Autoimmune thyroiditis in thymectomised and irradiated rats

Factors influencing the establishment of autoimmune thyroiditis induced in PVG/c strain rats by early thymectomy [(Tx) (21 days of age)] and sub-lethal irradiation [(X) (4 x 250 rad)] were investigated. The disease is generally accompanied by circulating antibodies to thyroglobulin and a sensitive micro enzyme-linked immunosorbent assay was developed in order to detect these antibodies. Evidence to demonstrate that the thyroiditis induced in these rats was not the consequence of direct damaging effects of irradiation was provided by post-irradiaton thyroid transplantation studies. The pathological change in the thyroids of Tx-X rats is considered to be the consequence of selective depletion of self-regulatory suppressor cells. This concept was supported by three series of observations. (1) The increased ability of Tx-X rats to respond with time to certain T-dependent antigens following repeated antigen injections. (2) The transfer of syngeneic lymphoid cells from normal animals to Tx-X rats shortly after irradiaiton prevented the development of thyroiditis and (3) direct evidence obtained by transfer studies for the absence of such cells in Tx-X animals. The natural suppressor cell involved in autoimmune regulation was further characterised and it was found that these cells were required to be both viable and syngeneic. Both T and B cell enriched fractions of lymphoid cells were equally effective in preventing the disease. Female Tx-X rats were at least 4-5 times more susceptible than male rats. This sex-related expression was found to be due to the influence of sex hormones rather than of genetic origin, since prepubertal gonadectomy increased the incidence of thyroiditis in both male and female Tx-X rats. Furthermore, the administration of testosterone to Tx-X rats brought about inhibition of disease. Similarly, oestrogen had a suppressive influence on the disease induction. In contrast, progesterone appeared to intensify the disease process. Testosterone administration was also found to be beneficial in Tx-X rats with established disease. In a majority of the cases, the treatment resulted in the complete resolution of the lesions but had little effect on serum autoantibody levels. The effects of sex hormones on lymphoid cell populations were examined using a cell-transfer assay system, Cells derived from normal males were more effective than those obtained from normal females in preventing the disease in Tx-X rats, whilst cells from normal gonadectomised animals were ineffective. The results of other areas of investigation were (1) the lack of the influence of the spleen in the disease process and (2) the inability to transfer the disease to normal animals by high titred antithyroglobulin sera. The major conclusions from these studies were: (1) Tx-X rats have defective suppressor-cell activity. (2) The control of organ-specific autoimmunity is determined by a balance between regulator (suppressor) and effector (stimulatory) cells. Sex hormones can markedly alter this balance. (3) Autoantibodies to thyroglobulin alone appear to be of no pathogenic significance in the Tx-X model