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1.
Karin Polzer Kirsten Neubert Silke Meister Benjamin Frey Wolfgang Baum Jrg H. Distler Eva Gückel Georg Schett Reinhard E. Voll Jochen Zwerina 《Arthritis \u0026amp; Rheumatology》2011,63(3):670-680
Objective
The proteasome inhibitor bortezomib has potent anti‐myeloma and bone‐protective activity. Recently, bortezomib was shown to directly inhibit osteoclastogenesis. The aim of this study was to analyze the influence and therapeutic effect of bortezomib in a mouse model of inflammatory arthritis.Methods
Heterozygous human tumor necrosis factor α (hTNFα)–transgenic mice and their wild‐type (WT) littermates were intravenously injected with 0.75 mg/kg of bortezomib or phosphate buffered saline twice weekly. The mice were assessed for clinical signs of arthritis. After 6 weeks of treatment, mice were analyzed for synovial inflammation, cartilage damage, bone erosions, and systemic bone changes. Osteoclast precursors from WT and hTNF‐transgenic mice were isolated from bone marrow, treated with bortezomib, and analyzed for osteoclast differentiation, bone resorption, and expression of osteoclast‐specific genes as well as apoptosis and ubiquitination.Results
Bortezomib‐treated hTNF‐transgenic mice showed moderately increased inflammatory activity and dramatically enhanced bone erosions associated with a significant increase in the number of synovial osteoclasts. Interestingly, bortezomib did not alter systemic bone turnover in either hTNF‐transgenic mice or WT mice. In vitro, treatment with therapeutically relevant concentrations of bortezomib resulted in increased differentiation of monocytes into osteoclasts and more resorption pits. Molecularly, bortezomib increased the expression of TNF receptor−associated factor 6, c‐Fos, and nuclear factor of activated T cells c1 in osteoclast precursors.Conclusion
In TNF‐mediated bone destruction, bortezomib treatment increased synovial osteoclastogenesis and bone destruction. Hence, proteasome inhibition may have a direct bone‐resorptive effect via stimulation of osteoclastogenesis during chronic arthritis.2.
Georg Schett Kurt Redlich Silvia Hayer Jochen Zwerina Brad Bolon Colin Dunstan Birgit Grtz Andreas Schulz Helga Bergmeister Giorgos Kollias Günter Steiner Josef S. Smolen 《Arthritis \u0026amp; Rheumatology》2003,48(7):2042-2051
Objective
To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.Methods
We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.Results
Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (−37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (−85%) compared with wild‐type controls. Osteoclast‐covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast‐mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF‐mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast‐covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast‐mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin‐1β (IL‐1β), and IL‐6. However, OPG decreased bone formation parameters (osteoblast‐covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti‐TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti‐TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.Conclusion
OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.3.
Activation of p38 MAPK is a key step in tumor necrosis factor–mediated inflammatory bone destruction
Jochen Zwerina Silvia Hayer Kurt Redlich Klaus Bobacz Giorgos Kollias Josef S. Smolen Georg Schett 《Arthritis \u0026amp; Rheumatology》2006,54(2):463-472
Objective
To investigate whether activation of p38 MAPK is a crucial signaling factor in inflammatory bone destruction mediated by tumor necrosis factor (TNF). Mice overexpressing TNF were treated with 2 different inhibitors of p38 MAPK, and the effect of this treatment on joint inflammation and structural damage was assessed.Methods
Human TNF‐transgenic mice received systemic treatment with 2 different p38 MAPK inhibitors (RO4399247 and AVE8677). Treatment was started at the time of symptom onset and lasted for 6 weeks. Mice were assessed for clinical signs of arthritis, bone erosion, and cartilage damage. In addition, the effect of these inhibitors on osteoclast generation in vitro and in vivo was assessed.Results
Both p38 MAPK inhibitors significantly reduced clinical signs of TNF‐mediated arthritis. This was attributable to reducing synovial inflammation by 50% without affecting the cellular composition of the infiltrate. Synovial expression of interleukin‐1 and RANKL was reduced upon p38 MAPK blockade, and activation of the molecular target MAPK‐activated protein kinase 2 (MAPKAP‐2) was also inhibited. Proteoglycan loss of articular cartilage was reduced by 50%, although p38 MAPK inhibition did not change matrix molecule synthesis by cultivated chondrocytes. Importantly, bone loss was almost completely prevented by p38 MAPK inhibition. The numbers of synovial osteoclasts and precursors were dramatically reduced, and both p38 MAPK inhibitors also inhibited in vitro osteoclastogenesis at micromolar concentrations and blocked activation of MAPKAP‐2 as well as differentiation markers in cultured osteoclast precursors.Conclusion
These results suggest the major importance of p38 MAPK for TNF‐mediated inflammatory bone destruction in arthritis and suggest that inhibition of p38 MAPK might be an important tool for reducing structural damage in rheumatoid arthritis.4.
Petra Herrak Birgit Grtz Silvia Hayer Kurt Redlich Erika Reiter Jürg Gasser Helga Bergmeister Giorgos Kollias Josef S. Smolen Georg Schett 《Arthritis \u0026amp; Rheumatology》2004,50(7):2327-2337
Objective
Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast‐targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions.Methods
Human tumor necrosis factor (TNF)–transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti‐TNF, at the onset of arthritis.Results
Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (−60%) and was almost completely blocked by repeated administration of ZA (−95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti‐TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass.Conclusion
ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.5.
Jochen Zwerina Silvia Hayer Makiyeh Tohidast‐Akrad Helga Bergmeister Kurt Redlich Ulrich Feige Colin Dunstan Giorgos Kollias Günter Steiner Josef Smolen Georg Schett 《Arthritis \u0026amp; Rheumatology》2004,50(1):277-290
Objective
To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin‐1 (IL‐1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF‐driven arthritis model.Methods
Human TNF–transgenic (hTNFtg) mice were treated with anti‐TNF (infliximab), IL‐1 receptor antagonist (IL‐1Ra; anakinra), or osteoprotegerin (OPG; an OPG‐Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically.Results
Synovial inflammation was inhibited by anti‐TNF (−51%), but not by IL‐1Ra or OPG monotherapy. The combination of anti‐TNF with either IL‐1Ra (−91%) or OPG (−81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti‐TNF (−79%) and OPG (−60%), but not by IL‐1Ra monotherapy. The combination of anti‐TNF with IL‐1Ra, however, completely blocked bone erosion (−98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti‐TNF (−43%) and was weakly, but not significantly, inhibited by IL‐1Ra, but was not inhibited by OPG monotherapy. The combination of anti‐TNF with IL‐1Ra was the most effective double combination therapy in preventing cartilage destruction (−80%). In all analyses, the triple combination of anti‐TNF, IL‐1Ra, and OPG was not superior to the double combination of anti‐TNF and IL‐1Ra.Conclusion
Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL‐1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL‐1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.6.
Stephan Blüml Nikolaus B. Binder Birgit Niederreiter Karin Polzer Silvia Hayer Stefanie Tauber Georg Schett Clemens Scheinecker George Kollias Edgar Selzer Martin Bilban Josef S. Smolen Giulio Superti‐Furga Kurt Redlich 《Arthritis \u0026amp; Rheumatology》2010,62(6):1608-1619
Objective
To investigate the mechanisms leading to the influx of inflammatory hematopoietic cells into the synovial membrane and the role of tumor necrosis factor receptor I (TNFRI) and TNFRII in this process in an animal model of rheumatoid arthritis (RA).Methods
We performed bone marrow transplantations in human TNF–transgenic mice using hematopoietic cells from wild‐type, TNFRI−/−, TNFRII−/−, and TNFRI/II−/− mice as donors and assessed the severity of arthritis histologically. Generation of osteoclasts from the different genotypes was analyzed in vitro and in vivo. Apoptosis was analyzed using annexin V staining as well as TUNEL assays.Results
Despite lacking responsiveness to TNF in their hematopoietic compartment, mice not only developed full‐blown erosive arthritis but even showed increased joint destruction when compared with mice with a TNF‐responsive hematopoietic compartment. We demonstrated different roles of the 2 different TNFRs in the regulation of these processes. The absence of TNFRI on hematopoietic cells did not affect joint inflammation but markedly attenuated erosive bone destruction via reduced synovial accumulation of osteoclast precursors. In contrast, the absence of TNFRII on hematopoietic cells increased joint inflammation as well as erosive bone destruction via the regulation of osteoclast precursor apoptosis.Conclusion
Our findings indicate that selective blockade of TNFRI, leaving the antiinflammatory effects of TNFRII unaltered instead of unselectively blocking TNF, might be advantageous in patients with RA.7.
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.8.
Roland Axmann Christina Bhm Gerhard Krnke Jochen Zwerina Josef Smolen Georg Schett 《Arthritis \u0026amp; Rheumatology》2009,60(9):2747-2756
Objective
To investigate the efficacy of a murine anti–interleukin‐6 receptor (anti–IL‐6R) antibody in directly blocking tumor necrosis factor (TNF)– and RANKL‐mediated osteoclastogenesis in vitro and in vivo.Methods
The efficacy of a murine antibody against IL‐6R in blocking osteoclast differentiation of mononuclear cells stimulated with RANKL was tested. In addition, arthritic human TNFα–transgenic mice were treated with anti–IL‐6R antibody, and osteoclast formation and bone erosion were assessed in arthritic paws.Results
Blockade of IL‐6R dose dependently reduced osteoclast differentiation and bone resorption in monocyte cultures stimulated with RANKL or RANKL plus TNF. In human TNFα–transgenic mice, IL‐6R blockade did not inhibit joint inflammation, but it strongly reduced osteoclast formation in inflamed joints as well as bone erosion in vivo. Neither the cell influx into joints nor the synovial expression of IL‐6 and RANKL changed with IL‐6R blockade, while the synovial expression of IL‐1 was significantly reduced. In contrast, TNF‐mediated systemic bone loss was not inhibited by IL‐6R blockade.Conclusion
These data suggest that blockade of IL‐6R directly affects osteoclast formation in vitro and in vivo, suggesting a direct and specific effect of anti–IL‐6R therapy on osteoclasts independently of its antiinflammatory effects. This effect adds significantly to the structure‐sparing potential of pharmacologic blockade of IL‐6R in arthritis.9.
L. Marinova‐Mutafchieva R. O. Williams K. Funa R. N. Maini N. J. Zvaifler 《Arthritis \u0026amp; Rheumatology》2002,46(2):507-513
Objective
To determine the involvement of mesenchymal progenitor cells in the induction of collagen‐induced arthritis (CIA).Methods
DBA/1 mice were immunized with type II collagen in adjuvant or adjuvant alone, and the presence of mesenchymal cells in the joints of prearthritic mice was studied by immunohistochemistry.Results
An analysis of the joints on day 10 postimmunization (at least 10 days before the onset of arthritis) revealed synovial hyperplasia without leukocytic infiltration. Large, round cells expressing bone morphogenetic protein receptors (BMPRs), which serve as markers for primitive mesenchymal cells, were present in increased numbers in the bone marrow adjacent to the joint, in the synovium itself, and within enlarged bone canals that connect the bone marrow to the synovium. Similar changes were observed in mice given adjuvant without collagen. Adjuvant‐induced infiltration of BMPR+ cells and enlargement of bone canals were abrogated by anti‐tumor necrosis factor (anti‐TNF) treatment and were absent in TNFR p55/p75−/− mice. Increased numbers of bone marrow cells and enlarged bone canals were observed in nonimmunized TNF transgenic mice (which spontaneously develop arthritis).Conclusion
These findings suggest that in CIA, there is an antigen‐independent (innate) prearthritic phase that prepares the joint for the subsequent immune‐mediated arthritis. The induction phase involves marrow‐derived mesenchymal cells and requires the presence of TNF.10.
Q. Zhang I. R. Badell E. M. Schwarz K. E. Boulukos Z. Yao B. F. Boyce L. Xing 《Arthritis \u0026amp; Rheumatology》2005,52(9):2708-2718
Objective
To investigate why bisphosphonates are less effective at preventing focal bone loss in rheumatoid arthritis (RA) patients than in those with generalized osteoporosis, and the mechanisms involved.Methods
The response of osteoclasts to alendronate (ALN) in tumor necrosis factor–transgenic (TNF‐Tg) mice that develop erosive arthritis and in wild‐type littermates was studied. TNF‐Tg and wild‐type mice were given ALN, and the osteoclast numbers in the inflamed joints and in the long bones were compared. The expression levels of Bcl‐xL in the osteoclasts of TNF‐Tg and wild‐type mice were examined by immunostaining. The effect of overexpression of Bcl‐xL and Ets‐2 proteins on ALN‐induced osteoclast apoptosis was determined using an in vitro osteoclast survival assay and retrovirus transfer approach.Results
ALN reduced osteoclast numbers in the metaphyses by 97%, but by only 46% in the adjacent inflamed joints. Bcl‐xL expression was markedly higher in osteoclasts in the joints than in those in the metaphyses of TNF‐Tg mice. Bcl‐xL or Ets‐2 overexpression protected osteoclasts from ALN‐induced apoptosis, and TNF stimulated Bcl‐xL and Ets‐2 expression in osteoclasts. Overexpression of Ets‐2 increased Bcl‐xL messenger RNA in osteoclasts, while a dominant‐negative form of the Ets‐2 blocked the protective effect of Bcl‐xL or TNF on ALN‐induced apoptosis.Conclusion
The reduced efficacy of bisphosphonates to stop bone erosion in the inflamed joints of RA patients may result from local high levels of TNF up‐regulating Ets‐2 expression in osteoclasts, which in turn stimulates Bcl‐xL expression in them and reduces their susceptibility to bisphosphonate‐induced apoptosis.11.
12.
Makoto Urushibara Hiroshi Takayanagi Takako Koga Sunhwa Kim Miho Isobe Yasuyuki Morishita Takumi Nakagawa Monika Leffler Tatsuhiko Kodama Hisashi Kurosawa Tadatsugu Taniguchi 《Arthritis \u0026amp; Rheumatology》2004,50(3):794-804
Objective
Suppression of bone destruction is required as part of an effective therapeutic strategy for autoimmune arthritis. Although numerous antirheumatic drugs are in clinical use, little is known about whether they inhibit bone destruction by acting on activated T cells or other cell types, such as bone‐resorbing osteoclasts. This study was undertaken to determine whether leflunomide has a direct action on the osteoclast lineage and to gain insights into the molecular basis for the bone‐protective effect of leflunomide.Methods
The direct effect of leflunomide on osteoclast differentiation was investigated using an in vitro culture system of bone marrow monocyte/macrophages stimulated with receptor activator of NF‐κB ligand (RANKL) and macrophage colony‐stimulating factor. The molecular mechanism of the inhibition was analyzed by genome‐wide screening. The T cell–independent effect of leflunomide was examined in rag‐2−/− mice.Results
Leflunomide blocked de novo pyrimidine synthesis and RANKL‐induced calcium signaling in osteoclast precursor cells in vitro; hence, the induction of nuclear factor of activated T cells c1 (NF‐ATc1) was strongly inhibited. The inhibition of this pathway is central to the action of leflunomide, since the inhibition was overcome by ectopic expression of NF‐ATc1 in the precursor cells. Leflunomide suppressed endotoxin‐induced inflammatory bone destruction even in rag‐2−/− mice.Conclusion
Leflunomide has a direct inhibitory effect on RANKL‐mediated osteoclast differentiation by inhibiting the induction of NF‐ATc1, the master switch regulator for osteoclast differentiation. Our study suggests that the direct inhibitory action of leflunomide on osteoclast differentiation constitutes an important aspect in the amelioration of bone destruction, and that the RANKL‐dependent NF‐ATc1 induction pathway is a promising target for pharmacologic intervention in arthritic bone destruction.13.
Kurt Redlich Silvia Hayer Andrea Maier Colin R. Dunstan Makiyeh Tohidast‐Akrad Susanne Lang Birgit Türk Peter Pietschmann Wolfgang Woloszczuk Silva Haralambous George Kollias Günter Steiner Josef S. Smolen Georg Schett 《Arthritis \u0026amp; Rheumatology》2002,46(3):785-792
Objective
To study the effects of osteoclast‐targeted therapies, such as osteoprotegerin (OPG) and pamidronate, on joint inflammation and bone destruction using a tumor necrosis factor α (TNFα)‐transgenic mouse model.Methods
Mice were placed into 5 groups that received either OPG, pamidronate, a combination of both agents, infliximab as a positive control, or phosphate buffered saline as a negative control. Treatment was initiated at the onset of arthritis, continued over 6 weeks, and thereafter, the clinical, radiologic, and histologic outcomes were assessed.Results
A significant improvement in clinical symptoms, as assessed by the reduction of paw swelling, was only found in the infliximab group, whereas all other treatment groups failed to show significant improvement. However, when assessing structural damage with radiographic analysis, a significant retardation of joint damage was evident in animals treated with OPG (55% reduction of erosions), pamidronate (50% reduction of erosions) the combination therapy of OPG and pamidronate (64% reduction of erosions), and with infliximab (66% reduction of erosions). Confirming these data, quantitative histologic analysis revealed a significant reduction in the size of bone erosions in all treatment groups (OPG 56%, pamidronate 53%, OPG and pamidronate 81%, and infliximab 46%) compared with the control group. Furthermore, a significant reduction of osteoclast numbers was seen in animals treated with OPG alone or in combination with pamidronate as well as in animals treated with infliximab.Conclusion
These data suggest that OPG alone or in combination with bisphosphonates is an effective therapeutic tool for the prevention of TNFα‐mediated destruction of bone by reducing the number of bone‐resorbing cells in the inflammatory tissue.14.
15.
16.
Marije I. Koenders Renoud J. Marijnissen Isabel Devesa Erik Lubberts Leo A. B. Joosten Johannes Roth Peter L. E. M. van Lent Fons A. van de Loo Wim B. van den Berg 《Arthritis \u0026amp; Rheumatology》2011,63(8):2329-2339
Objective
To examine whether synovial interleukin‐17 (IL‐17) expression promotes tumor necrosis factor (TNF)–induced joint pathologic processes in vivo, and to analyze the surplus ameliorative value of neutralizing IL‐17 in addition to TNF during collagen‐induced arthritis (CIA).Methods
Adenoviral vectors were used to induce overexpression of IL‐17 and/or TNF in murine knee joints. In addition, mice with CIA were treated, at different stages of arthritis, with soluble IL‐17 receptor (sIL‐17R), TNF binding protein (TNFBP), or the combination.Results
Overexpression of IL‐17 and TNF resulted in joint inflammation and bone erosion in murine knees. Interestingly, IL‐17 strikingly enhanced both the joint‐inflammatory and joint‐destructive capacity of TNF. Further analysis revealed a strongly enhanced up‐regulation of S100A8, IL‐1β, and matrix metalloproteinase (MMP) messenger RNA, only when both TNF and IL‐17 were present. Moreover, the increase in irreversible cartilage destruction was not merely the result of enhanced inflammation, but also was associated with a direct synergistic effect of these cytokines in the joint. S100A9 deficiency in mice protected against IL‐17/TNF–induced expression of cartilage NITEGE neoepitopes. During established arthritis, the combination of sIL‐17R and TNFBP was more effective than the anticytokine treatments alone, and significantly inhibited further joint inflammation and cartilage destruction.Conclusion
Local synovial IL‐17 expression enhances the role of TNF in joint destruction. Synergy between TNF and IL‐17 in vivo results in striking exaggeration of cartilage erosion, in parallel with a synergistic up‐regulation of S100A8, IL‐1β, and erosive MMPs. Moreover, neutralizing IL‐17 in addition to TNF further improves protection against joint damage and is still effective during late‐stage CIA. Therefore, compared with anti‐TNF alone, combination blocking of TNF and IL‐17 may have additional therapeutic value for the treatment of destructive arthritis.17.
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.18.
19.
Teruhisa Hirayama Simon Dai Sabiha Abbas Yasuhiro Yamanaka Yousef Abu‐Amer 《Arthritis \u0026amp; Rheumatology》2005,52(9):2719-2729