DESCRIPTION: (Adapted from the Investigator's Abstract) Epidemiological studies
have clearly established that human papillomas (HPV) infection is a major risk
factor for cervical cancer. A number of individuals undergo remission either
spontaneously or after clinical intervention, while others, particularly those
exhibiting immudeficiency, seem to proceed to develop invasive cancer. It is
important to understand the immunological basis for the clinical remission of
HPV-associated cervical neoplasia for designing proper intervention strategies.
We have determined cell-mediated immunity (CMI) responses specific to synthetic
peptides from E6 and E7, the two major oncoproteins of high risk type HPV
(HPV-16), in a subset of patients attending the colposcopic clinic. These
patients underwent excisional or ablative treatment for cervical intra
epithelial neoplasia (CIN) at least six months prior to enrolling in the study.
Significant differences were observed in proliferative responses directed
against peptides from both the E6 (p=0.002) and E7 (p<0.001) between women
without cytological or histological evidence of CIN (disease-free group) and
those with a histological diagnosis of recurrence for CIN. Additional pilot
studies on in vitro cytokine production mediated by the E6 and E7 peptides,
showed a predominant TH1-cytokine profile in women from the disease-free group,
while women with disease recurrence exhibited TH2-cytokine responses. On the
other hand, none of the women in any of the study groups exhibited circulating
antibodies reactive with the E6 and E7 peptides used in the study. Based on our
results showing significantly high levels of HPV-peptide-specific TH1 responses
in disease-free patients only, we hypothesize that HPV-specific CMI directed
against the E6 and E7 oncoproteins is important for protection/recovery from
HPV-associated CIN. To test this hypothesis, we propose to conduct a
prospective cohort study of women positive for high-risk HPV types and treated
for CIN by loop electrosurgical procedure. Our goals are to identify HPV
peptides that can potentially serve as markers of protective immunity and for
inclusion in immunotherapeutic and/or immunoprophylactic vaccine formulations
against HPV-associated CIN. We will assess the pattern of the HPV-specific
immunological responses over time, in particular CMI against E6 and E7 peptides
corresponding to high-risk HPV types. We will also determine as to whether an
association exists between the immune responses and additional HPV-related
factors (persistence of infection and HPV type), and other risk factors
associated with CIN such as smoking, sexual behavior, intrinsic and extrinsic
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