© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 245-250, Copyright © 1997 by Oxford University Press
M Clerici, M Merola, E Ferrario, D Trabattoni, ML Villa, B Stefanon, DJ Venzon, GM Shearer, G De Palo and E Clerici
BACKGROUND: Genital infection with certain strains of human papillomavirus
(HPV) is associated with a high risk of malignant transformation, and
HPV-associated cervical intraepithelial neoplasia (CIN) can become invasive
cancer. Host factors are critical in regulating tumor growth, and cytokines
that modulate immunologic control may be of particular importance. The type
1 cytokines interleukin 2 (IL-2) and interferon gamma (IFN gamma) are
immunostimulatory and are thus capable of limiting tumor growth. The type 2
cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10) are
immunoinhibitory and are thus capable of stimulating tumor growth. PURPOSE:
We analyzed the production of cytokines by peripheral blood mononuclear
cells (PBMCs) in women with CIN associated with localized or extensively
spread HPV infection. METHODS: Thirty women diagnosed with CIN and 10 age-
and sex-matched healthy control subjects were enrolled in the study
conducted at Istituto Nazionale Tumori, Milan, Italy. The following
parameters were analyzed: 1) HPV infection of the cervix and other sites of
the lower genital tract by colposcopic, cytologic, and histologic
examinations; 2) HPV typing; 3) in vitro production of IL-2 by PBMCs in
response to stimulation with soluble antigen (influenza [FLU] antigen) or
to cell-associated human leukocyte antigen (HLA) alloantigen; and 4) in
vitro production of the type 1 cytokines IL-2 and IFN gamma and of the type
2 cytokines IL-4 and IL-10 by PBMCs in response to mitogen stimulation.
Statistical significance was determined by nonparametric tests (two-sided).
RESULTS: High-grade CIN associated with HPV infection was detected in all
case patients, and HPV type 16 or 18 infection was detected in cervical
tissue of 21 (70%) of 30 case patients. HPV infection that had spread to
other sites of the lower genital tract, thus resulting in more extensive
disease, was detected in 16 (53%) of the 30 individuals with CIN, whereas
HPV infection was limited to the portio in 14 (47%). IL-2 production by
PBMCs in response to stimulation with soluble antigen or HLA alloantigen
was reduced in the group with extensive disease compared with that in the
group with localized disease or with that in healthy control subjects. In
contrast, IL-4 and IL-10 production in response to mitogen stimulation was
elevated in the group with extensive disease compared with that in the
group with localized disease or with that in healthy control subjects. The
highest production of IL-4 and IL-10 was detected in patients with HPV
infection that had extended beyond the genital tract. CONCLUSIONS: CIN is
characterized by different immunologic profiles, in which HPV infection is
or is not confined to the portio. Production of cytokines that mainly
enhance potentially protective cell-mediated immunity is defective in the
women in whom extended HPV infection was observed. A pronounced shift from
type 1 to type 2 cytokine production is associated with more extensive HPV
infection. IMPLICATIONS: These data reinforce the need for detailed
analyses of immune dysregulation in CIN patients. They also suggest the
potential usefulness of the cytokine assays for determining prognosis or
deciding whether cytokine-based therapy is indicated.
ARTICLES
Cytokine production patterns in cervical intraepithelial neoplasia: association with human papillomavirus infection
Cattedra di Immunologia, Universita degli Studi di Milano, Italy.
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