ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 11 OC57

Treatment of experimental hyperthyroid Graves’ disease with decoy TNF-family ligand receptors, suggests an essential role for BAFF in production of thyroid stimulating antibodies

JA Gilbert1, SL Kalled2, J Moorhead3, D Hess2, P Rennert2, Z Li2, Z Khan3 & J-P Banga1

1Division Gene and Cell Based Therapy, King’s College School of Medicine, London, United Kingdom; 2Dept Immunology and Inflammation, Biogen Idec Inc, Massachusetts, United States; 3Dept Histopathology, King’s College Hospital, London, United Kingdom.

Introduction and Aims: Graves’ disease (GD) is mediated by thyroid stimulating antibodies (TSAbs) to the TSH receptor (TSHR). Treatments for GD have remained unchanged for more than 40 years with less than 50% of patients achieving long term remission with medical therapy. Experimental animal models have been described which facilitate understanding of disease mechanisms and permit studies of novel immunotherapeutic interventions. However studies aiming to perturb the Th1/Th2 balance of the autoimmune response have failed to modify the course of established GD. Recently identified TNF superfamily ligands; B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL) and their receptors (BAFFR) and B cell maturation antigen (BCMA) have been implicated in auto-antibody production. We investigated the therapeutic effects of blockade of BAFF or BAFF+APRIL in a murine model of GD, using soluble decoy TNF receptor proteins BAFFR-Fc and BCMA-Fc.

Methods: BALB/c mice (n=110) were immunized with adenovirus TSHR-A-subunit construct to induce elevated serum levels of TSAbs and thyroxine (T4). These mice were randomized to treatment with either BAFFR-Fc, BCMA-Fc, IgG or PBS. Serum TSAbs and T4 were measured pre- and post treatment (RIA). Splenic plasma cell populations were assessed using anti-mouse syndecan-1(CD138).

Results: In animals with established hyperthyroidism, blockade of BAFF or BAFF+APRIL with BAFFR-Fc and BCMA-Fc led to significant reductions in serum T4 compared with pre-treatment values (78% and 100% mice per group respectively; P<0.01). Significant reductions in serum T4 were also observed compared with control groups (P<0.01). This was supported by a parallel pattern of declining TSAbs in mice treated with BCMA-Fc (P<0.05). However, splenic sections from mice treated with BAFFR-Fc or BCMA-Fc revealed persistence of plasma cells.

Conclusion: This is the first report of attenuation of established induced hyperthyroidism in a murine model of GD using immunotherapeutic agents targeting autoreactive B cells.

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