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Departments of Pathology [T. D. d. G., H. J. B., J. M. M. W., M. J. S., F. S. D., C. J. L. M. M., R. J. S.] and Obstetrics and Gynecology [A. J. R., T. J. M. H., R. H. M. V.] Free University Hospital, 1007 MB Amsterdam, the Netherlands, and Cancer Research Campaign Department of Immunology, Paterson Institute for Cancer Research, Christie Hospital National Health Service Trust, Manchester M20 9BX, United Kingdom [M. F. D-K., P. L. S.]
T-cell-mediated immune responses against oncogenic human papillomaviruses (HPVs) are believed to play a role in the prevention of cervical carcinogenesis. The in vitro production of interleukin 2 by CD4+ T helper (Th) cells in response to overlapping 20-mer peptides covering the HPV-16 E7 oncoprotein sequence was determined in 72 women with cytological evidence of premalignant cervical intraepithelial neoplasia (CIN) who participated in a nonintervention follow-up (FU) study. In addition, 15 HPV-16 + cervical carcinoma patients were tested. Positive Th cell reactivity was restricted to patients infected by HPV-16 and related types and showed a strong association with viral persistence and disease progression, as evidenced by the high frequency of positive responders among women with persistent HPV-16 infections who ended FU with high-grade CIN III lesions [14 of 15 (93%)]. Women with cervical carcinoma showed responses at a significantly reduced rate [7 of 15 (47%); P = 0.014]. Over the FU period (10–34 months), the level of E7-induced interleukin 2 production from the lymphocytes of CIN patients who had cleared HPV-16 infection showed an inverse correlation with time relative to the last positive HPV DNA test, with 8 of 13 of these patients showing positive responses after clearance. By contrast, among women with persistent HPV-16 infections and developing CIN III lesions (n = 8), there was a rise in Th cell activity over the course of FU. The majority of women responded to an immunogenic region in the carboxyl terminus of the E7 protein (amino acids 67–98). The observed HPV-16 E7-specific Th cell responses may develop as a consequence of increased antigen availability resulting either from clearance or from progression of cervical lesions.
1 Supported by grants from the Prevention Fund (Grant 28-1502.2) and the University Stimulation Fund of the Free University to (T. D. d. G., H. J. B., J. M. M. W., M. J. S., A. J. R., T. J. M. H., C. J. L. M. M., and R. J. S.). M. F. D-K. and P. L. S. received financial support from the Cancer Research Campaign. P. L. S. was visiting professor of the Pasman Chair for Internatonalisation of the Oncology Research Institute of the Vrije Universiteit, Amsterdam.
2 To whom correspondence should be addressed, at Department of Pathology, Free University Hospital, P. O. Box 7057, 1007 MB Amsterdam, the Netherlands. Phone: 31-20-4444070; Fax: 31-20-4442964; E-mail: pathol@azvu.nl.
Received 12/19/97. Accepted 2/18/98.
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