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Low-Dose Immunization with Adenovirus Expressing the Thyroid-Stimulating Hormone Receptor A-Subunit Deviates the Antibody Response toward That of Autoantibodies in Human Graves’ Disease

Autoimmune Disease Unit (C.-R.C., P.P., G.D.C., H.A., S.M.M., B.R.), Cedars-Sinai Research Institute and School of Medicine, University of California, Los Angeles, California 90048; and Department of Pharmacology 1 (Y.N.), Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 Japan

Address all correspondence and requests for reprints to: Basil Rapoport, M.D., Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California. E-mail: rapoportb{at}cshs.org.

Immunization with adenovirus expressing the TSH receptor (TSHR) induces hyperthyroidism in 25–50% of mice. Even more effective is immunization with a TSHR A-subunit adenovirus (65–84% hyperthyroidism). Nevertheless, TSHR antibody characteristics in these mice do not mimic accurately those of autoantibodies in typical Graves’ patients, with a marked TSH-blocking antibody response. We hypothesized that this suboptimal antibody response was consequent to the standard dose of TSHR-adenovirus providing too great an immune stimulus. To test this hypothesis, we compared BALB/c mice immunized with the usual number (10¹¹) and with far fewer viral particles (10⁹ and 10⁷). Regardless of viral dose, hyperthyroidism developed in a similar proportion (68–80%) of mice. We then examined the qualitative nature of TSHR antibodies in each group. Sera from all mice had TSH binding-inhibitory (TBI) activity after the second immunization, with TBI values in proportion to the viral dose. After the third injection, all groups had near-maximal TBI values. Remarkably, in confirmation of our hypothesis, immunization with progressively lower viral doses generated TSHR antibodies approaching the characteristics of autoantibodies in human Graves’ disease as follows: 1) lower TSHR antibody titers on ELISA and 2) lower TSH-blocking antibody activity without decrease in thyroid-stimulating antibody activity. In summary, low-dose immunization with adenovirus expressing the free TSHR A-subunit provides an induced animal model with a high prevalence of hyperthyroidism as well as TSHR antibodies more closely resembling autoantibodies in Graves’ disease.

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