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ID PMID Title PublicationDate abstract
21275454 Cost effectiveness of interferon-gamma release assay for tuberculosis screening of rheumat 2010 Dec 1 BACKGROUND: The prevalence of tuberculosis (TB) in rheumatoid arthritis (RA) patients is higher than that in the general population, and RA patients are considered a high-risk group. Currently, TB screening of RA patients receiving immunosuppressive therapy such as tumor necrosis factor-α (TNFα) antagonists is performed by the tuberculin skin test (TST) in Japan. Interferon-gamma release assays (QuantiFERON®-TB Gold In-Tube [QFT] and T-SPOT.TB®) are new alternatives to the TST to diagnose latent TB infection (LTBI) and active TB, and offer higher specificity and no cross-reactivity with Bacillus Calmette-Guérin (BCG) vaccine. We evaluated the cost effectiveness of QFT versus TST in non-BCG-vaccinated and BCG-vaccinated RA patients. METHODS: We constructed a Markov model to evaluate the cost effectiveness of QFT and TST. The target population is a hypothetical cohort of 1000 RA patients, using a societal perspective and the lifetime horizon. All costs and clinical benefits were discounted at a fixed annual rate of 3%. RESULTS: In base-case analysis, the QFT strategy was the most cost effective ($US1044.52; 23.03499 quality-adjusted life-years [QALYs]) compared with the TST strategy for non-BCG-vaccinated RA patients ($US1824.61; 22.98153 QALYs) and for BCG-vaccinated RA patients ($US2096.34; 22.98153 QALYs) [year 2009 values]. The incidence of TB in RA patients with TNFα antagonist therapy influenced the cost effectiveness. When the incidence of TB in RA patients with TNFα antagonist therapy is under 0.00066, the TST strategy is more cost effective than the QFT strategy. CONCLUSIONS: QFT screening is more effective and less costly than the TST for both BCG-vaccinated and non-BCG-vaccinated RA patients prior to TNFα antagonist therapy in Japan. These findings may be applicable to other countries when choosing optimal LTBI screening of RA patients.
20610799 Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signalin 2010 Oct LRP1 is a type-1 transmembrane receptor that mediates the endocytosis of diverse ligands. LRP1 β-chain proteolysis results in release of sLRP1 that is present in human plasma. In this study, we show that LPS and IFN-γ induce shedding of LRP1 from RAW 264.7 cells and BMMs in vitro. ADAM17 was principally responsible for the increase in LRP1 shedding. sLRP1 was also increased in vivo in mouse plasma following injection of LPS and in plasma from human patients with RA or SLE. sLRP1, which was purified from human plasma, and full-length LRP1, purified from mouse liver, activated cell signaling when added to cultures of RAW 264.7 cells and BMMs. Robust activation of p38 MAPK and JNK was observed. The IKK-NF-κB pathway was transiently activated. Proteins that bind to the ligand-binding clusters in LRP1 failed to inhibit sLRP1-initiated cell signaling, however an antibody that targets the sLRP1 N terminus was effective. sLRP1 induced expression of regulatory cytokines by RAW 264.7 cells, including TNF-α, MCP-1/CCL2, and IL-10. These results demonstrate that sLRP1 is generated in inflammation and may regulate inflammation by its effects on macrophage physiology.
19847310 An eight-gene blood expression profile predicts the response to infliximab in rheumatoid a 2009 Oct 22 BACKGROUND: TNF alpha blockade agents like infliximab are actually the treatment of choice for those rheumatoid arthritis (RA) patients who fail standard therapy. However, a considerable percentage of anti-TNF alpha treated patients do not show a significant clinical response. Given that new therapies for treatment of RA have been recently approved, there is a pressing need to find a system that reliably predicts treatment response. We hypothesized that the analysis of whole blood gene expression profiles of RA patients could be used to build a robust predictor to infliximab therapy. METHODS AND FINDINGS: We performed microarray gene expression analysis on whole blood RNA samples from RA patients starting infliximab therapy (n = 44). The clinical response to infliximab was determined at week 14 using the EULAR criteria. Blood cell populations were determined using flow cytometry at baseline, week 2 and week 14 of treatment. Using complete cross-validation and repeated random sampling we identified a robust 8-gene predictor model (96.6% Leave One Out prediction accuracy, P = 0.0001). Applying this model to an independent validation set of RA patients, we estimated an 85.7% prediction accuracy (75-100%, 95% CI). In parallel, we also observed a significantly higher number of CD4+CD25+ cells (i.e. regulatory T cells) in the responder group compared to the non responder group at baseline (P = 0.0009). CONCLUSIONS: The present 8-gene model obtained from whole blood expression efficiently predicts response to infliximab in RA patients. The application of the present system in the clinical setting could assist the clinician in the selection of the optimal treatment strategy in RA.
19589888 Soluble receptor for advanced glycation end products: a new biomarker in diagnosis and pro 2009 Oct The formation of advanced glycation end products (AGEs) is a result of the non-enzymatic reaction between sugars and free amino groups of proteins. AGEs, through interacting with their specific receptor for AGEs (RAGE), result in activation of pro-inflammatory states and are involved in numerous pathologic situations. The soluble form of RAGE (sRAGE) is able to act as a decoy to avoid interaction of RAGE with its pro-inflammatory ligands (AGEs, HMGB1, S100 proteins). sRAGE levels have been found to be decreased in chronic inflammatory diseases including atherosclerosis, diabetes, renal failure and the aging process. The use of measuring circulating sRAGEs may prove to be a valuable vascular biomarker and in this review, we describe the implications of sRAGE in inflammation and propose that this molecule may represent a future therapeutic target in chronic inflammatory diseases.
20457283 Immunological profile in primary Sjögren syndrome: clinical significance, prognosis and l 2010 Jul OBJECTIVE: To study evolution of pSS immunological profile, impact on pSS activity and the long-term evolution of patients with atypical auto-antibodies in a bicentric cohort of patients with pSS (n=445, mean age 53.6+/-14years, mean follow-up 76.1+/-51months). RESULTS: 212 patients were SSA positive and 131 were both SSA and SSB positive. During follow-up, SSA antibodies disappear in 8 patients; 2 of them exhibit new systemic complications of pSS. 68 patients had cryoglobulinemia. 52 patients had other anti-nuclear antibodies (ANA) specificities: anti-RNP (n=12), anti-centromere (n=14), anti-DNA native (n=19), anti-Scl70 (n=3), anti-JO1 (n=3), anti-Sm (n=3) and anti-histone (n=1). Fourteen patients developed ANA-associated auto-immune disease during the follow-up: 5 polymyositis (mean apparition delay 78months), 6 systemic lupus erythematosus (mean occurrence delay 77months) and 2 systemic sclerosis (mean occurrence delay 133+/-64months). Among these 14 patients, only three presented atypical-ANA at pSS diagnosis. Cryoglobulinemia and anti-SSA and SSB antibodies at diagnosis were associated with new systemic involvements. IN CONCLUSION: Cryoglobulinemia and SSA/SSB positivity are associated with systemic activity after diagnosis in pSS. Although atypical ANA are found in 12% of the cases, long-term evolution to ANA associated auto-immune diseases concerned patients with active immunological profile and extra-glandular manifestations.
20887520 Bisphosphonate associated osteonecrosis: an unusual case. 2010 Sep The management of bisphosphonate associated osteonecrosis of the jaws (bisphosphonate associated ONJ) is emerging as a significant problem in the field of dentistry and oral and maxillofacial surgery. We present a case of a 55-year-old female taking oral bisphosphonates, steroids and immunosuppressant agents presenting with a life-threatening neck swelling. We discuss management options, as well as recent guidelines for treatment.
20214335 [Effect of fengshiqing on interleukin-4, gamma-interferon and chemotactic factor in rats w 2009 Dec OBJECTIVE: To study the regulatory effect of fengshiqing (FSQ) on interleukin 4 (IL-4), gamma-interferon (gamma-IFN), macrophage inflammatory protein 1alpha (MIP-1alpha) and collagen type II antibody (C II Ab) in serum and supernatant of synovial cell culture of rat with rheumatoid arthritis (RA), to explore the mechanism of action of clearing-heat and activating blood method for treatment of RA. METHODS: RA rat model was induced by C II Ab combined with Freund's complete adjuvant, and the levels of IL-4, gamma-IFN, MIP-1alpha and C II Ab in serum and supernatant of synovial cell were detected by ELISA. RESULTS: As compared with the normal group, serum level of C II Ab in the model group was significantly higher (P < 0.01), serum and supernatant contents of IL-4 on the 14th and 28th day of modeling were lower and those of gamma-IFN and MIP-1alpha were higher, the difference showed statistical significance (P < 0.05 or P < 0.01). After being treated with FSQ and IL-4 contents in serum and supernatant as well as MIP-1alpha in supernatant restored on the 14th day (P < 0.05 or P < 0.01), while all the indexes restored on the 28th day. CONCLUSION: FSQ could evidently up-regulate the level of IL-4 and down-regulate that of MIP-1alpha in serum and local synovial membrane in RA rats, and shows a suppressive trend of gamma-IFN, so as to maintain the Th1/Th2 equilibrium, suppress the cellular and humoral immune response in the local synovial membrane, and alleviate the chronic changes of arthritis, synovitis and vasculitis.
19147181 Sarcoidosis appearing during anti-tumor necrosis factor alpha therapy: a new "class effect 2010 Feb OBJECTIVES: To report 2 cases of sarcoidosis that developed during treatment with tumor necrosis factor alpha (TNFalpha) antagonists, infliximab and adalimumab, used for inflammatory rheumatic disease and to review previously reported cases. METHODS: We describe 2 patients, the first with psoriatic arthritis, the second with rheumatoid arthritis, who developed noncaseating granulomas of the lungs consistent with sarcoidosis while being treated with anti-TNFalpha drugs. A retrospective review of the literature was performed using the PubMed database. RESULTS: In our patients sarcoidosis developed after 2 years of continuous treatment with infliximab and adalimumab. Both patients presented with low-grade fever, chest pain, and dyspnea. The diagnosis of sarcoidosis was established by the typical well-formed noncaseating granulomas on transbronchial biopsy, after excluding all other granulomatous conditions. Following withdrawal of anti-TNFalpha agents and a brief course of steroids, the clinical picture resolved. Thirteen additional cases of sarcoidosis that developed after anti-TNFalpha treatment have been reported, and in 9 of these the causative agent was etanercept. CONCLUSIONS: The development of sarcoidosis during treatment with TNFalpha antagonists represents a rare and paradoxical adverse event. The occurrence of sarcoidosis with all 3 available agents suggests a new "class effect" probably linked to a cytokine disequilibrium in patients receiving anti-TNFalpha treatment.
20002448 Flk-1+ mesenchymal stem cells aggravate collagen-induced arthritis by up-regulating interl 2010 Mar The immunomodulatory ability of mesenchymal stem cells (MSCs) may be used to develop therapies for autoimmune diseases. Flk-1(+) MSCs are a population of MSCs with defined phenotype and their safety has been evaluated in Phase 1 clinical trials. We designed this study to evaluate whether Flk-1(+) MSCs conferred a therapeutic effect on collagen-induced arthritis (CIA), an animal model of rheumatic arthritis, and to explore the underlying mechanisms. Flk-1(+) MSCs, 1-2 x 10(6), were injected into CIA mice on either day 0 or day 21. The clinical course of arthritis was monitored. Serum cytokine profile was determined by cytometric bead array kit or enzyme-linked immunosorbent assay. Flk-1(+) MSCs and splenocytes co-culture was conducted to explore the underlying mechanisms. Flk-1(+) MSCs did not confer therapeutic benefits. Clinical symptom scores and histological evaluation suggested aggravation of arthritis in mice treated with MSCs at day 21. Serum cytokine profile analysis showed marked interleukin (IL)-6 secretion immediately after MSC administration. Results of in vitro culture of splenocytes confirmed that the addition of Flk-1(+) MSCs promoted splenocyte proliferation and increased IL-6 and IL-17 secretion. Moreover, splenocyte proliferation was also enhanced in mice treated with MSCs at day 21. Accordingly, MSCs at low concentrations were found to promote lipopolysaccharide-primed splenocytes proliferation in an in vitro co-culture system. We propose that Flk-1(+) MSCs aggravate arthritis in CIA model by at least up-regulating secretion of IL-6, which favours Th17 differentiation. When Flk-1(+) MSCs are used for patients, we should be cautious about subjects with rheumatoid arthritis.
19474226 Patients' views of a multimedia resource featuring experiences of rheumatoid arthritis: pi 2009 Jun The Internet is used increasingly for health information and patient support. Online health information users gravitate to websites that feature patient experiences. However, experiential accounts may mislead if they are unrepresentative. The quality of experiential websites remains unexplored. Obtaining user feedback online can be problematic. This study explored views of www.dipex.org/arthritis, a website based on, and featuring, clips from interviews about experiences of rheumatoid arthritis (RA). Thirty-seven rheumatology outpatients viewed the site and completed a questionnaire. Overall the website appeared relevant and understandable and could be recommended. Comments highlighted the need to update the site regularly with experiences of new treatments; to ensure positive and negative experiences are balanced; and to ensure information is easy to find. The site has since been updated with new experiences and rewritten summaries that present a better balance of experiences. Changes were incorporated in an entire site redesign launched in autumn 2008 as www.healthtalkonline.org.
20565245 Familial case of Blau syndrome associated with a CARD15/NOD2 mutation. 2010 Sep PURPOSE: Blau syndrome is a rare autosomal dominant disorder characterized by early onset granulomatous arthritis, uveitis, skin rash and camptodactyly. We report a familial case of Blau syndrome associated with a CARD15/NOD2 mutation. METHODS: PCR amplification and automated DNA sequencing of the complete CARD15/NOD2 coding sequence was performed. RESULTS: Molecular analysis in affected subjects disclosed a heterozygous c.1147G>C point mutation in CARD15/NOD2 exon 4, that predicts a p.E383K change at the protein level. CONCLUSIONS: Blau syndrome should be considered in the differential diagnosis of childhood uveitis and the genetic analysis of the CARD15/NOD2 gene is helpful in the diagnosis.
20039407 Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. 2010 Jan OBJECTIVE: Dkk-1 is an inhibitory molecule that regulates the Wnt pathway, which controls osteoblastogenesis. This study was undertaken to explore the potential role of Dkk-1 in ankylosing spondylitis (AS), a prototypical bone-forming disease. METHODS: Serum Dkk-1 levels were measured in 45 patients with AS, 45 patients with rheumatoid arthritis (RA), 15 patients with psoriatic arthritis (PsA), and 50 healthy subjects by sandwich enzyme-linked immunosorbent assay (ELISA). A functional ELISA was used to assess the binding of Dkk-1 to its receptor (low-density lipoprotein receptor-related protein 6). Furthermore, we studied the effect of sera from patients with AS and healthy subjects on the activity of the Wnt pathway in the Jurkat T cell model, with and without a neutralizing anti-Dkk-1 monoclonal antibody, by Western immunoblotting. RESULTS: Serum Dkk-1 levels were significantly increased in patients with AS (mean +/- SEM 2,730 +/- 135.1 pg/ml) as compared with normal subjects (P = 0.040), patients with RA (P = 0.020), and patients with PsA (P = 0.049). Patients with AS receiving anti-tumor necrosis factor alpha (anti-TNFalpha) treatment had significantly higher serum Dkk-1 levels than patients with AS not receiving such treatment (P = 0.007). Patients with AS studied serially prior to and following anti-TNFalpha administration exhibited a significant increase in serum Dkk-1 levels (P = 0.020), in contrast to patients with RA, who exhibited a dramatic decrease (P < 0.001). Jurkat cells treated with serum from AS patients exhibited increased Wnt signaling compared with cells treated with control serum. In that system, Dkk-1 blockade significantly enhanced Wnt signaling in control serum-treated, but not AS serum-treated, Jurkat T cells. CONCLUSION: Our findings indicate that in patients with AS, circulating bone formation-promoting factors functionally prevail. This can be at least partially attributed to decreased Dkk-1-mediated inhibition.
19786405 Correlation between range of motion and implant fracture: a 5 year follow-up of 72 joints 2009 Dec Eighteen out of 18 rheumatoid patients (at one centre of a two-centre 30 patient study previously reported) with a mean age of 56 years, and 72/72 operated joints were randomized to Avanta/Sutter or Swanson MCP prostheses and followed for 5 years. Both ulnar deviation and extension lag were improved already at 6 weeks and remained improved at 5 years. The Avanta prosthesis had a better range of motion (ROM) than the Swanson. Six of nine patients with Avanta/Sutter implants had at least one implant fracture compared to 1/9 patients with the Swanson implant (P = 0.05) but fracture did not change the outcome subjectively. The ROM at 3 months correlated with the occurrence of an implant fracture at 5 years and a greater early ROM may be related to implant fracture. At 5 years patients remained satisfied and the deformities remained corrected.
20553683 Subclinical peripheral arterial disease in rheumatoid arthritis. 2010 Sep OBJECTIVE: Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis in the carotid arteries, but little is known about the magnitude of this process in peripheral arteries. Assessing preclinical atherosclerosis in both arterial beds in RA might provide additional prognostic value during risk stratification for primary prevention. Therefore in the present structural study we examined femoral versus carotid subclinical atherosclerosis in RA and controls. METHODS: Intima-media thickness (IMT) and atheromatous plaque presence and vulnerability in femoral versus carotid arteries were examined in 80 RA patients without overt cardiovascular disease or diabetes and 80 controls matched 1:1 for age, gender and traditional cardiovascular disease risk factors. RESULTS: Femoral IMT and plaque prevalence were increased in RA than controls (p=0.001 and 0.008, respectively). These increases remained significant after adjustment for potentially confounding factors that differed between groups, such as C-reactive protein and HDL-cholesterol serum levels, and statin use. Femoral plaque vulnerability did not differ between RA and controls. The presence of RA was found to be an independent predictor of increased femoral IMT (p=0.004), after adjustment for traditional cardiovascular risk factors, C-reactive protein and treatment with angiotensin converting enzyme inhibitors and statins. Femoral plaques were less frequent than carotid plaques in RA patients (22.5% vs 45.0% respectively, p=0.003) and in contrast to carotid plaques were independent of age and glucose levels. CONCLUSIONS: Subclinical peripheral atherosclerosis in RA is more advanced than in controls. Prospective studies are required to confirm that RA is an independent risk factor for peripheral arterial disease.
19382999 Rituximab-induced vasculitis: A case report and review of the medical published work. 2009 May Rituximab is an anti-CD20 chimeric murine/human monoclonal antibody mainly used in the treatment of patients with a cutaneous lymphoid malignancy. Among the side-effects associated with rituximab administration, vasculitis has been rarely reported. There are two reported cases in the English language medical published work. We describe a 38-year-old Korean man with cutaneous vasculitis occurring 1 day after rituximab administration.
20079608 Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 express 2010 Aug The aggressive phenotype of RA synovial fibroblasts (RASF) is characterised by the increased expression of matrix metalloproteinase (MMP)-1 as well as the small ubiquitin like modifier (SUMO)-1 and decreased expression of SUMO-specific protease SENP1. Since we showed an increased activity of acetyltransferases in this autoimmune disease, we wanted to analyze whether this affects the expression of MMP-1 and can be reversed by the reconstitution of SENP1. In RASF, the acetylation of histone H4 was significantly increased in the distal region of the MMP-1 promoter by 274 +/- 36% compared to OASF. Most interestingly, overexpression of SENP1 in RASF decreased acetylation specifically in this region by 51 +/- 0.5% and globally by 73 +/- 11%. Furthermore, the overexpression of SENP1 resulted in a downregulation of MMP-1 at both the mRNA (58 +/- 7%) and protein levels (28 +/- 6%), significantly reduced the invasiveness of RASF (from 34 +/- 9% to 2 +/- 2%) and led to an accumulation of histone deacetylase 4 (HDAC4) on the MMP-1 promoter (197 +/- 36%). Interestingly, SENP1 failed to modulate the expression of MMP-1 in the cells silenced for HDAC4. This is the first study linking the SUMOylation pathway and the production of MMP-1 to an epigenetic control mechanism mediated through histone acetylation which has a functional consequence for the invasiveness of RASF.
20686129 Mice producing less reactive oxygen species are relatively resistant to collagen glycopept 2010 Sep 1 The bottleneck for the induction of collagen-induced arthritis in mice is the recognition of immunodominant type II collagen (CII) peptide (CII259-273) bound to the MHC class II molecule A(q). We have shown previously that the posttranslationally glycosylated lysine at position 264 in this epitope is of great importance for T cell recognition and tolerance induction to CII as well as for arthritis development. The Ncf1 gene, controlling oxidative burst, has been shown to play an important role for immune tolerance to CII. To investigate the effect of oxidation on the efficiency of immune-specific vaccination with MHC class II/glycosylated-CII peptide complexes, we used Ncf1 mutated mice. We demonstrate that normal reactive oxygen species (ROS) levels contribute to the establishment of tolerance and arthritis protection, because only mice with a functional oxidative burst were completely protected from arthritis after administration of the glycosylated CII259-273 peptide in complex with MHC class II. Transfer of T cells from vaccinated mice with functional Ncf1 protein resulted in strong suppression of clinical signs of arthritis in B10.Q mice, whereas the Ncf1 mutated mice as recipients had a weaker suppressive effect, suggesting that ROS modified the secondary rather than the primary immune response. A milder but still significant effect was also observed in ROS deficient mice. During the primary vaccination response, regulatory T cells, upregulation of negative costimulatory molecules, and increased production of anti-inflammatory versus proinflammatory cytokines in both Ncf1 mutated and wild type B10.Q mice was observed, which could explain the vaccination effect independent of ROS.
20578590 [A review of the effects of prolactin hormone and cytokine on the development and pathogen 2010 May Prolactin (PRL) is not only a pituitary hormone with important role in the reproduction but it also acts as a cytokine involved in the immune response. Prolactin is produced by many immune system cells that express the prolactin receptor (PRL-R). PRL is then able to affect local microenvironment of the immune system organs and contribute to maturation as well as functioning of the immune system cells. The role of PRL in the immune reactions is stimulating; its presence significantly increases the ability of the immune cells to proliferate and produce cytokines such as TNF-alpha, IFN-gamma, IL-12, IL-1 beta. This effect results from activation of a number of intracellular pathways (Jak2/STAT, Ras/Raf/MAPK etc.) and activation of the genes linked to apoptosis and proliferation (Bcl-XL, Bcl-2, pim, XIAP) or transcription factors (IRF-1). Interestingly, PRL itself is unable to initiate an immune reaction; it is more a factor maintaining balance within immune reactions, contra-regulatory to glucocorticoids, which effect is manifested under critical circumstances of physical or psychological stress. Intensified immunosuppression during stress, combined with a lack of prolactin, has surprisingly been identified during experiments on mice and is also found in human medicine. On the other hand, increased prolactin serum levels were described in several systemic as well as organ-specific autoimmune diseases. PRL levels elevation in these diseases might result from several factors: an increased release of prolactin from the anterior pituitary due to inflammatory cytokines or reduced production of suppressive dopamine, or, alternatively, an increased production of prolactin in immune system cells. In some of these diseases, such as celiac disease and systemic lupus erythematosus (SLE), the PRL level correlates with the disease activity. This supports the hypothesis that PRL oversupply shifts the balance in the immune response towards higher activity of the immune system cells and initiation of the immune reaction. For example, in SLE, prolactin prolongs the life cycle of autoreactive B-lymphocytes and their ability to produce pathogenic autoantibodies. Further research into the effects of PRL and monitoring of patients with hyperprolactinaemia and autoimmune diseases will provide guidance on how to best utilize the possibly so far hidden prolactin potential. It is questionable whether pharmacotherapy could be used to decrease serum PRL levels in the treatment ofautoimmune diseases. However, the currently running studies suggest it might be possible to use PRL level detection as a marker of a disease activity.
19800199 Matrix metalloproteinase and G protein coupled receptors: co-conspirators in the pathogene 2009 Nov Similarities in the pathologies of autoimmune diseases and cancer have been noted for at least 30 years. Inflammatory cytokines and growth factors mediate cell proliferation, and proteinases, especially the collagenase, Matrix Metalloproteinase-1 (MMP-1), contribute to disease progression by remodeling the extracellular matrix and modulating the microenvironment. This review focuses on two cancers (melanoma and breast) and on the autoimmune disorder, rheumatoid arthritis (RA), and discusses the activated stromal cells found in these diseases. MMP-1 was originally thought to function only to degrade interstitial collagens, but recent studies have revealed novel roles for MMP-1 involving the G protein-coupled receptors: the chemokine receptor, CXCR-4, and Protease Activated Receptor-1 (PAR-1). Cooperativity between MMP-1 and CXCR4/SDF-1 signaling influences the behavior of activated fibroblasts in both RA and cancer. Further, MMP-1 is a vital part of an autocrine/paracrine MMP-1/PAR-1 signal transduction axis, a function that amplifies its potential to remodel the matrix and to modify cell behavior. Finally, new therapeutic agents directed at MMP-1 and G protein-coupled receptors are emerging. Even though these agents are more specific in their targets than past therapies, these targets are often shared between RA and cancer, underscoring fundamental similarities between autoimmune disorders and some cancers.
19333946 Treatment of experimental arthritis by inducing immune tolerance with human adipose-derive 2009 Apr OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose-derived MSCs (AD-MSCs). METHODS: DBA/1 mice with collagen-induced arthritis were treated with human AD-MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self-reactive Th1 cells were also determined. RESULTS: Systemic infusion of human AD-MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses. Human AD-MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin-10 in lymph nodes and joints. Human AD-MSCs also induced de novo generation of antigen-specific CD4+CD25+FoxP3+ Treg cells with the capacity to suppress self-reactive T effector responses. CONCLUSION: Human AD-MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell-based therapy for RA.