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Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis.

ABSTRACT: INTRODUCTION: We previously demonstrated that synovial sublining macrophages express folate receptor beta (FR?). The aim of this study was to evaluate the efficacy of intra-articular administration of a recombinant immunotoxin to FR? for treating rat antigen-induced arthritis. METHODS: A monoclonal antibody (mAb) to rat FR? was produced by immunizing mice with B300-19 cells (murine pre-B cells) transfected with the rat FR? gene. Recombinant immunotoxin was prepared by conjugating the Fv portion of the anti-rat FR? mAb heavy chain with a truncated Pseudomonas exotoxin A and the Fv portion of the anti-rat FR? mAb light chain. Antigen-induced arthritis was induced through intra-articular injection of methylated bovine serum albumin (mBSA) after two subcutaneous injections of mBSA and complete Freund's adjuvant. Immunotoxin was intra-articularly injected into the arthritis joint every other day for seven days after arthritis onset. Joint swelling was measured and histological scores of inflammation, synovial thickness, cartilage, and bone destruction were determined. Immunohistochemistry was performed to detect osteoclast and osteoclast precursor FR?-expressing macrophages and cathepsin K-positive cells on day 21. RESULTS: Intra-articular administration of the immunotoxin attenuated joint swelling (61% suppression; P < 0.01 compared to the control on day 21) and improved histological findings, particularly cartilage and bone destruction (scores of rats treated with control versus the immunotoxin: 2.2 versus 0.5; P < 0.01), by reducing the number of FR?-expressing macrophages and cathepsin K-positive cells. CONCLUSIONS: Intra-articular administration of an immunotoxin to FR? is effective for improving rat antigen-induced arthritis.

SUBMITTER: Nagai T

PROVIDER: S-EPMC3446483 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis.

Nagai Taku T Kyo Akira A Hasui Kazuhisa K Takao Sonshin S Matsuyama Takami T

Arthritis research & therapy 20120502 3

<h4>Introduction</h4>We previously demonstrated that synovial sublining macrophages express folate receptor beta (FRβ). The aim of this study was to evaluate the efficacy of intra-articular administration of a recombinant immunotoxin to FRβ for treating rat antigen-induced arthritis.<h4>Methods</h4>A monoclonal antibody (mAb) to rat FRβ was produced by immunizing mice with B300-19 cells (murine pre-B cells) transfected with the rat FRβ gene. Recombinant immunotoxin was prepared by conjugating th ...[more]

PMID: 22551402

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Project description:IntroductionAdrenomedullin is a potent vasodilatory and hypotensive peptide as well as an endogenous immunomodulatory factor with predominantly anti-inflammatory effects. The purpose of the present study was to evaluate the therapeutic effects of adrenomedullin in rabbits with antigen-induced arthritis, an experimental model of rheumatoid arthritis.MethodsFollowing the induction of arthritis in both knee joints by ovalbumin injection into the joint spaces of pre-immunized rabbits, increasing daily doses of adrenomedullin were injected into the knee joint spaces or saline was injected into the contralateral knee joint spaces as the control. For time-course experiments, adrenomedullin and saline were injected into the knee joint spaces daily for 7 days and 20 days. The degree of joint swelling and the histological change in the knee joints injected with adrenomedullin were compared with the control knee joints. Histological evaluation of the infrapatellar fat pads and synovial tissue was performed. TNFalpha, IL-6, vascular endothelial growth factor and transforming growth factor-beta mRNA levels in the synovial tissue were measured using real-time quantitative PCR.ResultsDaily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis decreased joint swelling. Histological examination revealed that adrenomedullin reduced edematous changes and the infiltration of inflammatory cells in the synovial tissues. Analysis of mRNA levels showed that adrenomedullin significantly reduced TNFalpha mRNA expression by 21% to 49% in a dose-dependent manner, and dose-dependently increased IL-6 mRNA expression by 45% to 121%.ConclusionsThese results suggest that daily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis ameliorated the inflammatory response in arthritic joints. Adrenomedullin may thus be useful as a treatment for rheumatoid arthritis; however, the effect of adrenomedullin on IL-6 production in the synovial tissue may be an undesirable adverse effect in rheumatoid arthritis therapy.

Project description:BackgroundJuvenile Idiopathic Arthritis (JIA) commonly affects joints of the lower limb including the knee, ankle, subtalar and other foot joints. Intra-articular corticosteroid injections (IACIs) are considered to be effective for short-term relief of synovitis, however, there appears to be a significant lack of published evidence from comparative effectiveness studies. The aim of this study was to identify and critically appraise the evidence for the efficacy of lower limb IACIs in children/adolescents with JIA.MethodsStudies were identified in databases Medline, Embase, CINAHL, AMED, PEDro, the Cochrane Library and TRIP, with no date restrictions. The primary search terms 'juvenile idiopathic arthritis', 'lower limb', 'knee'; 'ankle', 'foot' and 'intra-articular steroid injections' and related synonyms were used to develop a comprehensive pragmatic literature search strategy. Included studies were quantitative longitudinal design such as randomised controlled trials, pseudo-randomised and non-randomised experimental studies, cohort studies, and case-control studies. All outcomes measures were subject to analysis. Quality assessment was conducted using the Cochrane Collaboration criteria with additional criteria for sample population representativeness, quality of statistical analysis and compliant intervention use and presence of co-interventions. Qualitative data synthesis was conducted for the outcome domains. Meta-analyses were not possible as multiple randomised controlled trials for outcome measures were not available. Levels of evidence were assigned to each outcome measure.ResultsThe inclusion criteria were met by twenty-one studies. One study had high quality for internal validity and nine studies had high quality for external validity. No studies had high quality for both internal and external validity. Four outcome domains were identified. There was weak evidence for IACIs decreasing clinical signs and symptoms in the lower leg, improving joint range of motion, decreasing leg length discrepancy, and for imaging techniques detecting the effects of IACIs.ConclusionsThere is some weak evidence for the efficacy of IACIs improving certain outcome measures. However, there is also some inconclusive evidence due to a lack of quality studies. More high quality evidence is necessary to definitely determine the efficacy of IACIs for JIA in the lower leg.

Dataset Information

Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis.

Publications

Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis.

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