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Title: Graves' orbitopathy in a novel preclinical model
Author: Moshkelgosha, Sajad
ISNI:       0000 0004 5923 2578
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Background: Graves’ disease is an autoimmune disorder characterised by goitre, hyperthyroidism and Graves’ orbitopathy (GO). The hyperthyroidism is caused by thyroid hypertrophy and stimulation of function, resulting from anti-TSHR antibodies. Moreover, for pathophysiology of GO, there is compelling evidence on the role of antibodies to insulin-like growth factor 1 receptor (IGF-1R). However, the precise pathogenesis of GO remains unresolved, hampered by lack of an animal model. Our laboratory has previously shown that genetic immunisation leads to development of Graves’ disease. In addition, there were signs of orbital inflammation in some immune animals. Aims: The objective of my thesis was to modify and evaluate new regimes in the genetic delivery in order to develop a preclinical GO model. The new model would be characterised immunologically and by thyroid function studies. Furthermore, procedures would be developed to characterise the orbital tissue by histopathology, to allow better anatomical evaluation in correlation with MRI. In addition, study into the pathophysiology of the disease was another objective of this project. Results: Modifications in the immunisation scheme with hTSHR A-subunit plasmid in vivo electroporation were successfully established leading to induction of anti-TSHR response, thyroid dysfunction, and extensive remodelling of the orbital tissue. The orbital manifestations were characterised by infiltration of inflammatory cells including CD3+/CD4+ T cells, F4/80+ macrophages and mast cells, as well as hypertrophy of extraorbital muscles together with accumulation of glycosaminoglycan. In addition, orbital heterogeneity was apparent, where some immune mice (10%) showed extensive adipogenesis. Furthermore, other immune animals showed an intense CD3+ T cells infiltrate surrounding the optic nerve. A striking finding that underpins the experimental model was the in vivo MRI of mouse orbital region that provided a clear and quantifiable evidence of extraorbital muscle hypertrophy with orbital protrusion (proptosis). In addition, some animals exhibited congested eyelid manifestation of chemosis, which was characterised histologically as dilated orbital blood vessels and oedema. Immunisation with control plasmids failed to show any orbital pathology. High level of antibodies to hTSHR were present in sera of animals challenged with hTSHR A-subunit plasmid with predominantly TSH blocking antibodies, which led to profound hypothyroidism. Although, these findings support TSHR as the pathogenic antigen in GO, the enigmatic role of antibodies to IGF-1R in GO remains unclear. This study describes a significant response to IGF-1R in some animals immunised with hTSHR A-subunit plasmid. A definite way to study the nature of the anti-IGF-1R antibody response following challenge with a different immunogen (hTSHR A-subunit) is by development of monoclonal antibodies to IGF-1R induced in the model, attempts of which are also reported in the thesis. Conclusion: We successfully developed an experimental model that recapitulates orbital pathology in GO patients. The development of a new preclinical model for GO will facilitate molecular investigations into pathophysiology of the disease and evaluation of new therapeutic interventions.
Supervisor: Banga, Jasvinder-Paul Singh ; Christie, Michael Robert Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available