Abstract
BackgroundNovel molecules that specifically target human TNFα in rheumatoid arthritis pose problems for preclinical assessment of efficacy. In this study collagen antibody-induced arthritis (CAIA) has been induced in human TNFα transgenic mice to provide a novel model that has been optimised for the evaluation of molecules targeting human TNFα.MethodsTg1278TNFko mice lack murine TNFα and are heterozygous for multiple copies of the human TNFα transgene that is expressed under normal physiological control. To establish CAIA, a collagen II monoclonal antibody cocktail (CAb) at 2, 4 or 8 mg was injected i.p. on Day 0 followed by a lipopolysaccharide (LPS) boost (10 or 100 μg) i.p. on Day 1 or Day 4. Animals were assessed for arthritis symptoms using a clinical score, cytokine levels (human TNFα, IL-1β and IL-6) in sera and joints, and histopathology. The dependence of the model on human TNFα was determined by dosing animals with etanercept.ResultsTg1278TNFko animals treated with 2, 4 or 8 mg CAb on Day 0, with 100μg LPS on Day 4, had more severe arthritis and earlier symptoms than wild type animals at all doses of CAb tested. Subsequently it was found that the transgenic model did not require LPS at all for arthritis development but a lower dose of LPS (10 μg) was found necessary for reproducible and robust disease (close to 100% incidence, well-synchronised, with high arthritis scores). Furthermore the LPS challenge could be brought forward to Day 1 so that its’ actions to facilitate disease could be separated temporally from the arthritis phase (beginning about Day 4). Etanercept, administered immediately after the serum spike of cytokines associated with LPS had subsided, was able to dose-dependently inhibit arthritis development and this was associated with a marked protection of the joints histologically on Day 14. Etanercept was also able to reverse the signs of arthritis when given therapeutically allowing animals to be matched for disease burden before dosing begins.ConclusionsThe features of CAIA in Tg1278TNFko animals make the model well-suited to testing the next generation of therapeutics that will target human TNFα in rheumatoid arthritis.
Highlights
Novel molecules that target human TNFα in rheumatoid arthritis pose problems for preclinical assessment of efficacy
LPS challenge was associated with weight loss that was evident from time of challenge (Day 4) to Day 6 when weights were recorded
For wild type animals the weight loss amounted to approximately 16% but it was rather higher in the Tg1278TNFko animals at approximately 22%
Summary
Novel molecules that target human TNFα in rheumatoid arthritis pose problems for preclinical assessment of efficacy. Patients will have failed conventional treatments such as methotrexate before being considered suitable for anti TNFα therapy. The problem with this is that anti TNFα treatment might be more effective if initiated early, and current thinking is to identify and treat RA patients as quickly as possible in an attempt to induce long term remission [2]. Another problem with biologics is that they are inconvenient to administer when compared with conventional therapy
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