Toll-like receptor mediated modulation of T cell response by commensal intestinal microbiota as a trigger for autoimmune arthritis

Contains fulltext : 154313.pdf (publisher's version ) (Open Access)In autoimmune diseases, a disturbance of the balance between T helper 17 (Th17) and regulatory T cells (Tregs) is often observed. This disturbed balance is also the case in rheumatoid arthritis (RA). Genetic predisposition to RA confers the presence of several polymorphisms mainly regulating activation of T lymphocytes. However, the presence of susceptibility factors is neither necessary nor sufficient to explain the disease development, emphasizing the importance of environmental factors. Multiple studies have shown that commensal gut microbiota is of great influence on immune homeostasis and can trigger the development of autoimmune diseases by favoring induction of Th17 cells over Tregs. However the mechanism by which intestinal microbiota influences the Th cell balance is not completely understood. Here we review the current evidence supporting the involvement of commensal intestinal microbiota in rheumatoid arthritis, along with a potential role of Toll-like receptors (TLRs) in modulating the relevant Th cell responses to trigger autoimmunity. A better understanding of TLR triggering by intestinal microbiota and subsequent T cell activation might offer new perspectives for manipulating the T cell response in RA patients and may lead to the discovery of new therapeutic targets or even preventive measures

The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models.

Contains fulltext : 48096.pdf (publisher's version ) (Open Access)Interleukin-17 (IL-17) is a T cell cytokine spontaneously produced by cultures of rheumatoid arthritis (RA) synovial membranes. High levels have been detected in the synovial fluid of patients with RA. The trigger for IL-17 is not fully identified; however, IL-23 promotes the production of IL-17 and a strong correlation between IL-15 and IL-17 levels in synovial fluid has been observed. IL-17 is a potent inducer of various cytokines such as tumor necrosis factor (TNF)-alpha, IL-1, and receptor activator of NF-kappaB ligand (RANKL). Additive or even synergistic effects with IL-1 and TNF-alpha in inducing cytokine expression and joint damage have been shown in vitro and in vivo. This review describes the role of IL-17 in the pathogenesis of destructive arthritis with a major focus on studies in vivo in arthritis models. From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process. Moreover, IL-17 has the capacity to induce joint destruction in an IL-1-independent manner and can bypass TNF-dependent arthritis. Anti-IL-17 cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy

Novel therapeutic targets in rheumatoid arthritis

Item does not contain fulltextRheumatoid arthritis (RA) is an autoimmune disease that leads to inflammation and destruction of synovial joints. Despite the broad spectrum of antirheumatic drugs, this heterogeneous disease is still not well controlled in up to 30% of patients. Here, we discuss two pathways that are regarded as interesting novel therapeutic targets in the field of rheumatology: the Janus kinase (JAK) pathway and the T helper-17 (Th17) pathway [including interleukin (IL)-17, IL-21, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF)]. We also review the therapy potential of biologicals and small-molecule inhibitors blocking these pathways. Advances in combination therapy in addition to progress in biomarker screening will help us to further achieve effective and personalized healthcare for patients with RA

ZonMw ETH project 435004504 - Dataset of MIA rat osteoarthritis model treated with testosteron-aledronate microspheres

The aim of this project was to test the possible osteo-inductive properties of a microsphere-based slow release combination treatment, containing testosterone and alendronate, which is injected intra-articular in a mono-iodoacetate (MIA)-induced OA model. Specifically, we aimed to demonstrate a dose dependent increase in bone formation in the subchondral bone of the tibia (measured by microCT) and a subsequent reduction in joint pain (measured by Incapacitance tester). Before OA induction, all 60 rats were subjected to 3 baseline measurements with the Incapacitance tester, the knee joint was scanned with the microCT and blood was drawn. Following these baseline measurements, all rats received an intra-articular injection of MIA to induce OA (t=0). At t=3 days PLGA microspheres containing different amounts of testosterone (5, 15, 50 and 120 ug of testosterone) and a fixed amount of alendronate (7 ug) were injected in the OA joint, control animal received vehicle only (n=12). The effect of the MIA and microsphere injection on joint pain were monitored at t=3, 7, 14, 16, 22, 28 and 36 days with the Incapacitance tester (IT). The effect on bone formation was assessed by microCT at t=21 and 42 day (3 and 6 weeks). And in case effects on bone formation was observed, blood was drawn at t=42 days to measure bone specific biomarkers. At day 42 all animals were euthanized, and joints processed for further histological analysis. This dataset includes an experiment description and files containing (1) pain measurement using IT and (2) bone measurement using micoCT

ZonMw ETH project 435004504 - Dataset of MIA rat osteoarthritis model treated with testosteron-aledronate microspheres

The aim of this project was to test the possible osteo-inductive properties of a microsphere-based slow release combination treatment, containing testosterone and alendronate, which is injected intra-articular in a mono-iodoacetate (MIA)-induced OA model. Specifically, we aimed to demonstrate a dose dependent increase in bone formation in the subchondral bone of the tibia (measured by microCT) and a subsequent reduction in joint pain (measured by Incapacitance tester). Before OA induction, all 60 rats were subjected to 3 baseline measurements with the Incapacitance tester, the knee joint was scanned with the microCT and blood was drawn. Following these baseline measurements, all rats received an intra-articular injection of MIA to induce OA (t=0). At t=3 days PLGA microspheres containing different amounts of testosterone (5, 15, 50 and 120 ug of testosterone) and a fixed amount of alendronate (7 ug) were injected in the OA joint, control animal received vehicle only (n=12). The effect of the MIA and microsphere injection on joint pain were monitored at t=3, 7, 14, 16, 22, 28 and 36 days with the Incapacitance tester (IT). The effect on bone formation was assessed by microCT at t=21 and 42 day (3 and 6 weeks). And in case effects on bone formation was observed, blood was drawn at t=42 days to measure bone specific biomarkers. At day 42 all animals were euthanized, and joints processed for further histological analysis. This dataset includes an experiment description and files containing (1) pain measurement using IT and (2) bone measurement using micoCT

ZonMw ETH project 435004504 - Dataset of MIA rat osteoarthritis model treated with testosteron-aledronate microspheres

The aim of this project was to test the possible osteo-inductive properties of a microsphere-based slow release combination treatment, containing testosterone and alendronate, which is injected intra-articular in a mono-iodoacetate (MIA)-induced OA model. Specifically, we aimed to demonstrate a dose dependent increase in bone formation in the subchondral bone of the tibia (measured by microCT) and a subsequent reduction in joint pain (measured by Incapacitance tester). Before OA induction, all 60 rats were subjected to 3 baseline measurements with the Incapacitance tester, the knee joint was scanned with the microCT and blood was drawn. Following these baseline measurements, all rats received an intra-articular injection of MIA to induce OA (t=0). At t=3 days PLGA microspheres containing different amounts of testosterone (5, 15, 50 and 120 ug of testosterone) and a fixed amount of alendronate (7 ug) were injected in the OA joint, control animal received vehicle only (n=12). The effect of the MIA and microsphere injection on joint pain were monitored at t=3, 7, 14, 16, 22, 28 and 36 days with the Incapacitance tester (IT). The effect on bone formation was assessed by microCT at t=21 and 42 day (3 and 6 weeks). And in case effects on bone formation was observed, blood was drawn at t=42 days to measure bone specific biomarkers. At day 42 all animals were euthanized, and joints processed for further histological analysis. This dataset includes an experiment description and files containing (1) pain measurement using IT and (2) bone measurement using micoCT

Transcriptional profiling distinguishes inner and outer annulus fibrosus from nucleus pulposus in the bovine intervertebral disc

Contains fulltext : 178029.pdf (publisher's version ) (Open Access)BACKGROUND: Cells in the intervertebral disc have unique phenotypes and marker genes that separate the nucleus pulposus (NP), annulus fibrosus (AF) and articular cartilage (AC) have been identified. Recently, it was shown that phenotypic marker genes exhibit variable expression in humans. In this study, the bovine tail was used to determine the ability of marker genes to distinguish the outer and inner AF from NP tissue and isolated cells. METHODS: Bovine tail intervertebral discs from 13 donors were dissected and correct isolation of tissue was confirmed. mRNA was isolated directly from tissue or passage 0 monolayer cells and used for gene expression measurements (qPCR). Conventional marker genes (bAcan, bCol1a1, bCol2a1) and novel marker genes (bAdamts17, bBrachyury/T, bCD24, bCol5a1, bCol12a1, bFoxf1, bKrt19, bPax1, bSfrp2) were evaluated. RESULTS: As expected bAcan, bCol2a1 and bCol1a1 distinguished outer AF from NP tissue, while inner AF and NP could not be discriminated. The NP markers bT, bCd24 and bKrt19 were significantly higher expressed in NP than inner and outer AF tissue. bFoxF1 and bPax1 only distinguished IVD tissues from AC. The AF markers bAdamts17, bCol5a1, bCol12a1 and bSfrp2 were higher expressed in the outer AF compared with inner AF and NP tissue. Monolayer culturing strongly decreased bAcan, bCol2a1, bCD24 and bCol5a1 expression, while bCol1a1, bT, bKrt19 and bSfrp2 were not affected. CONCLUSION: The IVD phenotypic marker genes bT, bKrt19, bSfrp2 and bCol12a1 convincingly distinguished NP from outer AF in situ and in vitro

ZonMw ETH project 435004504 - Dataset of MIA rat osteoarthritis model treated with testosteron-aledronate microspheres: Pain measurement by incapacitance tester and bone analysis by microCT

The aim of this project was to test the possible osteo-inductive properties of a microsphere-based slow release combination treatment, containing testosterone and alendronate, which is injected intra-articular in a mono-iodoacetate (MIA)-induced OA model. Specifically, we aimed to demonstrate a dose dependent increase in bone formation in the subchondral bone of the tibia (measured by microCT) and a subsequent reduction in joint pain (measured by Incapacitance tester). Before OA induction, all 60 rats were subjected to 3 baseline measurements with the Incapacitance tester, the knee joint was scanned with the microCT and blood was drawn. Following these baseline measurements, all rats received an intra-articular injection of MIA to induce OA (t=0). At t=3 days PLGA microspheres containing different amounts of testosterone (5, 15, 50 and 120 ug of testosterone) and a fixed amount of alendronate (7 ug) were injected in the OA joint, control animal received vehicle only (n=12). The effect of the MIA and microsphere injection on joint pain were monitored at t=3, 7, 14, 16, 22, 28 and 36 days with the Incapacitance tester (IT). The effect on bone formation was assessed by microCT at t=21 and 42 day (3 and 6 weeks). And in case effects on bone formation was observed, blood was drawn at t=42 days to measure bone specific biomarkers. At day 42 all animals were euthanized, and joints processed for further histological analysis. This dataset includes an experiment description and files containing (1) pain measurement using IT and (2) bone measurement using micoCT