共查询到20条相似文献,搜索用时 15 毫秒
1.
Xin You Meng Pan Wenli Gao Her‐Shyong Shiah Jian Tao Dongqing Zhang Fotios Koumpouras Shuang Wang Hongyu Zhao Joseph A. Madri David Baker Yung‐Chi Cheng Zhinan Yin 《Arthritis \u0026amp; Rheumatology》2006,54(3):877-886
Objective
To test the effects of a novel tylophorine analog, DCB 3503, on the prevention and treatment of collagen‐induced arthritis (CIA) and to elucidate its underlying mechanisms.Methods
DBA/1J mice were immunized with type II collagen, and in some cases, lipopolysaccharide (LPS) was used to boost the development of arthritis. DCB 3503 was injected intraperitoneally before or after the onset of CIA. Mice were monitored to assess the effects of DCB 3503 on the clinical severity of the disease, and pathologic changes in the joints were examined histologically. Levels of tumor necrosis factor α (TNFα) and interleukin‐1β (IL‐1β) in serum and joint tissues were measured by enzyme‐linked immunosorbent assay and by cytometric bead array analysis. The effect of DCB 3503 on LPS‐induced proinflammatory cytokines from bone marrow–derived dendritic cells was determined by flow cytometry.Results
DCB 3503 significantly suppressed the development and progression of CIA. Moreover, DCB 3503 completely blocked the LPS‐triggered acceleration of joint inflammation and destruction. Consistent with its effects in vivo, DCB 3503 significantly suppressed the synthesis of proinflammatory cytokines in inflamed joints as well as cytokine synthesis by macrophages examined ex vivo. Treatment also reduced the levels of inflammatory cytokines (IL‐6, IL‐12, TNFα, and monocyte chemotactic protein 1) produced by bone marrow–derived dendritic cells in vitro. However, DCB 3503 showed no direct effects on T cell proliferation and B cell antibody response.Conclusion
Because of its ability to specifically suppress innate immune responses, DCB 3503 may be a novel therapeutic agent for inflammatory arthritis in humans.2.
Jun Deng Yang Liu Min Yang Shengjun Wang Miaojia Zhang Xiaohui Wang King‐Hung Ko Zichun Hua Lingyun Sun Xuetao Cao Liwei Lu 《Arthritis \u0026amp; Rheumatology》2012,64(11):3564-3573
Objective
To determine the role of leptin in modulating Th17 cell response and joint inflammation in mice with collagen‐induced arthritis (CIA).Methods
Leptin receptor expression on T cells was examined by polymerase chain reaction (PCR) analysis, immunofluorescence microscopy, and flow cytometry. Effects of leptin on Th17 cell differentiation and proliferation were evaluated by quantitative PCR, carboxyfluorescein diacetate succinimidyl ester proliferation assay, and flow cytometry. Dynamic changes in leptin concentrations in the joint tissue and synovial fluid of mice with CIA were determined by immunohistochemistry analysis and enzyme‐linked immunosorbent assay (ELISA). Arthritis symptoms and joint pathology in mice with CIA were assessed after injection of leptin into the knee joint. Th1 and Th17 cell populations in the spleen, draining lymph nodes, and joint tissue were analyzed by flow cytometry and enzyme‐linked immunospot assay. Interleukin‐17 messenger RNA and protein levels in the joint tissue were measured by PCR analysis and ELISA.Results
In culture, leptin treatment significantly increased Th17 cell generation from naive CD4+ T cells. During CIA development, markedly elevated levels of leptin were detected in the joint tissue and synovial fluid. Moreover, injection of leptin into the knee joint of collagen‐immunized mice resulted in an early onset of arthritis and substantially increased the severity of clinical symptoms, accompanied by more pronounced synovial hyperplasia and joint damage. Further examination by immunofluorescence microscopy confirmed the presence of significantly increased numbers of Th17 cells in the joint tissue and draining lymph nodes of leptin‐treated mice with CIA.Conclusion
The results of this study identify a previously undescribed function of leptin in enhancing Th17 cell response and exacerbating joint inflammation in mice with CIA.3.
Cong‐Qiu Chu David Swart Dina Alcorn Joel Tocker Keith B. Elkon 《Arthritis \u0026amp; Rheumatology》2007,56(4):1145-1151
Objective
The enhanced expression of experimental arthritis in the absence of interferon‐γ (IFNγ) suggests that IFNγ suppresses arthritis. Interleukin‐17 (IL‐17) is a pivotal T cell cytokine in arthritis, and in vitro studies have indicated that IFNγ suppresses IL‐17 production. We undertook this study to test the hypothesis that resistance to collagen‐induced arthritis (CIA) in C57BL/6 (B6) mice is regulated by IFNγ‐mediated suppression of IL‐17.Methods
Wild‐type (WT) B6 mice, IFNγ‐knockout (KO) B6 mice, and DBA/1 mice were immunized with type II collagen (CII) in Freund's complete adjuvant (CFA). Lymphocytes from immunized mice were analyzed for cytokine production ex vivo by intracellular staining or restimulation with CII and enzyme‐linked immunosorbent assays. In vivo blockade of IL‐17 was achieved with an anti–IL‐17 monoclonal antibody (mAb).Results
CII restimulation of T cells from CII/CFA‐immunized mice resulted in an ∼5‐fold increase in IL‐17 production in IFNγ‐KO B6 mice compared with WT B6 mice. Neutralization of IFNγ increased IL‐17 production in WT B6 mice, and neutralization of IL‐4 had a synergistic effect. Interestingly, the prototypical CIA‐susceptible strain DBA/1 also demonstrated a high IL‐17 and a low IFNγ cytokine profile compared with WT B6 mice. Administration of the anti–IL‐17 mAb attenuated arthritis in DBA/1 mice and almost completely prevented expression of arthritis in IFNγ‐KO B6 mice.Conclusion
These results indicate that sensitivity of IFNγ‐deficient B6 mice to CIA is associated with high IL‐17 production and that this cytokine is required for expression of arthritis in this strain.4.
Farida Djouad Vanessa Fritz Florence Apparailly Pascale Louis‐Plence Claire Bony Jacques Sany Christian Jorgensen Danile Noël 《Arthritis \u0026amp; Rheumatology》2005,52(5):1595-1603
Objective
Adult mesenchymal stem cells (MSCs) represent promising tools for therapeutic applications such as tissue engineering and cellular therapy. Recent data suggest that, due to their immunosuppressive nature, MSCs may be of interest to enhance allogeneic hematopoietic engraftment and prevent graft‐versus‐host disease. Using a murine model of rheumatoid arthritis (RA), this study investigated whether the immunosuppressive properties of MSCs could be of therapeutic value to inhibit reactive T cells in autoimmune diseases such as RA.Methods
In mice with collagen‐induced arthritis (CIA), we injected various doses of C3 MSCs at the time of immunization or booster injection, and subsequently evaluated the clinical and immunologic parameters. The immunosuppressive properties of MSCs were determined in vitro in mixed lymphocyte reactions with or without the addition of tumor necrosis factor α (TNFα).Results
In the CIA model of arthritis, MSCs did not confer any benefit. Both the clinical and the immunologic findings suggested that MSCs were associated with accentuation of the Th1 response. Using luciferase‐expressing MSCs, we were unable to detect labeled cells in the articular environment of the knee, suggesting that worsening of the symptoms was unlikely due to the homing of MSCs in the joints. Experiments in vitro showed that the addition of TNFα was sufficient to reverse the immunosuppressive effect of MSCs on T cell proliferation, and this observation was associated with an increase in interleukin‐6 secretion.Conclusion
Our data suggest that environmental parameters, in particular those related to inflammation, may influence the immunosuppressive properties of MSCs.5.
6.
7.
8.
9.
10.
11.
Jeroen N. Stoop Rachel A. Harry Alexei von Delwig John D. Isaacs John H. Robinson Catharien M. U. Hilkens 《Arthritis \u0026amp; Rheumatology》2010,62(12):3656-3665
Objective
Tolerogenic dendritic cells (DCs) are antigen‐presenting cells with an immunosuppressive function. They are a promising immunotherapeutic tool for the attenuation of pathogenic T cell responses in autoimmune arthritis. The aims of this study were to determine the therapeutic action of tolerogenic DCs in a type II collagen–induced arthritis model and to investigate their effects on Th17 cells and other T cell subsets in mice with established arthritis.Methods
Tolerogenic DCs were generated by treating bone marrow–derived DCs with dexamethasone and vitamin D3 during lipopolysaccharide‐induced maturation. Mice with established arthritis received 3 intravenous injections of tolerogenic DCs, mature DCs, or saline. Arthritis severity was monitored for up to 4 weeks after treatment. Fluorescence‐labeled tolerogenic DCs were used for in vivo trafficking studies. The in vivo effect of tolerogenic DCs on splenic T cell populations was determined by intracellular cytokine staining and flow cytometry.Results
Tolerogenic DCs displayed a semi‐mature phenotype, produced low levels of inflammatory cytokines, and exhibited low T cell stimulatory capacity. Upon intravenous injection into arthritic mice, tolerogenic DCs migrated to the spleen, liver, lung, feet, and draining lymph nodes. Treatment of arthritic mice with type II collagen–pulsed tolerogenic DCs, but not unpulsed tolerogenic DCs or mature DCs, significantly inhibited disease severity and progression. This improvement coincided with a significant decrease in the number of Th17 cells and an increase in the number of interleukin‐10–producing CD4+ T cells, whereas tolerogenic DC treatment had no detectable effect on Th1 cells or interleukin‐17–producing γ/δ T cells.Conclusion
Treatment with type II collagen–pulsed tolerogenic DCs decreases the proportion of Th17 cells in arthritic mice and simultaneously reduces the severity and progression of arthritis.12.
Cheryll Williams‐Skipp Thiagarajan Raman Robert J. Valuck Herschel Watkins Brent E. Palmer Robert I. Scheinman 《Arthritis \u0026amp; Rheumatology》2009,60(2):408-418
Objective
To examine the relative importance of tumor necrosis factor receptor I (TNFRI) signaling in the hematopoietic tissue compartment in the progression of collagen‐induced arthritis (CIA), a model of rheumatoid arthritis (RA).Methods
DBA/1 mice were administered a lethal radiation dose and were then rescued with bone marrow derived from either DBA/1 or TNFRI−/− mice. CIA was then induced, and disease progression was characterized.Results
Surprisingly, mice with CIA that received TNFRI−/− donor marrow developed increased disease severity as compared with control mice with CIA. This could not be attributed to an increased primary response to collagen or to the contribution of a non‐DBA genetic background. In mice that received TNFRI−/− bone marrow, histologic markers of advanced disease were evident shortly after initiation of the immune response to collagen and long before clinical evidence of disease. Serum TNFα was undetectable, whereas serum interleukin‐12 p40 levels were increased, at the end point of the study in mice that received TNFRI−/− bone marrow.Conclusion
These data raise the intriguing possibility of the existence of an antiinflammatory, TNFRI‐mediated circuit in the hematopoietic compartment. This circuit bears a resemblance to the switch in TNFα function that has been observed during the resolution of bacterial infections. These data suggest that TNFRI‐mediated signals in the radioresistant tissues contribute to disease progression, whereas TNFRI‐mediated signals in the radiosensitive tissues can contribute to protection from disease. We thus put forward the hypothesis that the degree of response to TNFα blockade in RA is dependent in part on the relative genetic strengths of these 2 pathways.13.
Leonie M. van Duivenvoorde Pascale Louis‐Plence Florence Apparailly Ellen I. H. van der Voort Tom W. J. Huizinga Christian Jorgensen Ren E. M. Toes 《Arthritis \u0026amp; Rheumatology》2004,50(10):3354-3364
Objective
Dendritic cells (DCs) are crucial for the initiation of T cell immunity and therefore play an important role in the initiation and regulation of immune responses in arthritis. Full mobilization of effector T cells depends on the proper maturation of DCs. Current evidence indicates that the type of T cell response induced is crucially dependent on the activation status of the DCs. In this study, we explored the immunologic effects of differentially matured DCs on the development of collagen‐induced arthritis (CIA).Methods
Bone marrow–derived DCs were cultured in the presence of granulocyte–macrophage colony‐stimulating factor (GM‐CSF). Before immunization with bovine type II collagen (CII) protein, mice were repeatedly injected with DCs that had been pulsed with CII. Immature, semimature, or fully mature DCs were injected. Mice were boosted on day 21 after CII immunization, and the disease course was monitored.Results
While vaccination with immature or lipopolysaccharide‐activated DCs had no significant effect on the disease course, administration of antigen‐loaded, tumor necrosis factor (TNF)–modulated DCs propagated in GM‐CSF with or without interleukin‐4 resulted in a delayed onset of arthritis and a lower clinical score. The response was antigen‐specific, since TNF‐treated DCs pulsed with a control antigen did not modify the disease course. A specific decrease in the collagen‐specific “Th1‐associated” IgG2a response was observed, whereas IgG1 titers were unaffected.Conclusion
CIA can be prevented through vaccination with TNF‐matured DCs in an antigen‐specific manner. These findings provide a rationale for immunotherapy using DCs in rheumatoid arthritis.14.
15.
16.
17.
18.
T. Saxne M. A. Palladino D. Heinegrd N. Talal F. A. Wollheim 《Arthritis \u0026amp; Rheumatology》1988,31(8):1041-1045
Synovial fluids from 6 of 12 patients with rheumatoid arthritis (RA) and from 3 of 11 patients with reactive arthritis contained measurable levels of tumor necrosis factor α (TNFα). Seven of 12 sera from RA patients contained TNFα, while only 1 of those from reactive arthritis patients was positive. Gamma-inter-feron was detected in the synovial fluids and sera of only the RA patients. Tumor necrosis factor β was not detected in any sera or synovial fluids. RA patients with detectable TNFα had higher erythrocyte sedimentation rates and synovial fluid leukocyte counts. 相似文献
19.
Hiroaki Saito Takefumi Kojima Mariko Takahashi William C. Horne Roland Baron Teruo Amagasa Keiichi Ohya Kazuhiro Aoki 《Arthritis \u0026amp; Rheumatology》2007,56(4):1164-1174
Objective
The cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor α (TNFα) recognition loop on TNF receptor I, and it prevents interactions of TNFα with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen‐induced arthritis (CIA) in mice with those of anti‐TNFα monoclonal antibody.Methods
CIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti‐TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed.Results
WP9QY treatment inhibited CIA‐induced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti‐TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA‐induced bone destruction at the knee joints to the same extent as did anti‐TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA‐induced systemic bone loss by WP9QY was more apparent than that by anti‐TNF antibody.Conclusion
The TNFα antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.20.
Undine Meusch Manuela Rossol Christoph Baerwald Sunna Hauschildt Ulf Wagner 《Arthritis \u0026amp; Rheumatology》2009,60(9):2612-2621