Early effects of tocilizumab on bone and bone marrow lesions in a collagen-induced arthritis monkey model

To understand the contribution of IL-6/IL-6R to subchondral bone and bone marrow abnormality in RA patients and the effects of tocilizumab on those abnormalities, we evaluated early change in a collagen-induced arthritis (CIA) monkey model with or without a single administration of tocilizumab. Six CIA cynomolgus monkeys received tocilizumab and 3 CIA monkeys received vehicle only. Their interphalangeal joints were analyzed using HE, silver impregnation (SI), or immunohistochemistry (RANKL) staining. The number of osteoclasts increased in the arthritis control but was suppressed in the tocilizumab-treated animals. Osteoblast/stromal cells of the arthritis control monkeys were of monolayer, while in the tocilizumab-treated monkeys, the cells were multi-layer or differentiated osteoblasts, and the meshwork of the reticulum fibers showed recovery in the SI. Hematopoietic marrow was replaced by interstitial fluid and reticulum fibers were eliminated in the arthritic model but showed recovery in the tocilizumab-treated animals. RANKL showed overproduction with arthritis and suppressed with tocilizumab treatment. The evidence indicates that IL-6/IL-6R is involved in subchondral bone and bone marrow change in RA patients. Tocilizumab treatment recovered changes in the CIA monkeys as a result of the co-differentiation between the osteoclasts and the osteoblast/stramal cells, at least partially through the suppression of RANKL overproduction.     

Clinical efficacy of a new CD28‐targeting antagonist of T cell co‐stimulation in a non‐human primate model of collagen‐induced arthritis

T cells have a central pathogenic role in the aetiopathogenesis of rheumatoid arthritis (RA), and are therefore a favoured target of immunotherapy aiming at physical or functional elimination. Here we report an efficacy test of FR104, a new co‐stimulation inhibitor directly targeting CD28 on T cells, in a translationally relevant model, the rhesus monkey model of collagen‐induced arthritis (CIA). As a relevant comparator we used abatacept [cytotoxic T lymphocyte antigen immunoglobulin (CTLA Ig)], an antagonist of CTLA‐4 binding to CD80/86 clinically approved for treatment of RA. Treatment with either compound was started at the day of CIA induction. Although FR104 previously demonstrated a higher control of T cell responses in vitro than abatacept, both compounds were equally potent in the suppression of CIA symptoms and biomarkers, such as the production of C‐reactive protein (CRP) and interleukin (IL)‐6 and anti‐collagen type II (CII) serum antibody (IgM/IgG). However, in contrast to abatacept, FR104 showed effective suppression of CII‐induced peripheral blood mononuclear cell (PBMC) proliferation. The current study demonstrates a strong potential of the new selective CD28 antagonist FR104 for treatment of RA.     

核因子-κB诱骗剂处理的DC对胶原诱导性关节炎大鼠外周血IFN-γ、IL-1O、抗Ⅱ型胶原抗体水平的影响

目的 探讨核因子-κB诱骗剂(NF-κB ODN Decoy)处理的DC对Ⅱ型胶原诱导性关节炎(CIA)大鼠血清IFN-γ、IL-10、抗Ⅱ型胶原抗体水平的影响及作用机制.方法 建立Ⅱ型胶原诱导性大鼠关节炎模型,NF-κB诱骗剂处理并负载牛Ⅱ型胶原(BⅡC)的大鼠脾脏来源的DC,在初次免疫第5天经尾静脉注射到CIA大鼠体内,并设空白对照组、CIA模型组和BⅡC-decoy-DC实验组.42 d后观察各组关节炎指数和病理变化,采用酶联免疫吸附法(ELISA)检测各组大鼠血清中IFN-γ、IL-10、抗Ⅱ型胶原抗体的含量.结果 与空白对照组相比,CIA模型组大鼠血清中IFN-γ、抗Ⅱ型胶原抗体含量升高,而IL-10含量降低(P＜0.05),而BⅡC-decoy-DC实验组经NF-κB诱骗剂处理并负载BⅡC获得的DC注射后,与CIA模型组相比,血清中IFN-γ、抗Ⅱ型胶原抗体含量降低,而IL-10含量升高,差异有统计学意义(P＜0.05).结论 NF-κB诱骗剂处理并负载BⅡC的DC具有明显抑制CIA大鼠外周血IFN-γ和抗BⅡC抗体产生,促进IL-10水平的增加,对类风湿关节炎有较好的治疗作用.     

Long-term anti-arthritic and anti-osteoporotic effects of raloxifene in established experimental postmenopausal polyarthritis

Both oestrogen deficiency and the inflammatory disease contribute to the generalized bone loss seen in postmenopausal rheumatoid arthritis (RA). Oestradiol and the selective oestrogen receptor modulator raloxifene have been shown to ameliorate the disease in collagen-induced arthritis (CIA), a well-established animal model for human RA. The aim of this study was to investigate whether raloxifene-treatment would be beneficial in long-term treatment of established CIA, both regarding anti-arthritic and anti-osteoporotic properties. Female dilute brown agouti mice were ovariectomized and CIA was induced. Raloxifene or vehicle treatment was administered 5 days per week, and the clinical arthritis score was evaluated continuously. At termination, bone mineral density was analysed, paws were collected for histological examination and sera were analysed for markers of bone and cartilage turnover, as well as antibodies to type II collagen and levels of interleukin (IL)-6. Treatment with raloxifene is beneficial in long-term treatment of established CIA. It hampers the disease severity and frequency, protects the joints from destruction and protects against the development of osteoporosis. The proinflammatory cytokine IL-6 was down-regulated in raloxifene-treated mice compared with controls. The serum levels of antibodies to collagen were not affected by raloxifene-treatment. Long-term treatment with raloxifene has both anti-arthritic and anti-osteoporotic effects in established experimental postmenopausal polyarthritis.     

组蛋白去乙酰化酶抑制剂TSA对小鼠胶原诱导性关节炎的治疗作用

目的 研究组蛋白去乙酰酶化抑制剂制滴菌素A(TSA)对小鼠胶原诱导性关节炎的作用,初步探讨其作用机制.方法 将雄性DBA/1小鼠随机分为胶原诱导性关节炎(CIA)模型组、预防性给药组、治疗性给药组、正常组.免疫后第35天处死小鼠,检测小鼠足爪炎症的肿胀度,病理切片观察炎症变化,MTT法检测脾淋巴细胞对胶原的增殖反应,实时荧光定量PCR检测TSA对小鼠脾细胞IFN-γ、IL-4 mRNA表达的影响,ELISA检测IFN-γ、IL-4的含量.结果 CIA模型组关节炎评分、对CⅡ的增殖反应、IFN-γ水平均高于正常对照组;给药组关节炎评分、对CⅡ的增殖反应低于CIA模型组;给药组IFN-γ水平低于CIA组,但IL-4水平高于CIA组.结论 TSA对CIA具有抑制作用,其可能机制是抑制T细胞的活化、增殖,调节Th1/Th2的失衡状态.     

Anti-IL-12 and anti-TNF antibodies synergistically suppress the progression of murine collagen-induced arthritis.

The co-ordinate role of the Th1 cytokine IL-12 and the proinflammatory cytokine TNF in arthritis was explored using the DBA/1 mouse model, collagen-induced arthritis (CIA). In this study, mice with established arthritis were treated with anti-IL-12 and/or anti-TNF antibodies for 10 days from the onset of disease. Clinical assessment showed that the combined antibody treatment ameliorated disease severity to a greater extent than anti-TNF alone. Supporting these observations, histological analysis revealed that there was a reduced joint damage in the mice that received combined anti-IL-12 and anti-TNF treatment, compared to the other treatment groups. Anti-IL-12 had no statistically significant effect on the clinical outcome of disease. The combination of anti-IL-12 and anti-TNF treatment was found to reduce collagen type II (CII)-specific lymph node cell IFN-gamma production and proliferation, as well as decrease the anti-CII IgG2a:IgG1 ratio more effectively than either treatment alone. When the antibodies were added to synovial cells from arthritic mice and bone marrow macrophages in vitro, anti-TNF diminished IL-12 production, but anti-IL-12 had no effect on TNF production. These data suggest that, through the partial regulation of IL-12, TNF modulates the immune response in arthritis, as well as the inflammatory response. The synergistic action of anti-TNF and anti-IL-12 on CIA may provide a new therapeutic approach for treating rheumatoid arthritis.     

类风湿性关节炎患者IL-6、IL-18和CRP的水平变化及意义

目的：研究类风湿性关节炎（RA）患者血清白细胞介素-6（IL-6）、白细胞介素-18（IL-18）和C-反应蛋白（CRP）水平的变化及其临床意义。方法：收集84例RA患者,以70例健康体检者作对照。采用双抗体夹心酶联免疫吸附法测定血清IL-6、IL-18和免疫荧光法测定CRP的水平,并测定血小板计数（Plt）、血沉（ESR）、类风湿因子（RF）。结果：RA患者的血清Plt、ESR、RF、IL-6、IL-18和CRP的含量明显高于健康对照组（P〈0.01）。RA患者活动期上述指标含量（除RF外）均显著高于稳定期（P〈0.01）,Plt升高RA患者组与Plt正常组相比,RF、ESR、IL-6、IL-18和CRP水平均有明显统计学差异（P〈0.05）。结论：IL-6、IL-18和CRP在RA患者的疾病发展过程中发挥着重要作用,它们的水平变化与RA患者病情有关,联合动态监测有助于临床观察RA患者的病情变化和治疗效果。     

Inhalation of Carbon Monoxide Ameliorates Collagen-induced Arthritis in Mice and Regulates the Articular Expression of IL-1β and MCP-1

Carbon monoxide (CO), long considered a toxic gas, has recently been shown to mediate anti-inflammatory effects in various animal models. The aim of this study was to investigate whether the inhalation of CO ameliorated collagen-induced arthritis (CIA) in mice. CIA was induced in female DBA/1 mice by the injection of an anti-type II collagen antibody and lipopolysaccharide. The CO treatment group was exposed to CO gas at a concentration of 200 ppm in a closed cage starting on the day of the injection with an anti-type II collagen antibody and throughout the remaining study period. The clinical arthritis scores was examined daily for swelling of the paws as a sign of arthritis. For histopathology, the sections of the hind legs were evaluated by hematoxylin-eosin staining. Moreover, we evaluated the expression of interleukin (IL)-1β and monocyte chemoattractant protein-1 (MCP-1) mRNA in the hind paws. Both clinical arthritis scores as well as histological findings of joint inflammation were significantly reduced in mice treated with CO gas inhalation compared to untreated mice. Further, CO significantly inhibited the increased expression of IL-1β and MCP-1 mRNA in paws at day 3 after the induction of arthritis. In conclusion, the inhalation of CO protected mice from the synovial inflammation of CIA. Based on these data, the beneficial effects of CO in murine RA model may be attributed to its anti-inflammatory properties.     

Anti-inflammatory effect of all-trans-retinoic acid in inflammatory arthritis

OBJECTIVE: To determine whether all-trans-retinoic acid (ATRA) improves the destruction of joints and the effect of cytokines on DBA/1J mice with collagen-induced arthritis (CIA). METHODS: Starting from the time of type II collagen injection, DBA/1J mice were injected intraperitoneally with PBS or 0.5 mg of ATRA 3 times per week for 35 days. The effects of treatment were monitored by determining arthritis and histological scores and measuring cellular proliferation, production of cytokines (IL-2, IL-10, IL-12, IL-6, IFN-gamma, and TNF-alpha) and IgG, and the expression of mRNAs for inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1), and CXCR3. RESULTS: The arthritis score and incidence of arthritis were lower in the mice treated with ATRA than in those treated with PBS. Histopathologic evidence of joint damage was 34% lower, and the infiltrations of macrophages were reduced in the mice treated with ATRA compared with those treated with PBS. Type II collagen- and ConA-stimulated proliferation of spleen cells, the production of cytokines (IL-6, IL-12, and TNF-alpha), the serum levels of total IgG and IgG1 anti-collagen antibodies, and the expression of mRNAs for MCP-1 were significantly reduced in the mice treated with ATRA than in those treated with PBS. CONCLUSION: ATRA improved the clinical course and reduced the production of inflammatory cytokines, immunoglobulin, and chemokines in murine CIA. These data suggest that ATRA might be also effective for the treatment of inflammatory arthritis like human rheumatoid arthritis.     

High doses of interleukin-12 inhibit the development of joint disease in DBA/1 mice immunized with type II collagen in complete Freund's adjuvant

Collagen-induced arthritis (CIA) is an (autoimmune) joint disease readily elicited in DBA/1 mice by immunization with type II collagen (CII) emulsified with complete Freund's adjuvant. It is a destructive arthritis involving about 50% of the limbs and occurs with an incidence of 70% to 100%. In this study we evaluated the effect of mouse recombinant interleukin-12 (mrIL-12) on CIA. Administration of mrIL-12 at high doses (1 μg/mouse, daily) for 2 or 3 weeks delayed the onset and reduced the incidence of CIA. Furthermore, the severity of CIA was much milder and in most cases restricted to single digits of the paws. Short-term administration of high doses of IL-12 exerted some, but less pronounced, disease-suppressing effect. In contrast, 10-fold lower doses of IL-12 given during the first 3 weeks, or high doses of IL-12 administered therapeutically proved to be ineffective. Only those regimens of IL-12 treatment that ameliorated CIA were associated with a down-regulation of the CII-specific antibody response. A strong inhibition of CII-specific IgG1 antibodies (10- to 20-fold) and a moderately (2- to 6-fold) suppressed IgG2b response was observed, whereas the level of CII-specific IgG2a antibodies remained high. Taken together, the results indicate that some initial events in the induction of CIA in DBA/1 mice injected with CII emulsified with CFA are suppressed by treatment with high doses of IL-12.     

Chemokines in human periodontal disease tissues

CIA in the rhesus monkey is an autoimmune-based polyarthritis with inflammation and erosion of synovial joints that shares various features with human rheumatoid arthritis (RA). The close phylogenetic relationship between man and rhesus monkey makes the model very suitable for preclinical safety and efficacy testing of new therapeutics with exclusive reactivity in primates. In this study we have investigated the prophylactic and therapeutic effects of a humanized monoclonal antibody (Daclizumab) against the alpha-chain of the IL-2 receptor (CD25). When Daclizumab treatment was started well after immunization but before the expected onset of CIA a significant reduction of joint-inflammation and joint-erosion was observed. A therapeutic treatment, initiated as soon as the first clinical signs of CIA were observed, proved also effective since joint-degradation was abrogated. The results of this study indicate that Daclizumab has clinical potential for the treatment of RA during periods of active inflammation and suppression of the destruction of the joint tissues.     

IL-15 exacerbates collagen-induced arthritis with an enhanced CD4+ T cell response to produce IL-17

IL-15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL-15 plays an important role in the development of murine collagen-induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL-15 KO mice but were increased in IL-15 Tg mice compared with wild-type (WT) mice. The levels of type II collagen (CII)-specific IL-17 production were significantly increased in IL-15 Tg mice compared with WT mice with CIA. Expression of IL-23R was up-regulated in CD4(+) T cells in IL-15 Tg mice but down-regulated in IL-15 KO mice compared with WT mice. In correlation with the expression levels of IL-23R, IL-17 production by CD4(+) T cells in response to exogenous IL-23 was increased in IL-15 Tg mice compared with WT mice. Furthermore, exogenous IL-15 synergized with IL-23 to induce CII-specific IL-17 production by CD4(+) T cells in vitro. Taken together, these results indicate that IL-15 plays an important role in the progression of CIA through increasing antigen-specific IL-17 production by CD4(+) T cells.     

Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-alpha and IL-1beta

We previously demonstrated the therapeutic effects of ethinyl estradiol (EE), an orally active estrogen and a component of birth control pills, in encephalitogenic autoimmune encephalomyelitis (EAE). In this study, we report the effectiveness of EE in treating collagen-induced arthritis (CIA) induced with bovine type II collagen (bCII) in DBA/1LacJ mice, a CIA susceptible strain. Both low and high doses of EE notably suppressed clinical and histological signs of CIA in a dose-dependent manner compared to vehicle-treated controls. Oral treatment with EE decreased proliferation and secretion of pro-inflammatory factors, TNF-alpha IFN-gamma, MCP-1 and IL-6 by bCII peptide-specific T cells, production of bCII-specific IgG2a antibodies, and mRNA for cytokines, chemokines and chemokine receptors in joint tissue. This is the first report demonstrating effective treatment of joint inflammation and clinical signs of CIA with orally administered ethinyl estradiol, thus supporting its possible clinical use for treating rheumatoid arthritis in humans.     

Pharmacological efficacy of anti-IL-1β scFv,Fab and full-length antibodies in treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that mainly causes the synovial joint inflammation and cartilage destruction. Interleukin-1β (IL-1β) is an important proinflammatory cytokine involved in the pathogenesis of RA. In this study, we constructed and expressed anti-IL-1β-full-length antibody in CHO-K1-SV, anti-IL-1β-Fab and anti-IL-1β-scFv in Rosetta. We compared the therapeutic efficacy of three anti-IL-1β antibodies for CIA mice. Mice with CIA were subcutaneously injected with humanized anti-IL-1β-scFv, anti-IL-1β-Fab or anti-IL-1β-full-length antibody. The effects of treatment were determined by arthritis severity score, autoreactive humoral, cellular immune responses, histological lesion and cytokines production. Compared with anti-IL-1β-scFv treatments, anti-IL-1β-Fab and anti-IL-1β-full-length antibody therapy resulted in more significant effect in alleviating the severity of arthritis by preventing bone damage and cartilage destruction, reducing humoral and cellular immune responses, and down-regulating the expression of IL-1β, IL-6, IL-2, IFN-γ, TNF-α and MMP-3 in inflammatory tissue. The therapeutic effects of anti-IL-1β-Fab and anti-IL-1β-full-length antibodies on CIA mice had no significant difference. However, production of anti-IL-1β-full-length antibody in eukaryotic system is, in general, time-consuming and more expensive than that of anti-IL-1β-Fab in prokaryotic systems. In conclusion, as a small molecule antibody, anti-IL-1β-Fab is an ideal candidate for RA therapy.     

抗VEGF中和抗体对Ⅱ型胶原诱导的关节炎形成的影响

目的：了解抗血管内皮生长因子（VEGF）中和抗体对Ⅱ型胶原（CoⅡ）诱导的关节炎（CIA）形成的影响。方法：于8～10wk龄的DBA／1J小鼠尾根部皮内注射鸡CoⅡ进行被动免疫，建立小鼠CIA模型，以CIA发生率、关节炎指数及关节组织的病理变化为指标，评价抗VEGF抗体对CIA形成的影响。结果：与对照组相比较．在CIA形成的早期，注射抗VEGF中和抗体能有效地抑制关节炎的产生及减轻其严重程度（P〈0．05）；而在CIA已形成后再注射抗VEGF中和抗体对关节炎的严重程度则无明显影响（P〉0．05）。结论：抗VEGF中和抗体明显抑制滑膜细胞增殖、血管新生及血管炎，因此有望成为类风湿性关节炎（RA）治疗的新型制剂。     

根尖牙乳头间充质干细胞移植对胶原诱导性关节炎的影响

目的:探讨根尖牙乳头间充质干细胞(SCAP)移植对胶原诱导性关节炎(CIA)的影响。方法:用域型胶原蛋白免疫20 只DBA/1J 品系小鼠诱导CIA,然后小鼠被随机平分为2 组(SCAP 治疗组及阳性对照组),于初次免疫后的第21 天分别静脉注射人SCAP 及PBS,另有6 只正常DBA/1J 小鼠作为阴性对照组。ELISA 检测TNF-α及抗C域抗体水平,通过关节炎指数评分组织病理学分析及显微CT 分析来评估关节炎的严重程度。流式细胞分析比较各组脾脏CD4+ Th 细胞亚群的水平。结果:一次性静脉输入SCAP 能明显降低实验性关节炎的严重程度,恢复Th 亚群的平衡。结论:SCAP 移植治疗能诱导调节性T 细胞水平,从而获得免疫耐受,缓解CIA 炎症。     

Meloxicam in acute episodes of soft-tissue rheumatism of the shoulder

OBJECTIVE AND DESIGN: A newly synthesized inhibitor of pyrimidine de novo biosynthesis, KF20444 (6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H-benzo [6,7] cyclohepta [1,2-b] quinoline-8-carboxylic acid), was evaluated as an inhibitor of dihydroorotate dehydrogenase (DHO-DHase) and tested in the rat collagen-induced arthritis (CIA) model. MATERIAL AND METHODS: Female Sprague Dawley rats, 5 weeks-old, were used for evaluation of KF20444 in the CIA model. Arthritis was evaluated by arthritis score, serum anti-type II collagen antibody titer, body weight loss, radiographical and histological changes. TREATMENT: KF20444 was orally administered 5 times per week (0.3, 1, 3 mg/kg/day). RESULTS: KF20444 inhibited rat liver dihydroorotate dehydrogenase in vitro with Ki = 8.5 +/- 3.2 nM, which was a comparable effect to that of brequinar sodium (Ki = 25.3 +/- 5.3 nM). The anti-proliferative effect of KF20444 was caused by cell cycle arrest at the S-phase. Treatment with 3 mg/kg/day of KF20444 completely prevented the development of CIA based on reduction of the arthritis score. The 50% effective dose (ED50) of KF20444 on arthritis score was 0.64 mg/kg. KF20444 ameliorated body weight loss associated with disease onset. The compound also inhibited the increase in serum anti-type II collagen antibody level, and reduced both pannus formation and bone erosion. Importantly, KF20444 suppressed the development of arthritis, even when it was administered after booster immunization of collagen. CONCLUSIONS: KF20444 is a novel immunosuppressant which inhibits DHO-DHase and its effects in CIA suggest that it could be useful in the treatment of rheumatoid arthritis.     

Altered influenza virus haemagglutinin (HA)-derived peptide is potent therapy for CIA by inducing Th1 to Th2 shift

There has been an increase in interest in the use of altered peptides as antigen-specific therapeutic agents in autoimmune diseases. Here we investigated the inhibitory effect and possible mechanism of an altered influenza virus haemagglutinin (HA)-derived peptide in collagen-induced arthritis (CIA). CIA was induced in DBA/1 mice by immunisation with type II collagen (CII). Altered HA308-317, wild-type HA308-317 or irrelevant peptide was administered intranasally beginning from arthritis onset. Clinical and histological scores were assessed, and cytokine levels in the serum or supernatants from splenocytes were determined. The percentages of Th1 and Th2 cells in response to different peptides were analysed by FACS both in vivo and in vitro. Our results showed that intranasal administration of altered HA308-317 peptide significantly ameliorated CIA. The therapeutic effect of altered HA308-317 peptide was associated with a substantial decrease in production of interferon (IFN)-γ, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, anti-CII IgG, IgG1 and IgG2a antibodies, and an markedly increase in production of IL-10 and IL-4 in serum or supernatants from splenocytes treated with altered HA308-317 peptide. The percentage of Th2 (CD4(+)IL-4(+)) cells was upregulated significantly by altered HA308-317 peptide with a decreased percentage of Th1 (T helper 1; CD4(+)INF-γ(+)) cells both in vivo and in vitro. These findings suggest that altered HA308-317 peptide might be a promising candidate for rheumatoid arthritis (RA) treatment.     

A new orally active anti-rheumatic drug targets IL-15 and IL-17]

Over production of interleukin (IL)-15 and IL-17 was observed in synovial fluids of rheumatoid arthritis (RA) patients. IL-15 activates T cells and induces IL-17 production whereas IL-17 stimulates synoviocytes to release several mediators of inflammation including IL-6, TNF-alpha, IL-8, and CCL2. Thus, it is presumed that IL-15 and IL-17 play important roles in the pathogenesis of RA. Based on these results, we investigated a new anti-rheumatic drug targets IL-15 and IL-17 and found a new pyrazoleanilide derivative, Y-320 that inhibits IL-15-induced IL-17 production by T cells at 10-nM order. Therapeutic treatment with Y-320 (0.3 to 3 mg/kg orally) significantly inhibited the progression of arthritis and joint destruction in type II collagen-induced arthritis (CIA) in DBA/1J mice. Y-320 inhibited the elevation of IL-17 mRNA expression in the joint of CIA mice. Concomitant treatment with Y-320 and anti-mouse TNF-alpha antibody showed a synergistic effect in mouse CIA. Moreover, therapeutic treatment with Y-320 (0.3 and 1 mg/kg orally) ameliorated CIA in cynomolgus monkeys. Our results suggest that Y-320, a small molecule inhibitor for IL-17 production, is a candidate for the new class of orally active anti-rheumatic drug.     

An anti-inflammatory role for interleukin-11 in established murine collagen-induced arthritis.

Interleukin-11 (IL-11) is a cytokine belonging to the IL-6 family which has both pro- and anti-inflammatory potential. Like IL-6 it can diminish tumour necrosis factor-alpha and IL-1 production, and augment immunoglobulin synthesis. We have explored the immunomodulatory effects of IL-11 treatment in mice in a model of inflammatory autoimmune joint disease, collagen-induced arthritis (CIA). Recombinant human IL-11 was administered at various doses to DBA/1 mice after the onset of CIA. IL-11 treatment caused a significant reduction in the clinical severity of established CIA, which was associated with protection from joint damage, as assessed by histology. Although there was a suggestion at high doses of IL-11 that the anticollagen type II (CII) response may have been augmented, there was no statistically significant effect of IL-11 treatment on anti-CII antibody levels. Similarly, the acute-phase reactant serum amyloid P was only elevated in mice receiving very high doses (50-100 microgram/day) of IL-11. Endogenous IL-11 was abundantly produced in synovial membrane cultures derived from CII-immunized mice with active disease, suggesting that, as in rheumatoid arthritis, this cytokine is spontaneously produced in the inflammatory response in CIA. The results presented here demonstrate an anti-arthritic immunoregulatory role for IL-11 in murine CIA, and suggest that IL-11 is a candidate therapeutic molecule for human inflammatory arthritic diseases.