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Disease-stage variance in functional CD4(+) T-cell responses against novel pan-human leukocyte antigen-D region presented human papillomavirus-16 E7 epitopes.
Clin Cancer Res 2004; 10(10):3301-8CC

Abstract

Given the anticipated clinical importance of helper and regulatory CD4(+) T cells reactive against human papillomavirus-16 E7 in the cervical carcinoma setting, we performed this study to identify novel E7-derived T helper (Th) epitopes and to characterize functional anti-E7 Th responses in normal donors and patients with cervical intraepithelial neoplasia I-III or cervical cancer. Candidate pan-HLA-DR (D region) binding peptides were identified and synthesized based on results obtained using a predictive computer algorithm, then applied in short-term in vitro T-cell sensitization assays. Using IFN-gamma/IL-5 (interleukin 5) enzyme-linked immunospot assays as readouts for Th1-type and Th2-type CD4(+) T-cell responses, respectively, we identified three E7-derived T helper epitopes (E7(1-12), E7(48-62), and E7(62-75)), two of which are novel. Normal donor CD4(+) T cells failed to react against these E7 peptides, whereas patients with premalignant cervical intraepithelial neoplasia I-III lesions displayed preferential Th1-type responses against all three E7 epitopes. Th1-type responses were still observed to the E7(48-62) but not to the E7(1-12) and E7(62-75) peptides in cancer patients, where these latter two epitopes evoked Th2-type responses. Notably all responders to the E7(1-12) and E7(62-75) peptides expressed the HLA-DR4 or -DR15 alleles, whereas all responders to the E7(48-62) peptide failed to express the HLA-DR4 allele. Our results are consistent with a model in which cervical cancer progression is linked to an undesirable Th1- to Th2-type shift in functional CD4(+) T cell responses to two novel E7-derived epitopes. These peptides may prove important in vaccines to promote and maintain protective Th1-type antihuman papillomavirus immunity and in the immune monitoring of treated patients harboring HPV-16(+) malignancies.

Authors+Show Affiliations

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15161683

Citation

Warrino, Dominic E., et al. "Disease-stage Variance in Functional CD4(+) T-cell Responses Against Novel Pan-human Leukocyte antigen-D Region Presented Human Papillomavirus-16 E7 Epitopes." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 10, no. 10, 2004, pp. 3301-8.
Warrino DE, Olson WC, Knapp WT, et al. Disease-stage variance in functional CD4(+) T-cell responses against novel pan-human leukocyte antigen-D region presented human papillomavirus-16 E7 epitopes. Clin Cancer Res. 2004;10(10):3301-8.
Warrino, D. E., Olson, W. C., Knapp, W. T., Scarrow, M. I., D'Ambrosio-Brennan, L. J., Guido, R. S., ... Storkus, W. J. (2004). Disease-stage variance in functional CD4(+) T-cell responses against novel pan-human leukocyte antigen-D region presented human papillomavirus-16 E7 epitopes. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 10(10), pp. 3301-8.
Warrino DE, et al. Disease-stage Variance in Functional CD4(+) T-cell Responses Against Novel Pan-human Leukocyte antigen-D Region Presented Human Papillomavirus-16 E7 Epitopes. Clin Cancer Res. 2004 May 15;10(10):3301-8. PubMed PMID: 15161683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Disease-stage variance in functional CD4(+) T-cell responses against novel pan-human leukocyte antigen-D region presented human papillomavirus-16 E7 epitopes. AU - Warrino,Dominic E, AU - Olson,Walter C, AU - Knapp,William T, AU - Scarrow,Meera I, AU - D'Ambrosio-Brennan,Lori J, AU - Guido,Richard S, AU - Edwards,Robert P, AU - Kast,W Martin, AU - Storkus,Walter J, PY - 2004/5/27/pubmed PY - 2004/12/16/medline PY - 2004/5/27/entrez SP - 3301 EP - 8 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 10 IS - 10 N2 - Given the anticipated clinical importance of helper and regulatory CD4(+) T cells reactive against human papillomavirus-16 E7 in the cervical carcinoma setting, we performed this study to identify novel E7-derived T helper (Th) epitopes and to characterize functional anti-E7 Th responses in normal donors and patients with cervical intraepithelial neoplasia I-III or cervical cancer. Candidate pan-HLA-DR (D region) binding peptides were identified and synthesized based on results obtained using a predictive computer algorithm, then applied in short-term in vitro T-cell sensitization assays. Using IFN-gamma/IL-5 (interleukin 5) enzyme-linked immunospot assays as readouts for Th1-type and Th2-type CD4(+) T-cell responses, respectively, we identified three E7-derived T helper epitopes (E7(1-12), E7(48-62), and E7(62-75)), two of which are novel. Normal donor CD4(+) T cells failed to react against these E7 peptides, whereas patients with premalignant cervical intraepithelial neoplasia I-III lesions displayed preferential Th1-type responses against all three E7 epitopes. Th1-type responses were still observed to the E7(48-62) but not to the E7(1-12) and E7(62-75) peptides in cancer patients, where these latter two epitopes evoked Th2-type responses. Notably all responders to the E7(1-12) and E7(62-75) peptides expressed the HLA-DR4 or -DR15 alleles, whereas all responders to the E7(48-62) peptide failed to express the HLA-DR4 allele. Our results are consistent with a model in which cervical cancer progression is linked to an undesirable Th1- to Th2-type shift in functional CD4(+) T cell responses to two novel E7-derived epitopes. These peptides may prove important in vaccines to promote and maintain protective Th1-type antihuman papillomavirus immunity and in the immune monitoring of treated patients harboring HPV-16(+) malignancies. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/15161683/Disease_stage_variance_in_functional_CD4_+__T_cell_responses_against_novel_pan_human_leukocyte_antigen_D_region_presented_human_papillomavirus_16_E7_epitopes_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15161683 DB - PRIME DP - Unbound Medicine ER -