A transgenic mouse that spontaneously develops pathogenic TSH receptor antibodies will facilitate study of antigen-specific immunotherapy for human Graves' disease.

Abstract

Graves' hyperthyroidism can be treated but not cured. Antigen-specific immunotherapy would accomplish this goal, for which purpose an animal model is an invaluable tool. Two types of animal models are available. First, pathogenic TSHR antibodies (TSHRAb) can be induced by injecting mice with fibroblasts co-expressing the human TSHR (hTSHR) and MHC class II, or in mammals using plasmid or adenovirus vectors encoding the hTSHR or its A-subunit. Second, a mouse model that spontaneously develops pathogenic TSHRAb resembling those in human disease was recently described. This outcome was accomplished by transgenic intrathyroidal expression of the hTSHR A-subunit in NOD.H2h4 mice that are genetically predisposed to develop thyroiditis but, without the transgene, do not generate TSHRAb. Recently, novel approaches to antigen-specific immunotherapy have been tested, primarily in the induced model, by injecting TSHR A-subunit protein or cyclic TSHR peptides. T-cell tolerance has also been induced in "humanized" HLA-DR3 mice by injecting synthetic peptides predicted in silico to mimic naturally processed TSHR T-cell epitopes. Indeed, a phase 1 study based on the latter approach has been conducted in humans. In the spontaneous model (hTSHR/NOD.H2h mice), injection of soluble or nanoparticle-bearing hTSHR A-subunits had the unwanted effect of exacerbating pathogenic TSHRAb levels. A promising avenue for tolerance induction, successful in other conditions and yet to be tested with the TSHR, involves encapsulating the antigen. In conclusion, these studies provide insight into the potential outcome of immunotherapeutic approaches and emphasize the importance of a spontaneous model to test future novel, antigen-specific immunotherapies for Graves' disease.