Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination

Smyth, Lesley A.; Poelgeest, Mariëtte I.E. van; Davidson, Emma; Kwappenberg, Kitty M. C.; Burt, Deborah J.; Sehr, Peter; Pawlita, Michael; Man, Stephen; Hickling, Julian; Fiander, Alison; Tristram, Amanda; Kitchener, Henry C; Offringa, Rienk; Stern, Peter L.; Burg, Sjoerd H. van der

doi:10.1158/1078-0432.ccr-03-0703

Cited by 125 publications

(108 citation statements)

References 10 publications

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“…In summary, we have shown that ELISPOT assays of IFN-g release are capable of revealing T-cell reactivities to HPV16 antigens in women with cervical dysplasia and can be used to establish the spectrum of T-cell responses induced during natural infection. The ELISPOT assay is becoming established as a good method for charting HPV-specific immunity, both during natural infection and following vaccination (van der Burg et al, 2001;de Jong et al, 2002de Jong et al, , 2004Steele et al, 2002;Baldwin et al, 2003;Welters et al, 2003;Smith et al, 2004;Smyth et al, 2004). Setting the vaccination studies aside, there are differences between the conclusions drawn from the studies looking at natural immunity and those obtained in this study.…”

Section: Seropositivity Is Related To Positive T-cell Reactivitymentioning

confidence: 78%

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

et al. 2005

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Infection with high-risk genital human papillomavirus (HPV) types is a major risk factor for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma. The design of effective immunotherapies requires a greater understanding of how HPV-specific T-cell responses are involved in disease clearance and/or progression. Here, we have investigated T-cell responses to five HPV16 proteins (E6, E7, E4, L1 and L2) in women with CIN or cervical carcinoma directly ex vivo. T-cell responses were observed in the majority (78%) of samples. The frequency of CD4 þ responders was far lower among those with progressive disease, indicating that the CD4 þ T-cell response might be important in HPV clearance. CD8 þ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8 þ T cells are not vitally involved in disease clearance. T-cell responses were demonstrated in the majority (80%) of cervical cancer patients, but are obviously ineffective. Our study reveals significant differences in HPV16 immunity during progressive CIN. We conclude that the HPV-specific CD4 þ T-cell response should be an important consideration in immunotherapy design, which should aim to target preinvasive disease.

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Section: Seropositivity Is Related To Positive T-cell Reactivitymentioning

confidence: 78%

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

et al. 2005

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“…9,10 Studies on the HPV18-specific T-cell immune response are scarce and limited to the identification of potential CTL epitopes 11,12 or vaccine-induced immunity. 13,14 Our studies on the presence and type of HPV16 E2-, E6-and E7-specific T-cell immunity in healthy subjects suggested that type 1 T-helper cell reactivity against HPV16 E2 and E6, which was present in the great majority of healthy individuals, played a role in protection to progressive infection. [15][16][17][18] In view of the behavioral differences between HPV16 and HPV18, in particular that in duration of viral persistence, we have analyzed the type 1 T-helper cell response to HPV18 oncoproteins E6 and E7 in healthy subjects and compared this with T-cell reactivity in HPV18-positive cancer patients.…”

mentioning

confidence: 84%

Detection of human papillomavirus type 18 E6 and E7‐specific CD4+ T‐helper 1 immunity in relation to health versus disease

Welters

Logt

Eeden

et al. 2005

Intl Journal of Cancer

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The most common high-risk human papillomavirus types, HPV16 and 18, differ markedly with respect to their interaction with the host. Clearance of HPV18 infections generally takes longer and HPV18-positive cancers have a poorer prognosis. We therefore evaluated Th1-type immunity against the E6 and E7 oncoproteins of HPV18 in healthy subjects and in patients with HPV18-positive genital cancer, and compared the results to our previously obtained data for HPV16. Approximately 20% of the healthy individuals displayed immunity against HPV18 E6. In contrast, none of the patients showed such responses, despite the presence of HPV18-positive lesions. Several of the patients did respond to HPV18 E7, whereas this immunity is rarely found in healthy subjects. This pattern of immune reactivity is essentially similar to that previously found for HPV16. It is unlikely that this similarity is the result of immunological cross-reactivity between the E6 and E7 antigens of HPV types 16 and 18. Our data confirm the relation between failure of E6-specific Th1 immunity and high-risk HPVinduced cervical neoplasia and argue that parameters other than these determine the differences in pathological impact between HPV types 16 and 18. ' 2005 Wiley-Liss, Inc.Key words: HPV18; healthy individuals; cervical cancer patients T-cell immunity One of the most common sexually transmitted diseases is genital infection with the human papillomavirus (HPV). Although most of the infections are cleared within~1 year, persistent infection with high-risk types HPV can ultimately result in development of anogenital cancers. 1 The most common high-risk HPV type in infection is HPV16 (2-year cumulative incidence of 7%) followed by HPV18 with a 2-year cumulative incidence of 4%. 2 Although HPV16 and 18 are both high-risk HPV types, they differ at several aspects. In general, HPV16 infections are cleared within 12 months, whereas clearance of HPV18 may take 17 months. 2,3 In addition, HPV16-DNA can be found in neoplastic cells as episomal and/or integrated forms. Conversely, HPV18-DNA is only found integrated in the host DNA, even in preneoplastic regions. 4 Furthermore, HPV16 is often present in squamous cell carcinomas, whereas HPV18 is generally detected in adenocarcinomas. 5,6 Finally, HPV181 tumours behave more aggressively than HPV161 tumours, in that patients bearing HPV181 tumours have a poorer prognosis and a shorter diseasefree survival. 7,8 Despite the marked differences between the two types of viruses, immunity to HPV16 is studied in great detail and HPV18 is grossly neglected. So far, only the serological response to HPV18 has been documented. 9,10 Studies on the HPV18-specific T-cell immune response are scarce and limited to the identification of potential CTL epitopes 11,12 or vaccine-induced immunity. 13,14 Our studies on the presence and type of HPV16 E2-, E6-and E7-specific T-cell immunity in healthy subjects suggested that type 1 T-helper cell reactivity against HPV16 E2 and E6, which was present in the great majority of healthy individual...

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“…Based on our previous reports, antigen-specific Tcell frequencies were considered to be increased compared to nonresponders when specific T-cell frequencies were 1/10,000. 27,28 HPV16 VLP ELISA For the detection of HPV16-specific antibodies in serum, we used an ELISA method previously described by Kirnbauer et al 29 Each serum sample was diluted 30 times and tested for reactivity against HPV16 virus-like particles (VLP, baculovirus-expressed capsids comprising the L1 protein) and against bovine papillomavirus (BPV) capsids, the latter disrupted by treatment with 0.1 M carbonate buffer to serve as a negative control. Both VLP and BPV were kindly provided by Prof. Dr. J. Dillner (LUNDS University, Sweden).…”

Section: Antigensmentioning

confidence: 99%

“…Based on our previous reports, responses were considered positive if peptide pool-specific T-cell frequencies were 10/100,000 PBMC. 27,28 These values are indicated in bold. Values below this threshold are shown in italics.…”

Section: Antigensmentioning

confidence: 99%

Distinct regulation and impact of type 1 T‐cell immunity against HPV16 L1, E2 and E6 antigens during HPV16‐induced cervical infection and neoplasia

Poelgeest

Nijhuis

Kwappenberg

et al. 2005

Intl Journal of Cancer

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Cervical cancer is the possible outcome of a genital infection with high-risk human papillomavirus type 16 (HPV16) and is preceded by a phase of persistent HPV infection during which the host immune system fails to eliminate the virus. Our previous work showed that failure is reflected by the absence of type 1 T-cell immunity against HPV16 early antigens E2 and E6 in patients with HPV161 cervical lesions. We now show that a majority of both patients with cervical lesions and healthy subjects display HPV16 L1 peptide-specific type 1 T-cell responses with similar magnitude. The T-cell response in patients was directed at a broad range of peptides within L1, suggesting that during persistent or repeated exposure to HPV16 L1, the immune system maximizes its efforts to counter the viral challenge. Unlike the type 1 T-cell responses against HPV16 early antigens E2 and E6, type 1 T-cell immunity against L1 does not correlate with health or disease. This argues that T-cell responses against early and late HPV16 antigens essentially differ in the manner in which they are induced and regulated, as well as in their impact on the subsequent stages of HPV16-induced cervical disease. ' 2005 Wiley-Liss, Inc.Key words: HPV16; T cell; L1; VLP; cervical cancer; healthy individuals Infection of both men and women with oncogenic human papillomavirus (HPV) types, such as HPV type 16 (HPV16), is quite common 1-3 and leads to progressive disease in only a minor fraction of infected subjects. [4][5][6] The majority of the infections and HPV-induced epithelial lesions spontaneously resolve, most likely through intervention by the adaptive immune response. [7][8][9] In a majority of healthy subjects (approximately 60%) strong type 1 Tcell reactivity directed at the nonstructural proteins HPV16 E2 and E6 can be detected, [10][11][12] suggesting that these proteins are important target antigens for a protective immune response in humans, similar to what was found in animal models. [13][14][15] These animal models also revealed that L1-specific immunity can protect against infection with the cottontail rabbit papilloma virus 16 or the canine oral papilloma virus. [17][18][19] A large HPV16 L1-VLP vaccination trial in humans revealed that vaccine-induced immunity could prevent persistent HPV16 infections. 20 Although the immunologic evaluation of this trial was focused on the role of neutralizing antibodies in preventing viral infection, VLP vaccination must also have affected the underlying CD41 Th responses and possibly Th-dependent cell-mediated effector functions.Previous work has shown that patients diagnosed with HPV16 1 CIN display proliferative responses against HPV16 L1 21,22 and that there was no difference in such proliferative responses (measured by IL-2 production) between patients who cleared their lesions or in whom lesions persisted. 23 Immunity in such subjects may differ not so much in the quantitative aspects of the immune response but more in the quality of the response, as is indicated by our studies on immunity against...

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Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination

Cited by 125 publications

References 10 publications

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia

Detection of human papillomavirus type 18 E6 and E7‐specific CD4+ T‐helper 1 immunity in relation to health versus disease

Distinct regulation and impact of type 1 T‐cell immunity against HPV16 L1, E2 and E6 antigens during HPV16‐induced cervical infection and neoplasia

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