CII)-induced Arthritis Research Articles

IL-23 induces IRF5 and polarizes inflammatory M1 macrophages to promote inflammation in a mouse model of arthritis (171.5)

Abstract Increased numbers of macrophages (MΦs) is an early hallmark of active arthritis. Expression of IL-23R has been identified on myeloid cells. We determined if IL-23 can regulate the pathogenesis of collagen II-induced arthritis (CIA) by directly modulating development of MΦs. AdIL-17 was injected to Il23p19-/- and Il23p19+/+ mice to induce equal levels of IL-17 yet Il23p19-/-mice were more resistant to CIA compared to Il23p19+/+ mice. Dramatic expansion of IL-23R+ MΦs, which are the major producers of IL-6 and TNFα in the draining LN of mice with CIA, occurred only in Il23p19+/+ but not Il23p19-/- mice. IL-23 suppressed the expression of anti-inflammatory TGFβ and IL-10 produced by M2 MΦs and promoted expression of inflammatory IL-6 and TNFα produced by M1 MΦs in vitro. IL-23 prevents the ability of M-CSF to promote development of anti-inflammatory M2 MΦs by inducing the expression of Irf5, an M1 specific transcription factor. Using GFP-Foxp3 reporter mice, accumulation of Foxp3+ Tregs were only observed in Il23p19-/- but not Il23p19+/+ mice with CIA. Coculture of IL-23 stimulated MΦs with naïve CD4 T cells prevented the development and function of Treg cells, which could be reversed in the presence of anti-IL-6. Our results suggest that IL-23 induces the expression of IRF5 and promotes M1 MΦs that perpetuate the development of CIA. One important function of IL-23-activated MΦs was to prevent the development of Treg cells via an IL-6 dependent mechanism.

Immune‐modulator Metallo‐peptide (IMMP) effect on an in vivo model of Rheumatoid Arthritis

The management of rheumatoid arthritis (RA) has witnessed significant changes over the past decade. The ambition to improve outcomes further, minimize safety concerns and provide more convenient means of administration are all factors that continue to drive continued drug development. The new emerging therapies for the management of RA illustrate much diversity, both in terms of both drug technology as well as the immunological target. Immuno‐modulator metallopeptides (IMMP) is a new factor that could act as biological drug for the management of RA. Our aim is to evaluate IMMP effect on an in vivo model of autoimmune RA. RA in Wistar rats was induced by administration of bovine collagen II. IMMP (50 ng/Kg), i.p., three times a week for 21 days was administrated to Wistar females rats with bovine collagen II‐induced arthritis. The IMMP treatment eliminated all inflammation in 25% of rats, in addition, the treatment reduced the inflammation in 50 % on other 25 % of rats, and meanwhile the remaining 50 % of animals there were no changes. anti‐inflammatory effect. IMMP treatment decreased the breakdown of bone and cartilage, as well as serum levels of the pro‐inflammatory cytokine IL‐4. Histological studies showed that IMMP did not produce alterations in the lymphoid tissues, as well as other organs.

Mice Deficient in CD38 Develop an Attenuated Form of Collagen Type II-Induced Arthritis

CD38, a type II transmembrane glycoprotein expressed in many cells of the immune system, is involved in cell signaling, migration and differentiation. Studies in CD38 deficient mice (CD38 KO mice) indicate that this molecule controls inflammatory immune responses, although its involvement in these responses depends on the disease model analyzed. Here, we explored the role of CD38 in the control of autoimmune responses using chicken collagen type II (col II) immunized C57BL/6-CD38 KO mice as a model of collagen-induced arthritis (CIA). We demonstrate that CD38 KO mice develop an attenuated CIA that is accompanied by a limited joint induction of IL-1β and IL-6 expression, by the lack of induction of IFNγ expression in the joints and by a reduction in the percentages of invariant NKT (iNKT) cells in the spleen. Immunized CD38 KO mice produce high levels of circulating IgG1 and low of IgG2a anti-col II antibodies in association with reduced percentages of Th1 cells in the draining lymph nodes. Altogether, our results show that CD38 participates in the pathogenesis of CIA controlling the number of iNKT cells and promoting Th1 inflammatory responses.

Gene silencing of IL-12 in dendritic cells inhibits autoimmune arthritis

BackgroundWe have previously demonstrated that immune modulation can be accomplished by administration of gene silenced dendritic cells (DC) using siRNA. In this study, we demonstrate the therapeutic utilization of shRNA-modified DC as an antigen-specific tolerogenic vaccine strategy for autoimmune arthritis.MethodsA shRNA that specifically targets IL-12 p35 was designed and cloned into a plasmid vectors (IL-12 shRNA). Bone marrow-derived DC from DBA/1 mice were transfected with the IL-12 shRNA construct in vitro. Mice with collagen II (CII)-induced arthritis (CIA) were treated with the modified DCs expressing the shRNA. Recall response and disease progression were assessed.ResultsAfter gene silencing of IL-12 in DC, DC were shown to selectively inhibit T cell proliferation on recall responses and in an MLR. In murine CIA, we demonstrated that administration of IL-12 shRNA-expressing DC that were pulsed with CII inhibited progression of arthritis. The therapeutic effects were evidenced by decreased clinical scores, inhibition of inflammatory cell infiltration in the joint, and suppression of T cell and B cell responses to CII.ConclusionWe demonstrate a novel tolerance-inducing protocol for the treatment of autoimmune inflammatory joint disease in which the target antigen is known, utilizing DNA-directed RNA interference.

Statins accelerate the onset of collagen type II-induced arthritis in mice

IntroductionStatins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia, hypertension, or type II diabetes. Next to their cholesterol-lowering activity, statins have immunomodulatory properties. Based on these properties, we hypothesized that statin use may eventually lead to dysregulation of immune responses, possibly resulting in autoimmunity. We have recently shown in an observational study that statin use was associated with an increased risk of developing rheumatoid arthritis. Our objective was to investigate whether a causal relationship could be established for this finding.MethodsThe mouse collagen type II (CII)-induced arthritis (CIA) model was used, with immunization, challenge, and euthanasia at days 0, 21, and 42, respectively. Statins were given orally before (day -28 until day 21) or after (day 21 until day 42) CIA induction. Atorvastatin (0.2 mg/day) or pravastatin (0.8 mg/day) was administered. Arthritis was recorded three times a week. Serum anti-CII autoantibodies and cytokines in supernatants from Concanavalin-A-stimulated lymph node cells and CII-stimulated spleen cells were measured.ResultsStatin administration accelerated arthritis onset and resulted in 100% arthritic animals, whereas only seven out of 12 nonstatin control animals developed arthritis. Atorvastatin administration after CIA induction resulted in earlier onset than atorvastatin administration before induction, or than pravastatin administration before or after induction. The arthritic score of animals given pravastatin before CIA induction was similar to that of the nonstatin controls, whereas the other groups that received statins showed higher arthritic scores. Atorvastatin administration, especially before CIA induction, increased anti-CII autoantibody production. IL-2 and IL-17 production by lymph node and spleen cells was higher in CIA animals than in PBS controls, but was not affected by statin administration. While IFNγ production was not affected by CIA induction, atorvastatin administration before CIA induction increased the production of this cytokine.ConclusionThese data support previous results from our observational studies, indicating a role for statins in the induction of autoimmunity.

Evaluation of antiarthritic and immunomodulatory activity of Barleria lupulina

ObjectiveBarleria lupulina Lindl (Acanthaceae) (B. lupulina) has been traditionally used in the treatment of rheumatoid arthritis but, no scientific data has been published supporting the claimed ethnomedical use. This study was designed to investigate the anti-arthritic potential of B. lupulina leaves and its role in immunomodulation. MethodsMethanol extract of B. lupulina (MEBL) leaves (300 and 600 mg/kg BW) was tested for its antiarthritic activity by various models namely, formalin-induced arthritis, adjuvant induced arthritis, collagen type II-induced arthritis and monosodium iodoacetate induced osteoarthritis. Immunomodulatory activity of the same was tested by measuring WBC Count, Spleen Weight, Spleen WBC Count and Delayed Type Hypersensitivity (DTH) Reaction. ResultsMEBL extracts 300 mg/kg and 600 mg/kg showed statistically significant inhibition (P<0.05 and P<0.001) of the edema formation and Myeloperoxidase (MPO) during experimental period and activities of antioxidants were restored significantly. MEBL extracts 300 mg/kg and 600 mg/kg significantly increased the Hemoglobin (Hb) level, serum albumin, total protein, calcium and phosphorus levels and reverted back the levels of WBC count and Erythrocyte Sedimentation Rate (ESR) (P<0.05 and P<0.01). Histopathological studies of ankle joints also supported this finding. Immunomodulatory study revealed an increase in the blood leukocytes count, weight of spleen, spleenic leukocytes count and increase in paw volume on delayed type hypersensitivity footpad thickness suggesting an uplift of immune status. ConclusionsThe present study concluded that, MEBL holds antiarthritic and Immunomodulatory activity. Although subsequent study is required to evaluate the active constituents responsible for the activity.

Effects of chondroitin sulfate-C on articular cartilage destruction in murine collagen-induced arthritis.

The effects of chondroitin sulfate-C (CAS 25322-46-7, Chondroitin ZS Tab) on type II collagen (CII)-induced arthritis (CIA) in mice were evaluated. DBA/1J mice were immunized with bovine CII emulsified in Freund's complete adjuvant, followed by a booster injection 21 days later. Chondroitin sulfate-C at doses of 100, 300 and 1000 mg/kg was administered orally once daily beginning 14 days before initial immunization. An arthritis index and hind paw edema were examined from day 0 to day 49, when the mice were killed by ether anesthesia for histopathological examination. The delayed-type hypersensitivity (DTH) reaction, serum anti-CII antibody titer, and histopathologic characteristics of both synovitis and destruction of articular cartilage were analyzed. Both the arthritis index and the serum anti-CII antibody titer were reduced by treatment with chondroitin sulfate-C in a dose-dependent manner. Chondroitin sulfate-C (1000 mg/kg) significantly inhibited hind paw edema, synovitis and destruction of the articular cartilage, but not DTH reaction.

Pathogenic Autoreactive B Cells Are Not Negatively Selected toward Matrix Protein Collagen II

We have addressed the importance of B cell tolerance to collagen type II, a matrix protein, which is a target in rheumatoid arthritis (RA) and its mouse models. We generated a germline-encoded anti-collagen type II (CII) IgH replacement anti-C1 B cell mouse strain (ACB) to investigate how B cell tolerance to CII, a matrix protein, is subverted and to further understand pathogenesis of RA. Phenotypic analysis revealed that CII-specific B cells were surprisingly neither deleted nor anergized. Instead, they were readily detected in all lymphoid organs. Spontaneously produced autoantibodies could bind directly to cartilage surface without detectable pathology. However, exaggerated arthritis was seen after injection of anti-CII Abs specific for other epitopes. In addition, Abs from CII-specific hybridomas generated from ACB mice induced arthritis. Interestingly, IgH/L chain sequence data in B cell hybridomas revealed a lack of somatic mutations in autoreactive B cells. The ACB model provides the first possibility, to our knowledge, to study B cell tolerance to a matrix protein, and the observations made in the study could not be predicted from previous models. B cell-reactive epitopes on CII are largely shared between human RA and rodent CII-induced arthritis; this study, therefore, has important implications for further understanding of pathological processes in autoimmune diseases like RA.

Inhibitory effects of the root extract of Dipsacus asperoides C.Y. Cheng et al T.M.Ai on collagen-induced arthritis in mice

Ethnopharmacological relevanceDipsaci radix, the dried root of Dipsacus asperoides C.Y. Cheng et al T.M.Ai is used as a medicinal plant in oriental clinics for the treatment of bone diseases and functions by strengthening bone and healing bone fractures. Aim of the studyThis study investigated the therapeutic efficacy of Dipsaci radix in treating rheumatoid arthritis using a type II collagen (CII)-induced arthritis (CIA) mouse model. Materials and methodsArthritis was induced in male DBA/1 mice by immunization with CII. Dipsaci radix water (DR-W) extract at 50mg/kg and 100mg/kg was orally administered from days to after the induction of arthritis. Arthritic score, serum levels of anti-CII IgG2a, the inflammatory mediator prostaglandin E2 (PGE2), and inflammatory cytokines (TNF-α, IL-1β and IL-6), and histological changes in the ankle joint were analyzed in CIA mice. ResultsArthritic induction increased the arthritic score, as well as serum levels of anti-CII IgG2a antibody, PGE2, TNF-α, IL-1β and IL-6 in mice. However, administration of DR-W extract in CIA mice significantly reduced arthritic scores and serum levels of anti-CII IgG2a antibody, PGE2, TNF-α, IL-1β and IL-6 compared with those in vehicle-treated CIA mice. Furthermore, histopathological improvement in joint architecture was also observed in DR-W extract-treated CIA mice. ConclusionsDR-W extract has anti-inflammatory and anti-arthritic effects in arthritic mice. This suggests that Dipsaci radix might be used as a therapeutic agent for the treatment of human arthritis.

Neutral aminopeptidase and dipeptidyl peptidase IV in the development of collagen II-induced arthritis

This study evaluated the hypothesis that neutral (APN) and dipeptidyl-IV (DPPIV) aminopeptidase activity levels would be critical for the susceptibility to arthritis in collagen-induced model (CIA). The macroscopic signs of arthritis in CIA rats were checked and peripheral blood, synovial fluid and synovial tissue from knee joint were withdrawn. Soluble (SF) and solubilized membrane-bound (MF) fractions from the synovial tissue and peripheral blood mononuclear cells (PBMCs) were obtained. APN and DPPIV activities were fluorometrically quantified. Severe swelling in both the entire hind paws was the minimum criterion to select CIA rats with arthritis. These arthritic rats had high APN in plasma, synovial fluid and SF of the synovial tissue, together with low APN and DPPIV in MF of PBMCs and hallmark histological changes in tibio-tarsal joint. CIA rats with no macroscopic signs of arthritis were diagnosed as resistant and they had low APN in MF of the synovial tissue, low DPPIV in SF of PBMCs and high DPPIV in plasma together with histological aspects of tibio-tarsal joint similar to healthy control rats. Data suggested that APN and DPPIV activity levels are related to the development of arthritis, being protective or inducer of the susceptibility. Understanding what is controlling the compartment-specific changes of these peptidases and looking at ways in which to manipulate their activities may lead to a better knowledge of the arthritic processes and novel treatments.

Therapeutic effects of total coumarins from Urtica dentata Hand on collagen-induced arthritis in Balb/c mice

Ethnopharmacological relevanceUrtica dentata Hand (UDH), the root of Laportea bulbifera (Sieb. et. Zucc.) Wedd, has long been utilized in traditional Chinese medicine for the treatment of rheumatoid arthritis and some other autoimmune diseases. Coumarins are the main active principles contributing to UDH's efficacy, but the mechanisms have not been fully clarified. Aim of studyTo explore effects of total coumarins (TC) isolated from UDH on the development of type II collagen (CII)-induced arthritis (CIA) in Balb/c mice. Materials and methodsArthritis was induced in Balb/c mice by immunization with an emulsion of 200mg CII and complete Freund's adjuvant (CFA). The CIA mice were then given with a suspension of TC or saline by intragastric (i.g.) administration every other day. The incidence and severity of disease and histopathology of inflammation were assessed. Inflammatory response was determined by measuring the levels of different inflammation mediators in serum. The effect of TC on differentiation of CD4+CD25+ Foxp3+Treg cells was examined by flow cytometry. The phenotype of bone marrow-derived dendritic cells (DCs), T-bet mRNA level and IL-12p70 secretion by DCs were also detected. ResultsPharmacologically, treatment with TC for type II collagen induced arthritis in mice through oral administration displayed significant and dose-dependent drop of clinical arthritis score and paw swelling, compared with the untreated CIA mice. Pathologic changes showed that TC protected tissues against bone destruction, whereas an almost complete destruction occurred in the CIA model group. The protective status was associated with a substantial decrease in the production of IFN-γ and IL-2, an increase of IL-10 and TGF-β and suppressive expression of T-bet in DCs. TC also induced the generation of CD4+CD25+ Treg cells with a Treg phenotype Foxp3. TC-treated DCs were characterized as low expression of MHC class II and CD86 molecules, as well as a reduction of IL-12p70. ConclusionsOur data suggest that TC provides substantial therapeutic protection against CIA by eliciting immune tolerance and it would be a valuable candidate for further investigation as a new anti-arthritic agent.

The sympathetic nervous system stimulates anti-inflammatory B cells in collagen-type II-induced arthritis

BackgroundAs previously shown, the sympathetic nervous system (SNS) shows proinflammatory activity during initiation of arthritis but is anti-inflammatory in established collagen-induced arthritis (CIA). Interleukin 10 (IL-10)-producing B cells suppress arthritis...

Collagen Type II and a Thermo-Responsive Polymer of N-Isopropylacrylamide Induce Arthritis Independent of Toll-Like Receptors : A Strong Influence by Major Histocompatibility Complex Class II and Ncf1 Genes

We established and characterized an arthritis mouse model using collagen type II (CII) and a thermo-responsive polymer, poly(N-isopropylacrylamide) (PNiPAAm). The new PNiPAAm adjuvant is TLR-independent, as all immunized TLR including MyD88-deficient mice developed an anti-CII response. Unlike other adjuvants, PNiPPAm did not skew the cytokine response (IL-1β, IFN-γ, IL-4, and IL-17), as there was no immune deviation towards any one type of immune spectrum after immunization with CII/PNiPPAm. Hence, using PNiPAAm, we studied the actual immune response to the self-protein, CII. We observed arthritis and autoimmunity development in several murine strains having different major histocompatibility complex (MHC) haplotypes after CII/PNiPAAm immunization but with a clear MHC association pattern. Interestingly, C57Bl/6 mice did not develop CII-induced arthritis, with PNiPAAm demonstrating absolute requirement for a classical adjuvant. Presence of a gene (Ncf1) mutation in the NADPH oxidation complex has a profound influence in arthritis and using PNiPAAm we could show that the high CIA severity in Ncf1 mutated mice is independent of any classical adjuvant. Macrophages, neutrophils, eosinophils, and osteoclasts but not mast cells dominated the inflamed joints. Furthermore, arthritis induction in the adjuvant-free, eosinophil-dependent Vβ12 DBA/1 mice could be shown to develop arthritis independent of eosinophils using CII/PNiPAAm. Thus, biocompatible and biodegradable PNiPAAm offers unique opportunities to study actual autoimmunity independent of TLR and a particular cytokine phenotype profile.

Protective effect of soy protein on collagen-induced arthritis in rat

To evaluate preventive and therapeutic effects of soy protein on collagen-induced arthritis rats. Sprague-Dawley rats immunized with bovine type II collagen emulsified in adjuvant and treated with soy protein (7 g/kg), dexamethasone (1 mg/kg), and casein (in control groups) by daily gavages feedings for 30 days. Score of arthritis recorded every day for each paws of animal. Tumor necrosis factor-alpha, interleukin6, leptin, and adiponectin were measured in serums. Treatment with soy protein resulted in significant delay in time to onset of arthritis as well as significantly decreased arthritis incidence, clinical arthritis severity score, histopathological arthritis severity score, and in vivo cell-mediated immunity to collagen (P < 0.05). Administration of soy protein significantly suppressed the progression of collagen II-induced arthritis and inhibited the production of tumor necrosis factor-alpha, interleukin6, leptin, and adiponectin. Soy protein appeared to be a potent immunomodulatory inhibitor of collagen II-induced arthritis in rats. It could delay onset of RA and reduced cartilage erosion and synovitis inflammation. Therefore, it may be a useful protein in the prevention and treatment of rheumatoid arthritis patient.

Monoclonal Anti-HMGB1 (High Mobility Group Box Chromosomal Protein 1) Antibody Protection in Two Experimental Arthritis Models

High mobility group box chromosomal protein 1 (HMGB1) is a DNA-binding nuclear protein that can be released from dying cells and activated myeloid cells. Extracellularly, HMGB1 promotes inflammation. Experimental studies demonstrate HMGB1 to be a pathogenic factor in many inflammatory conditions including arthritis. HMGB1-blocking therapies in arthritis models alleviate disease and confer significant protection against cartilage and bone destruction. So far, the most successful HMGB1-targeted therapies have been demonstrated with HMGB1-specific polyclonal antibodies and with recombinant A box protein, a fragment of HMGB1. The present study is the first to evaluate the potential of a monoclonal anti-HMGB1 antibody (2G7, mouse IgG2b) to ameliorate arthritis. Effects of repeated injections of this antibody have now been studied in two conceptually different models of arthritis: collagen type II-induced arthritis (CIA) in DBA/1 mice and in a spontaneous arthritis disease in mice with combined deficiencies for genes encoding for the enzyme DNase type II and interferon type I receptors. These mice are unable to degrade phagocytozed DNA in macrophages and develop chronic, destructive polyarthritis. Therapeutic intervention in CIA and prophylactic administration of anti-HMGB1 monoclonal antibody (mAb) in the spontaneous arthritis model significantly ameliorated the clinical courses. Anti-HMGB1 mAb therapy also partially prevented joint destruction, as demonstrated by histological examination. The beneficial antiarthritic effects by the anti-HMGB1 mAb in two diverse models of arthritis represent additional proof-of-concept, indicating that HMGB1 may be a valid target molecule to consider for development of future clinical therapy.

Changes and significance of IL-25 in chicken collagen II-induced experimental arthritis (CIA)

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease. It is a systemic inflammatory disease, characterized by chronic, symmetrical, multi-articular synovial arthritis. IL-25 (IL-17E) is a member of the recently emerged cytokine family (IL-17s), which is expressed in Th2 cells and bone marrow-derived mast cells. Unlike the other members of this family, IL-25 is capable of inducing Th2-associated cytokines (IL-4, IL-5, and IL-13) and also promotes the release of some pro-immune factors (IL-6 and IL-8). IL-25 is also a pleiotropic factor, which constitutes a tissue-specific pathological injury and chronic inflammation. In this study, we used chicken collagen II-induced experimental arthritis (CIA) model in DBA/1 mice to investigate the relationship between IL-25 and other inflammatory factors, revealing the possible mechanism in CIA. Our results showed that the expression level of IL-25 was enhanced in the late stage of CIA, and IL-17 was increased in the early stage of the disease. It is well known that IL-17 has a crucial role in the development of RA pathogenesis, and IL-25 plays a significant role in humoral immune. For reasons given above, we suggested that the IL-25 inhibited IL-17 expression to some extent, while enhancing the production of IL-4. It was confirmed that IL-25 not only regulated the cellular immune, but also involved the humoral immune in rheumatoid arthritis.

A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis

IntroductionJanus kinase 2 (JAK2) is involved in the downstream activation of signal transducer and activator of transcription 3 (STAT3) and STAT5 and is responsible for transducing signals for several proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), including interleukin (IL)-6, interferon γ (IFNγ) and IL-12. In this paper, we describe the efficacy profile of CEP-33779, a highly selective, orally active, small-molecule inhibitor of JAK2 evaluated in two mouse models of RA.MethodsCollagen antibody-induced arthritis (CAIA) and collagen type II (CII)-induced arthritis (CIA) were established before the oral administration of a small-molecule JAK2 inhibitor, CEP-33779, twice daily at 10 mg/kg, 30 mg/kg, 55 mg/kg or 100 mg/kg over a period of 4 to 8 weeks.ResultsPharmacodynamic inhibition of JAK2 reduced mean paw edema and clinical scores in both CIA and CAIA models of arthritis. Reduction in paw cytokines (IL-12, IFNγ and tumor necrosis factor α) and serum cytokines (IL-12 and IL-2) correlated with reduced spleen CII-specific T helper 1 cell frequencies as measured by ex vivo IFNγ enzyme-linked immunosorbent spot assay. Both models demonstrated histological evidence of disease amelioration upon treatment (for example, reduced matrix erosion, subchondral osteolysis, pannus formation and synovial inflammation) and reduced paw phosphorylated STAT3 levels. No changes in body weight or serum anti-CII autoantibody titers were observed in either RA model.ConclusionsThis study demonstrates the utility of using a potent and highly selective, orally bioavailable JAK2 inhibitor for the treatment of RA. Using a selective inhibitor of JAK2 rather than pan-JAK inhibitors avoids the potential complication of immunosuppression while targeting critical signaling pathways involved in autoimmune disease progression.

Etiological role of cigarette smoking in rheumatoid arthritis: Nasal exposure to cigarette smoke condensate extracts augments the development of collagen-induced arthritis in mice

Cigarette smoking is a major environmental risk factor for rheumatoid arthritis (RA). However, the experimental bases supporting the etiological role of cigarette smoking in RA have not been fully provided. We have reported that cigarette smoke condensate (CSC), by means of subcutaneous injection into DBA/1J mice with collagen and complete Freund’s adjuvant or intraperitoneal injection one day before immunization, augmented the development of arthritis in the mouse model of collagen type II-induced arthritis (CIA). However, these experimental procedures may not be appropriate for cigarette smoking. In this study, we nasally exposed mice to mainstream CSC and found that CSC augmented the induction and development of arthritis and antibody level against collagen. Histological examination confirmed the augmenting effect of CSC. These findings provide experimental bases supporting the etiological role of cigarette smoking in RA.

Cocoa diet diminishes the anti-collagen humoral response in collagen-induced arthritis in rats

Collagen type II-induced arthritis (CIA) shares immunological and pathological characteristics with human rheumatoid arthritis. Anti-collagen (CII) autoantibodies appear to be a primary mechanism of immunopathogenesis in this model [1]. On the other hand, previous studies have shown that rats fed cocoa exhibit a lower antibody production after ovoalbumin immunization [2].

Combined effects of bucillamine and etanercept on a rat type II collagen-induced arthritis model

The combined effects of bucillamine (Buc) and etanercept (ETN) on a rat model of type II collagen (CII)-induced arthritis (CIA) after treatment onset were investigated. In the combination treatment, rats received Buc 30 mg/kg orally administered once daily from the onset of arthritis or from 4 days after the onset of arthritis and ETN 0.3 mg/kg subcutaneously administered once on the day of onset. The effects of monotherapy with Buc and ETN, respectively, and of Buc + ETN combination therapy on the resulting polyarthritis were evaluated by histopathological analyses and measurements of hindpaw volumes, serum anti-collagen antibody and immunoglobulin levels, and cytokine levels. The Buc + ETN therapeutic combination reduced hindpaw swelling, synovial proliferation, bone destruction, new bone formation, and inflammatory cell infiltration in CIA. Montherapy with Buc showed a tendency to ameliorate these symptoms, while monotherapy with ETN reduced hindpaw swelling at 4 days after administration but did not maintain treatment efficacy toward the end of the experimental period. Histopathological findings did not reveal any efficacy of the ETN therapy. ETN alone increased the serum immunoglobulin levels, while its combination with Buc reduced these levels. Similar results were obtained for serum anti-CII antibody titers. The Buc + ETN combination treatment also reduced serum interleuking (IL)-1α and granulocyte macrophage colony-stimulating factor and tended to reduce serum IL-1β and IL-6 levels. These results suggest that a combination therapy of Buc and ETN may be effective for the treatment of rheumatoid arthritis (RA).