Induction of Human Papillomavirus Type 16-specific Immunologic Responses in a Normal and an Human Papillomavirus-infected Populations

Overview

Journal Immunology

Specialty Allergy & Immunology

Date 2005 Apr 12

PMID 15819706

Citations 5

Authors

Wen-Fang Cheng

Chien-Nan Lee

Yi-Ning Su

Ming-Cheng Chang

Wen-Chun Hsiao

Chi-An Chen

Chang-Yao Hsieh

Affiliations

Soon will be listed here.

Abstract

Human papillomavirus (HPV) infection, especially with the oncogenic genotypes, is the most important risk factor for developing cervical cancer. We focused on generating HPV16 E7-specific cytotoxic CD8(+) T lymphocytes and evaluating HPV16 E7-specific immune responses in HPV16-infected and uninfected populations. Peripheral blood mononuclear cells (PBMCs) were first collected from an uninfected group with an human lymphocyte antigen (HLA) A2 haplotype (four volunteers). Mature monocyte-derived dendritic cells (DCs) were generated from the PBMCs and pulsed with one of two HLA-A2-restricted E7 peptides, aa 11-20 [YMLDLQPETT] and aa 86-93 [TLGIVCPI], as antigen presenting cells. The autologous naive or cultured PBMCs were then cultured with peptide-pulsed DCs to detect the HPV16 E7-specific immune responses by a variety of techniques such as enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunospot (ELISPOT) assay and cytotoxic T lymphocyte assay. Interferon-gamma (IFN-gamma) from E7-specific cytotoxic CD8(+) T lymphocytes stimulated with the respective peptide was detected by ELISA. Using ELISPOT analysis, a marked increase in the number of IFN-gamma-secreting CD8(+) E7-specific lymphocytes was observed following peptide stimulation. Cultured CD8(+) T lymphocytes were highly cytotoxic against the CaSki cells. PBMCs were then collected from an HPV16-infected population of the HLA-A2 haplotype, including four persons of HPV16 infection only, four with cervical intraepithelial neoplasia (CIN) lesions, and four cervical cancer patients. We then compared the immunologic responses to E7 between HPV16-infected and uninfected populations by ELISA and ELISPOT assay. The E7-specific immunologic responses of the HPV16-infected populations were significantly higher than those of the uninfected population. In addition, persons with an HPV16 infection only or those with CIN lesions generated higher E7-specific immunologic responses than cervical cancer patients. Our results demonstrate methods for evaluating E7-specific immunologic responses and reflect the biological responses of HPV16-infected people during different periods of cervical disease.

Citing Articles

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References

Gong J, Nikrui N, Chen D, Koido S, Wu Z, Tanaka Y . Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumor immunity. J Immunol. 2000; 165(3):1705-11. DOI: 10.4049/jimmunol.165.3.1705. View

Schoell W, Mirhashemi R, Liu B, Janicek M, Podack E, Penalver M . Generation of tumor-specific cytotoxic T lymphocytes by stimulation with HPV type 16 E7 peptide-pulsed dendritic cells: an approach to immunotherapy of cervical cancer. Gynecol Oncol. 1999; 74(3):448-55. DOI: 10.1006/gyno.1999.5504. View

Simon M, Waring P, Lobigs M, Nil A, Tran T, Hla R . Cytotoxic T cells specifically induce Fas on target cells, thereby facilitating exocytosis-independent induction of apoptosis. J Immunol. 2000; 165(7):3663-72. DOI: 10.4049/jimmunol.165.7.3663. View

Cheng W, Hung C, Hsu K, Chai C, He L, Ling M . Enhancement of sindbis virus self-replicating RNA vaccine potency by targeting antigen to endosomal/lysosomal compartments. Hum Gene Ther. 2001; 12(3):235-52. DOI: 10.1089/10430340150218387. View

Cheng W, Hung C, Chai C, Hsu K, He L, Ling M . Enhancement of sindbis virus self-replicating RNA vaccine potency by linkage of herpes simplex virus type 1 VP22 protein to antigen. J Virol. 2001; 75(5):2368-76. PMC: 114820. DOI: 10.1128/JVI.75.5.2368-2376.2001. View

Simon R, Steinberg S, Hamilton M, Hildesheim A, Khleif S, Kwak L . Clinical trial designs for the early clinical development of therapeutic cancer vaccines. J Clin Oncol. 2001; 19(6):1848-54. DOI: 10.1200/JCO.2001.19.6.1848. View

van der Burg S, Ressing M, Kwappenberg K, De Jong A, Straathof K, de Jong J . Natural T-helper immunity against human papillomavirus type 16 (HPV16) E7-derived peptide epitopes in patients with HPV16-positive cervical lesions: identification of 3 human leukocyte antigen class II-restricted epitopes. Int J Cancer. 2001; 91(5):612-8. DOI: 10.1002/1097-0215(200002)9999:9999<::aid-ijc1119>3.0.co;2-c. View

Cheng W, Hung C, Chai C, Hsu K, He L, Rice C . Enhancement of Sindbis virus self-replicating RNA vaccine potency by linkage of Mycobacterium tuberculosis heat shock protein 70 gene to an antigen gene. J Immunol. 2001; 166(10):6218-26. DOI: 10.4049/jimmunol.166.10.6218. View

Nestle F . Dendritic cell vaccination for cancer therapy. Oncogene. 2001; 19(56):6673-9. DOI: 10.1038/sj.onc.1204095. View

10.

Jager E, Jager D, Knuth A . Clinical cancer vaccine trials. Curr Opin Immunol. 2002; 14(2):178-82. DOI: 10.1016/s0952-7915(02)00318-7. View

11.

Cheng W, Hung C, Hsu K, Chai C, He L, Polo J . Cancer immunotherapy using Sindbis virus replicon particles encoding a VP22-antigen fusion. Hum Gene Ther. 2002; 13(4):553-68. DOI: 10.1089/10430340252809847. View

12.

Helmerhorst T, Meijer C . Cervical cancer should be considered as a rare complication of oncogenic HPV infection rather than a STD. Int J Gynecol Cancer. 2002; 12(3):235-6. DOI: 10.1046/j.1525-1438.2002.t01-3-01126.x. View

13.

Koutsky L, Ault K, Wheeler C, Brown D, Barr E, Alvarez F . A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002; 347(21):1645-51. DOI: 10.1056/NEJMoa020586. View

14.

Nonn M, Schinz M, Zumbach K, Pawlita M, Schneider A, Durst M . Dendritic cell-based tumor vaccine for cervical cancer I: in vitro stimulation with recombinant protein-pulsed dendritic cells induces specific T cells to HPV16 E7 or HPV18 E7. J Cancer Res Clin Oncol. 2003; 129(9):511-20. DOI: 10.1007/s00432-003-0462-6. View

15.

Penn I . Second malignant neoplasms associated with immunosuppressive medications. Cancer. 1976; 37(2 Suppl):1024-32. DOI: 10.1002/1097-0142(197602)37:2+<1024::aid-cncr2820370806>3.0.co;2-v. View

16.

Nasiell K, Roger V, NASIELL M . Behavior of mild cervical dysplasia during long-term follow-up. Obstet Gynecol. 1986; 67(5):665-9. DOI: 10.1097/00006250-198605000-00012. View

17.

Rellihan M, Dooley D, Burke T, Berkland M, Longfield R . Rapidly progressing cervical cancer in a patient with human immunodeficiency virus infection. Gynecol Oncol. 1990; 36(3):435-8. DOI: 10.1016/0090-8258(90)90159-i. View

18.

Connor M, Stern P . Loss of MHC class-I expression in cervical carcinomas. Int J Cancer. 1990; 46(6):1029-34. DOI: 10.1002/ijc.2910460614. View

19.

Chen L, Thomas E, Hu S, Hellstrom I, Hellstrom K . Human papillomavirus type 16 nucleoprotein E7 is a tumor rejection antigen. Proc Natl Acad Sci U S A. 1991; 88(1):110-4. PMC: 50759. DOI: 10.1073/pnas.88.1.110. View

20.

Sacerdote P, Rubboli F, Locatelli L, Ciciliato I, Mantegazza P, Panerai A . Pharmacological modulation of neuropeptides in peripheral mononuclear cells. J Neuroimmunol. 1991; 32(1):35-41. DOI: 10.1016/0165-5728(91)90069-j. View