Human papillomavirus type 16-specific T cell responses and their association with recurrence of cervical disease following treatment.

Human papillomavirus type 16 (HPV-16) L1- and E7-specific T cell responses were measured in 58 women with abnormal cervical cytology in a prospective study. On recruitment, patients responded most frequently and with the highest numbers of responding cells to the L1 region aa 311-345 and this response was significantly associated with the presence of cervical disease (P=0.041). Responses to the L1 peptide aa 281-295 were significantly higher in patients with CIN III than in those with HPV/CIN I or CIN II lesions (P=0.027). The E7 region aa 70-98 was the most immunogenic in patients with squamous intraepithelial lesions of the cervix (SIL) but the responses detected were not significantly higher than in patients without SIL. Following treatment, the T cell response profiles of patient groups did not change significantly. However, on analysis of the responses of individual patients with and without recurrent disease on follow-up, significant differences were found. Recurrence of disease was associated with T cell responses to the E7 region aa 70-98 at the patient's first clinic visit (P=0.017). Recurrence of disease was also accompanied by an increase in the total number of L1-specific short-term T cell lines (STLs) at follow-up, whereas absence of disease was accompanied by a decrease in L1-specific STLs. The data also suggested a possible link between E7 70-98-specific responses and acquisition of disease by patients who were previously disease-free. Further studies are warranted to determine whether this response could be useful as a marker of recurrent disease in some patients.

A functional site on the human TSH receptor: a potential therapeutic target in Graves' disease.

OBJECTIVE: Identifying sites on the TSH-receptor that are involved in the pathological stimulation of the thyroid by autoantibodies in Graves' disease would aid the development of new therapies. We tested a series of monoclonal antibodies that recognize the native receptor for their ability to inhibit stimulation of the receptor in vitro. PATIENTS AND METHODS: Heterologous cells expressing the recombinant human TSH-receptor were stimulated with TSH or serum samples from 13 Graves' disease patients or the MRC Long-Acting Thyroid Stimulator standard B (LATS-B) and their cAMP responses measured. The effect on this stimulation of various doses of purified monoclonal antibodies with defined epitopes was determined. RESULTS: Antibodies against one epitope (residues 381-384) inhibited TSH-stimulated cyclic adenosine monophosphate (cAMP) production (1 microg/ml causing 50% inhibition of the response to 100 microU/ml TSH) and also inhibited cAMP production induced by sera from approximately 40% (6/14) of Graves' disease patients, including the MRC LATS-B standard. CONCLUSIONS: Residues 381-384 of the human TSH-receptor are important in the physiological and pathological stimulation of the thyroid. This opens the possibility of more specific therapy of some Graves' disease patients by agents directed against this epitope.