Establishment and characterization of a sustained delayed-type hypersensitivity model with arthritic manifestations in C57BL/6J mice

Abstract

IntroductionRheumatoid arthritis (RA) is a chronic progressive, inflammatory and destructive autoimmune disease, characterised by synovial joint inflammation and bone erosion. To better understand the pathophysiology and underlying immune mechanisms of RA various models of arthritis have been developed in different inbred strains of mice. Establishment of arthritis models with components of adaptive immunity in the C57BL/6J strain of mice has been difficult, and since most genetically modified mice are commonly bred on this background, there is a need to explore new ways of obtaining robust models of arthritis in this strain. This study was undertaken to establish and characterise a novel murine model of arthritis, the delayed-type hypersensitivity (DTH)-arthritis model, and evaluate whether disease can be treated with compounds currently used in the treatment of RA.MethodsDTH-arthritis was induced by eliciting a classical DTH reaction in one paw with methylated bovine serum albumin (mBSA), with the modification that a cocktail of type II collagen monoclonal antibodies was administered between the immunisation and challenge steps. Involved cell subsets and inflammatory mediators were analysed, and tissue sections evaluated histopathologically. Disease was treated prophylactically and therapeutically with compounds used in the treatment of RA.ResultsWe demonstrate that DTH-arthritis could be induced in C57BL/6 mice with paw swelling lasting for at least 28 days and that disease induction was dependent on CD4+ cells. We show that macrophages and neutrophils were heavily involved in the observed pathology and that a clear profile of inflammatory mediators associated with these cell subsets was induced locally. In addition, inflammatory markers were observed systemically. Furthermore, we demonstrate that disease could be both prevented and treated.ConclusionsOur findings indicate that DTH-arthritis shares features with both collagen-induced arthritis (CIA) and human RA. DTH-arthritis is dependent on CD4+ cells for induction and can be successfully treated with TNFα-blocking biologics and dexamethasone. On the basis of our findings we believe that the DTH-arthritis model could hold potential in the preclinical screening of novel drugs targeting RA. The model is highly reproducible and has a high incidence rate with synchronised onset and progression, which strengthens its potential.

Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

“…In contrast to CAIA and the K/BxN models, disease development in DTHA is dependent on CD4 + T cells, and thus adds the dimension of the adaptive immune system while still being significantly immune-complex and neutrophildriven [24]. Depletion of CD4 + T cells prior to immunisation in DTHA completely prevents disease development [24] and depletion post induction of arthritis reduces disease severity significantly (our unpublished data).…”

“…The mice display systemic manifestations and severe paw inflammation and bone erosion, but only in the antigen-challenged paw. The dose of anti-CII given to induce DTHA does not have any arthritogenic effect without combining it with the DTH foot pad response [24]. The model is ideally suited for testing compounds thought to have an effect in the earliest stages of an arthritis flare development, as treatment onset can be synchronised precisely with disease onset, which is defined exactly by the experimenter as the time of foot pad challenge with mBSA.…”

“…Depletion of CD4 + T cells prior to immunisation in DTHA completely prevents disease development [24] and depletion post induction of arthritis reduces disease severity significantly (our unpublished data). However, depletion of CD4 + T cells after initiation of CIA does not ameliorate disease [25], indicating that T cells are important for CIA primarily in the immunisation phase after which the B cells drive disease progression through the production of anti-type II collagen antibodies.…”

“…However, depletion of CD4 + T cells after initiation of CIA does not ameliorate disease [25], indicating that T cells are important for CIA primarily in the immunisation phase after which the B cells drive disease progression through the production of anti-type II collagen antibodies. Previously, we have shown that etanercept (a TNFa-inhibitor) could ameliorate disease in DTHA both when administered at arthritis induction and post arthritis induction [24], suggesting predictive validity of the model for efficacy of new anti-arthritic biologics. Not all preclinical data generated in the CIA model has been directly transferrable to RA, including data on anti-IL-1, which showed good efficacy in CIA, but limited therapeutic potential in human RA [26].…”

“…C5aR-blockade could potentially prevent or abrogate an arthritis flare in patients, and therefore the purpose of the present study was to study the early effects of a blocking, non-cell-depleting anti-C5aR mAb. For this purpose we chose the highly synchronised delayed-type hypersensitivity arthritis (DTHA) model, previously described by us [24]. It is a single-paw arthritis model in C57BL/6 mice, induced by modifying a classical methylated bovine serum albumin (mBSA)-induced DTH foot pad response by i.v.…”