Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves' disease

We performed genetic immunization of outbred NMRI mice, using a cDNA encoding the human thyrotropin receptor (TSHr). All mice produced antibodies capable of recognizing the recombinant receptor expressed at the surface of stably transfected Chinese hamster ovary (CHO) cells, and sera from most of th...

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Bibliographic Details
Published in:The Journal of clinical investigation 2000-03, Vol.105 (6), p.803-811
Main Authors: Costagliola, S, Many, M C, Denef, J F, Pohlenz, J, Refetoff, S, Vassart, G
Format: Article
Language:English
Subjects:
Animals
Autoantibodies - biosynthesis
Autoimmune Diseases - etiology
Autoimmune Diseases - immunology
CHO Cells
Cricetinae
Cricetulus
Disease Models, Animal
DNA, Complementary - adverse effects
Edema - pathology
Female
Glycosaminoglycans - analysis
Graves Disease - etiology
Graves Disease - immunology
Graves Disease - pathology
Humans
Immunization - adverse effects
Immunoglobulins, Thyroid-Stimulating - biosynthesis
Male
Mice
Oculomotor Muscles - pathology
Receptors, Thyrotropin - biosynthesis
Receptors, Thyrotropin - immunology
Th2 Cells - immunology
Thyrotropin - blood
Thyroxine - blood
Vaccines, DNA - adverse effects
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Summary:We performed genetic immunization of outbred NMRI mice, using a cDNA encoding the human thyrotropin receptor (TSHr). All mice produced antibodies capable of recognizing the recombinant receptor expressed at the surface of stably transfected Chinese hamster ovary (CHO) cells, and sera from most of the immunized mice blocked TSH-dependent stimulation of cAMP accumulation in cells expressing the TSHr. Five out of 29 female mice showed sign of hyperthyroidism including elevated total T4 and suppressed TSH levels. The serum of these mice contained thyroid-stimulating activity, as measured in a classic assay using CHO cells expressing recombinant TSHr. In contrast, only 1 male out of 30 had moderately elevated serum total T4 with undetectable TSH values. The hyperthyroid animals had goiters with extensive lymphocytic infiltration, characteristic of a Th2 immune response. In addition, these animals displayed ocular signs reminiscent of Graves' ophthalmopathy, including edema, deposit of amorphous material, and cellular infiltration of their extraocular muscles. Our results demonstrate that genetic immunization of outbred NMRI mice with the human TSHr provides the most convincing murine model of Graves' disease available to date.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI7665