Induction of hyperthyroidism in mice by intradermal immunization with DNA encoding the thyrotropin receptor

Area of Science:

• Immunology
• Endocrinology
• Molecular Biology

Background:

• Intramuscular plasmid DNA encoding the human thyrotropin receptor (TSHR) induces Graves' disease (GD) symptoms in outbred mice.
• Inbred mouse strains have shown resistance to TSHR DNA-induced GD, indicating a need for alternative delivery methods or models.

Purpose of the Study:

• To investigate if intradermal (i.d.) injection of TSHR DNA can induce hyperthyroidism in BALB/c mice.
• To determine if coinjection with cytokine-producing plasmids influences the outcome of TSHR DNA-induced GD.

Main Methods:

• BALB/c mice received i.d. injections of TSHR DNA at 0, 3, and 6 weeks.
• Immune responses and disease markers were assessed at 8 or 10 weeks.
• Flow cytometry, thyroxine (TT4) level measurements, and antibody detection (including thyroid-stimulating antibodies - TSAb) were employed.

Main Results:

• 67% of mice developed TSHR-specific antibodies.
• 27% of mice exhibited elevated TT4 levels, goiters, and activated thyroid follicular cells.
• TSAb were detected in 2 of 4 hyperthyroid mice.
• Coinjection with IL-2 or IL-4 plasmids abolished hyperthyroidism and TSAb production.
• Coinjection with IL-12 did not significantly enhance GD incidence or severity.

Conclusions:

• Intradermal delivery of human TSHR DNA can break tolerance and induce GD in inbred mice.
• The data suggest TSAb production in this murine model is not Th2-dependent.
• Codelivery of TSHR and IL-12 DNA may not be sufficient to increase GD incidence or severity.