Vas V. Row

T LYMPHOCYTE SENSITIZATION AND SUPPRESSOR T LYMPHOCYTE DEFECT IN PATIENTS LONG AFTER TREATMENT FOR GRAVES’DISEASE

Circulating thyroid autoantibodies, T lymphocyte sensitization and suppressor T lymphocyte function were examined in thirty‐nine patients who had been treated for a mean of 10±2 years previously for hyperthyroid Graves’disease. Nineteen had been treated with radioactive iodine (131I), two with subtotal thyroidectomy, and eighteen were in long‐term remission after previous propylthiouracil (PTU) therapy. Sensitization of T lymphocytes to human thyroid antigen was studied by means of a modified migration inhibition factor test, using T lymphocyte enriched preparations, and antigen‐specific suppressor T lymphocyte function was assessed by the ability of T lymphocytes to suppress the production of migration inhibition factor by sensitized T lymphocytes of patients with active Graves’disease in response to human thyroid antigen. Despite effective correction of the hyperthyroid state in all patients, T lymphocyte sensitization to human thyroid antigen was still demonstrable in twelve of nineteen patients treated with 131I (63%), in nine of eighteen patients in remission after PTU treatment (50%) and in one of two patients after thyroidectomy. All those showing such sensitization also manifested a suppressor T lymphocyte defect. In three of the patients (all after 131I therapy) showing no such sensitization, there was nevertheless evidence of a suppressor T lymphocyte defect. On the other hand, thirteen patients (nine in the post‐PTU group, four in the post‐131I group) showed evidence of complete immunological remission. There was no correlation between the abnormal immunological findings and the number of years after treatment of the hyperthyroidism.

Lack of Effect of Methimazole on Thyrocyte Cell-Surface Antigen Expression

The nature of the immunosuppressive effect of antithyroid drugs has been a subject of controversy. It has been claimed that these agents exert a direct effect on the immune system, although we and others have suggested that the drugs affect the thyroid cells primarily with consequent reduced thyrocyte-immunocyte signalling. This may occur from reduced thyroid hormone production and/or reduced antigen presentation by the thyrocytes to local T lymphocytes. Using a cytotoxicity assay system, with chromium-51 labelling, monoclonal antibodies against thyroperoxidase (TPO) and HLA-DR, and complement, we have measured the expression of TPO and HLA-DR on cultured normal human thyroid cells; we have also measured thyroglobulin (Tg) release by radioimmunoassay into the medium of the cultured cells. The thyroid cells were stimulated with TSH or thyrotropin binding inhibitory immunoglobulin (TBII) for 48 hours before measuring for TPO induction, and with interferon gamma (IFN-gamma) (with or without TSH or TBII) for thyrocyte HLA-DR expression. A dosage of 1.6 milliunits per ml of TSH resulted in a significant increase in TPO expression on thyrocytes when compared with control unstimulated thyroid cells (p less than 0.001). The concentrations of Tg released into the medium with TSH or TBII were also significantly higher than those of the control thyrocytes. IFN-gamma at 200 units per ml induced HLA-DR expression, but did not induce thyrocyte TPO expression, or Tg release. Addition of the antithyroid drug, methimazole (MMI), at different concentrations, in addition to the other stimulators, IFN-gamma, TSH, or TBII, did not result in any inhibition of TPO, Tg release, or HLA-DR expression on the thyroid cells. It would thus appear that the pathways for stimulation for the expression of TPO and HLA-DR appear to be different. Finally, MMI does not cause its immunosuppressive effect by any reduction of thyroid antigen expression or release.

THE USE OF THE E‐ROSETTE AS A TEST FOR REMISSION IN GRAVES’DISEASE TREATED WITH ANTITHYROID DRUGS

E‐rosettes (T‐lymphocytes) have been demonstrated to be increased in the peripheral blood of patients with untreated Graves’disease and decreased when these patients go into remission induced by antithyroid drugs. In patients similarly treated but not in remission, a high percentage of E‐rosettes persisted. The degree of suppression by T3 of the thyroidal 131I uptake correlated well with the percentage of E‐rosettes. We suggest that E‐rosette counts may prove to be a useful test for detecting remissions in thyrotoxic patients treated with antithyroid drugs.

Immunoregulatory Abnormalities in Autoimmune Thyroid Disease

In human autoimmune thyroid disease, much of the initial evidence with respect to an organ-specific suppressor T lymphocyte (Ts) defect initially came from studies of a modified migration inhibition factor (MIF) test using preparations of T lymphocytes 1-9