-inflammation therapies.
17046122 Ulnar subluxation of the extensor tendons in elderly osteoarthritic females: a neglected d 2007 Feb Ulnar subluxation of the extensor digitorum communis tendons at the metacarpophalangeal joints occurs rarely in the absence of rheumatoid disease or a history of trauma. Three elderly women presented with chronic ulnar subluxation of the extensor tendons of spontaneous onset. They did not have rheumatoid arthritis and had suffered no acute injury. Seven extensor tendon relocations were performed. The treatment options for this condition are discussed. Recognition of this condition is important if permanent loss of function and disability is to be avoided.
18422565 Tumour necrosis factor inhibitors in ankylosing spondylitis. 2008 Oct Ankylosing spondylitis (AS) is the most common form of spondyloarthropathy. Non-steroidal anti-inflammatory medications and exercise are used to manage the chronic inflammatory spinal pain and stiffness. Up to 20% of patients have a peripheral inflammatory arthritis, which is treated with standard disease-modifying anti-rheumatic drugs especially sulfasalazine and methotrexate. Patients may also have extra-articular manifestations, such as anterior uveitis, psoriasiform skin lesions and inflammatory bowel disease. Anti-tumour necrosis (TNF) therapy has been used with great success in rheumatoid arthritis. There are now good data of the efficacy of anti-TNF therapies in the short and medium terms in AS. Etanercept, infliximab and adalimumab have been shown in randomized placebo-controlled trials of short duration to significantly reduce disease activity, including pain and stiffness as well as improving function, spinal movement and quality of life. It is hoped that long-term therapy will prevent radiologic progression and ankylosis and studies of long-term efficacy are awaited. Anti-TNF therapies are generally well tolerated in AS. It is important to screen for latent tuberculosis before the commencement of anti-TNF therapy. The side-effect profile of anti-TNF therapies in AS does not appear different from that in rheumatoid arthritis. Currently, treatment with anti-TNF therapy in AS is indicated in established disease with radiographic damage. There is evidence that response to therapy is greater in patients with earlier disease and less damage. Future developments may see this therapy extended to patients with pre-radiographic AS.
17081730 Second-generation peptidomimetic inhibitors of antigen presentation effectively treat auto 2006 Nov Peptidomimetic compounds that bind to major histocompatibility complex class II molecules and are resistant to cathepsins can competitively inhibit the presentation of processed protein antigens. Therefore, compounds that bind to autoimmune disease-associated class II molecules are expected to compete with autoantigens for presentation and thereby interrupt the disease process. The first generation of such competitors developed for rheumatoid arthritis-associated HLA-DR molecules, although resistant to cathepsins, has remained sensitive to plasma proteases, and was thus unlikely to be effective in vivo. We have therefore produced a second generation of compounds that are resistant to cathepsins and stable in plasma while maintaining binding affinity for HLA-DR molecules associated with rheumatoid arthritis and multiple sclerosis. Selected compounds of this series are shown to inhibit antigen presentation in vivo, as well as effectively treat collagen induced arthritis and experimental autoimmune encephalomyelitis in HLA-DR transgenic mouse models.
18178865 MHC class II derived recombinant T cell receptor ligands protect DBA/1LacJ mice from colla 2008 Jan 15 We previously demonstrated the therapeutic effects of MHC class II derived recombinant T cell receptor ligands (RTL), single-chain two domain complexes of the alpha1 and beta1 domains of MHC class II molecules genetically linked with an immunodominant peptide, in experimental autoimmune encephalomyelitis. In the current study, we produced a monomeric murine I-Aq-derived RTL construct covalently linked with bovine collagen type II peptide (bCII257-270) suitable for use in DBA/1LacJ mice that develop collagen-induced arthritis (CIA), an animal model of human rheumatoid arthritis, after immunization with bCII protein in CFA. In this study, we demonstrate that the I-Aq-derived RTLs reduced the incidence of the disease, suppressed the clinical and histological signs of CIA and induced long-term modulation of T cells specific for arthritogenic Ags. Our results showed that the I-Aq/bCII257-270 molecule could systemically reduce proinflammatory IL-17 and IFN-gamma production and significantly increase anti-inflammatory IL-10, IL-13, and FoxP3 gene expression in splenocytes. Moreover, I-Aq/bCII257-270 molecule could also selectively inhibit IL-1beta, IL-6, and IL-23 expression in local joint tissue. This is the first report demonstrating effective prevention of joint inflammation and clinical signs of CIA with an I-Aq-derived RTL, thus supporting the possible clinical use of this approach for treating rheumatoid arthritis in humans.