Immunohistologic analysis of the phenomenon of spontaneous regression of numerous flat warts

Aiba, Setsuya; Rokugo, Masakazu; Tagami, Hachiro

doi:10.1002/1097-0142(19860915)58:6<1246::aid-cncr2820580612>3.0.co;2-e

Cited by 76 publications

(26 citation statements)

References 16 publications

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“…The majority of these cancers expresses the HPV16-derived E6 and E7 oncoproteins (2), which are therefore attractive targets for T cell-mediated immunotherapy (3). Several observations, such as the spontaneous regression of most premalignant cervical lesions (4 -6) and the infiltration of CD4 ϩ T cells and macrophages in regressing genital warts (7,8), suggest that therapeutic vaccination may prevent progression from oncogenic HPV infection through cervical intraepithelial neoplasia to cervical cancer. This notion is supported by the fact that an increase in HPV infection was found in immunosuppressed (9) and immunodeficient (10) patients.…”

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confidence: 99%

Established Human Papillomavirus Type 16-Expressing Tumors Are Effectively Eradicated Following Vaccination with Long Peptides

Zwaveling

Mota

Nouta

et al. 2002

The Journal of Immunology

382

327

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Peptide-based vaccines aimed at the induction of effective T cell responses against established cancers have so far only met with limited clinical success and clearly need to be improved. In a preclinical model of human papillomavirus (HPV)16-induced cervical cancer we show that prime-boost vaccinations with the HPV16-derived 35 amino-acid long peptide E743–77, containing both a CTL epitope and a Th epitope, resulted in the induction of far more robust E7-specific CD8+ T cell responses than vaccinations with the minimal CTL epitope only. We demonstrate that two distinct mechanisms are responsible for this effect. First, vaccinations with the long peptide lead to the generation of E7-specific CD4+ Th cells. The level of the induced E7-specific CD8+ T cell response proved to be dependent on the interactions of these Th cells with professional APC. Second, we demonstrate that vaccination with the long peptide and dendritic cell-activating agents resulted in a superior induction of E7-specific CD8+ T cells, even when T cell help was excluded. This suggests that, due to its size, the long peptide was preferably endocytosed, processed, and presented by professional APCs. Moreover, the efficacy of this superior HPV-specific T cell induction was demonstrated in therapeutic prime-boost vaccinations in which the long peptide admixed with the dendritic cell-activating adjuvant oligodeoxynucleotide-CpG resulted in the eradication of large, established HPV16-expressing tumors. Because the vaccine types used in this study are easy to prepare under good manufacturing practice conditions and are safe to administer to humans, these data provide important information for future clinical trials.

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confidence: 99%

Established Human Papillomavirus Type 16-Expressing Tumors Are Effectively Eradicated Following Vaccination with Long Peptides

Zwaveling

Mota

Nouta

et al. 2002

The Journal of Immunology

382

327

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“…Cellmediated immune responses play an important role in antitumor responses. 6,7) It has been demonstrated that immunization with E7 or L1DE7 1-60 protein activates CTL responses and induces tumor protection in vivo. 13,22) In our study, immunization with mE6 1-120 /mE7 1-60 also elicited specific CTLs, which was demonstrated by the fact that these CTLs specifically lysed target cells expressing E6 and E7, but not Lewis lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Efficient Expression of Modified Human Papillomavirus 16 E6/E7 Fusion Protein and the Antitumor Efficacy in a Mouse Model

Zhou

Qian

Zhao

et al. 2004

Biological & Pharmaceutical Bulletin

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Modern research has identified infection with human papillomavirus (HPV) as a major risk factor for the development of cervical neoplasia and cervical cancer.1) More than 90% of cervical cancers contain HPV DNA, with type 16 being the most prevalent.2) In most cases, the early viral E6 and E7 genes of high-risk HPV are integrated into the human genome and constitutively expressed in cervical cancer and cervical intraepithelial neoplasia (CIN). In addition, the two oncoproteins play a key role in the induction and maintenance of the transformation phenotype.3,4) Therefore they are tumor-specific antigens and serve as ideal targets for the development of immunotherapy to prevent and treat HPV-16 associated CIN and cervical cancer. 5) Specific cell-mediated immune responses are believed to be critical for the elimination of HPV-infected cells or HPV-transformed cells. This assumption is based on the observations that in the majority of individuals HPV-induced lesions regress spontaneously, and that immunodeficient patients, like AIDS patients, develop significantly more HPV-associated lesions in the skin and anogenital tissue than immunocompetent individuals.6,7) E7-and/or E6-specific cytotoxic T lymphocytes (CTLs) have been identified in patients with HPV16 ϩ cervical cancers. 8,9) Moreover, various studies in animal models indicated that it is possible to induce protection against HPV-containing tumors or to generate E6/E7-specific CTLs. [10][11][12][13][14][15][16][17] To augment CTL responses, various types of vaccines have been developed, such as E7 linked to heat-shock proteins or intracellular sorting molecules, [18][19][20] peptide/protein loaded on dendritic cells (DCs), 13) DNA, or RNA-transfected DCs. 21)Protein-based immunization is a simple, safe, and effective approach in vaccination against infectious and malignant diseases. Immunization with purified E7 protein or L1DE7 1-60 could yield efficient protection against tumor cells. 13,14,22) However, the E6-specific T cell immune response also plays a pivotal role in protection against persistent HPV infection and associated development of malignancies. Human CTL epitopes for the most frequent HLA-A molecules derived from E6 have been identified, most of which are located in the N-terminus.23) In addition, E6-specific CTLs have been detected in cervical cancer patients.24) Therefore a single protein comprising HPV16 E6 and E7 might elicit more potent immune responses. It has been demonstrated that the recombinant E6/E7 fusion protein could be engulfed by DCs in vitro, then undergo intracellular processing in the class I pathway, making the peptide fragments available for CTL recognition.25) However, to the best of our knowledge, the expression level of the recombinant HPV16 E6/E7 fusion protein is very low (2.5% of total host protein), which limits its further application, and its antitumor efficacy in vivo has not yet been tested.To improve the immunogenicity of HPV16 E6/E7 and investigate the antitumor efficacy in vivo, we modified the E6/E7 fusion ge...

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“…The evidence from immunosuppressed patients (Alloub et al, 1989;Kent et al, 1987;Sillman et al, 1984;Lutzner et al, 1983;Mullen et al, 1976) and regressing warts (Fierlbeck et al, 1989;Aiba et al, 1986) suggests an important role for the immune system in papillomavirus infections.…”

mentioning

confidence: 99%

Delayed-type hypersensitivity response to human papillomavirus type 16 E6 protein in a mouse model

Chambers

Stacey

Arrand

et al. 1994

Journal of General Virology

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A mouse model incorporating the epitheliotropic nature of human papillomavirus (HPV) infections has been used to study an immune response to HPV type 16 (HPV-16) E6 protein in vivo. Using a transplantation technique, a novel immortal keratinocyte cell line expressing the E6 protein has been grafted onto syngeneic mice to re-form a differentiated epithelium overlying a granulation tissue bed. By this approach the presentation of viral antigens to the immune system can be modelled in a way analogous to the natural infection. Here we report a delayed-type hypersensitivity (DTH) reaction in grafted mice challenged intradermally with a recombinant vaccinia virus expressing the HPV-16 E6 protein. The specificity of the response was confirmed by the absence ofa DTH reaction to challenge with virus expressing either HPV-16 E7 or LI protein.More than 65 different types of human papillomavirus (HPV) have been described, classified on the basis of nucleotide homology. At least 20 genotypes are associated with lesions of the genital tract. Benign genital warts (condylomata acuminata of low malignant potential) are most frequently associated with types 6 and 11, whereas types 16 and 18 are found predominantly in anogenital dysplasias and carcinomas.Our understanding of the immunobiology of papillomaviruses, although limited, is central to any strategy for prophylactic or therapeutic intervention. The evidence from immunosuppressed patients (Alloub et al.,

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Immunohistologic analysis of the phenomenon of spontaneous regression of numerous flat warts

Cited by 76 publications

References 16 publications

Established Human Papillomavirus Type 16-Expressing Tumors Are Effectively Eradicated Following Vaccination with Long Peptides

Established Human Papillomavirus Type 16-Expressing Tumors Are Effectively Eradicated Following Vaccination with Long Peptides

Efficient Expression of Modified Human Papillomavirus 16 E6/E7 Fusion Protein and the Antitumor Efficacy in a Mouse Model

Delayed-type hypersensitivity response to human papillomavirus type 16 E6 protein in a mouse model

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