An Animal Model of Graves’ Orbitopathy

Graves’ orbitopathy (GO) is an inflammatory orbital disease that frequently arises as a consequence of Graves’ disease, a common autoimmune thyroid condition. The thyrotropin stimulating hormone receptor (TSHR) is the defined autoantigen in Graves’ disease and has been considered to be the immunological target in the orbital complication. Mechanistic insights into pathogenesis of GO for development of therapeutic agents remain completely undefined, due to the lack of an animal model. Earlier reported models have proved to be disappointing failures. An experimental model of GO has been developed, based upon genetic immunization of inbred mice with human TSHR ectodomain plasmid by close-field electroporation, with a high disease incidence. Inflammatory lesions characterized by CD3 + T cells and macrophages were localized in the orbital muscle tissue. Other pathological manifestations in some animals were characterized by extensive adipogenesis of orbital fat and recapitulate different aspects of pathology seen in patients with GO. Additional pathological features were reminiscent of eyelid inflammation involving chemosis, with dilated and congested orbital blood vessels. Early studies indicate the replication of the model in authors’ independent laboratories. The development of a reproducible model of GO will provide an invaluable tool to understand the pathogenic mechanisms to allow identification of novel targets for development of effective therapies for this disease.