Graves' disease in severe combined immunodeficient mice

Area of Science:

• Immunology
• Endocrinology
• Transplantation Immunology

Background:

• Graves' disease (GD) is an autoimmune thyroid disorder.
• Thyroid-stimulating immunoglobulin (TSAb) against the TSH receptor (TSHR) causes thyroid overstimulation.
• Current GD models have limitations in fully recapitulating the disease.

Purpose of the Study:

• To develop a novel humanized mouse model of Graves' disease.
• To investigate the role of TSHR-specific T cells in GD pathogenesis.
• To identify immunodominant epitopes on the TSHR.

Main Methods:

• Xenografting of human Graves' thyroid tissue into severe combined immunodeficient (SCID) mice.
• Reconstitution of SCID mice with autologous peripheral blood mononuclear cells (PBMC) or T cell lines.
• In vitro and in vivo stimulation of T cells with recombinant human TSHR extracellular domain and peptides.
• Irradiation of thyroid xenografts to induce antigen release.

Main Results:

• SCID mice reconstituted with TSHR-specific T cell lines produced TSAb.
• Elevated serum T3 levels were observed in mice with functional Graves' thyroid tissue xenografts.
• TSAb-dependent survival and function of human Graves' thyroid tissue were confirmed.
• Identification of TSHR peptide 158-176 as a potential immunodominant epitope.

Conclusions:

• A functional humanized mouse model for Graves' disease has been established.
• TSHR-specific T cells are crucial for TSAb production and disease manifestation.
• TSHR peptide 158-176 is a key epitope in the autoimmune response in Graves' disease.