| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2003: ¥6,400,000 (Direct Cost: ¥6,400,000)
Fiscal Year 2002: ¥7,600,000 (Direct Cost: ¥7,600,000)
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| Research Abstract |
Graves' disease (GD) is. an organ-specific autoimmune disease characterized by hyperthyroidism. Agonistic anti-thyrotropin receptor antibodies (Thyroid-stimulating ([TS]-Ab), which mimic the TSH action, are thought to cause GD. The precise immunological mechanism of TSAb production, however, remains elusive. Previous immunization approaches using TSH receptor led to transient hyperthyroidism, but did not seem sufficient for comprehensive understanding, of the development of autoimmune responses. To create GD-related autoimmunity in mice, we here generated TSAb-transgenic mice in which a patient-derived TSAb is expressed in B cells. Expression of the human TSAb in the mice resulted in various manifestations of hyperthyroidism including increased free thyroxine levels with concomitantly decreased TSH levels, increased thyroid uptake of technetium-pertechnetate, hyperthermia and thyroid hyperplasia. We found a correlation between the serum levels of human TSAb immunoglobulin and free thyroxine. In addition, conventional B cells expressing the TSAb were partially deleted in the, periphery while B 1 cells expressing the TSAb persisted and accumulated in the peritoneal cavity, a finding consistent with previous, demonstrations that the maintenance of B 1 cells plays an important role in the development of autoimmune diseases. Thus, our transgenic mouse may provide a novel and useful animal model for elucidating the pathogenesis and pathophysiology of GD.
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