Graves' disease in severe combined immunodeficient mice.

Abstract

Graves' disease (GD) is an autoimmune thyroid disorder involving an antibody (TSAb) directed against the TSH receptor (TSHR) producing thyroid stimulation. We have developed an animal model of GD by engrafting peripheral blood mononuclear cells or T cell lines plus autologous thyroid tissue into severe combined immunodeficient (SCID) mice. We xenografted Graves' thyroid tissue from six patients into six groups of SCID mice. Autologous PBMC and T cell lines reactive to recombinant human TSHR extracellular domain and non-TSHR lines were injected ip into the designated groups. In some of the studies, thyroid tissue was irradiated with 2000 rads before xenografting. Irradiation of xenografts induced thyroid tissue damage and release of thyroid antigens and hormones. Mice reconstituted with peripheral blood mononuclear cells or nonspecific T cell lines did not simulate GD. However, we achieved production of TSAb, elevation of serum T3, and TSAb-dependent survival and function of human Graves' thyroid tissue in SCID mice reconstituted with TSHR-specific T cell lines. We reconstituted SCID mice with PBMC and TSHR-specific T cell lines that recognized TSHR peptide 158-176. This may be in vivo evidence of the importance of peptide 158-176 as an immunodominant epitope on the TSHR extracellular domain.