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.
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 (10(11)) and with far fewer viral particles (10(9) and 10(7)). 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.
Autoimmune Disease Unit, Cedars-Sinai Research Institute and School of Medicine, University of California, Los Angeles 90048, USA.
Chun-Rong
CR
Chen
Pavel
P
Pichurin
Gregorio D
GD
Chazenbalk
Holly
H
Aliesky
Yuji
Y
Nagayama
Sandra M
SM
McLachlan
Basil
B
Rapoport
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D015292:Glycoprotein Hormones, alpha Subunit / Q000276:immunology*; D006111:Graves Disease / Q000276:immunology*; D006801:Humans; D007114:Immunization; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology; D014771:Virion
D001323:Autoantibodies; D015292:Glycoprotein Hormones, alpha Subunit; D018828:Immunoglobulins, Thyroid-Stimulating