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  • 1
    Keywords: PEPTIDE ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; Germany ; human ; PROTEIN ; PROTEINS ; TUMORS ; MICE ; RELEASE ; COMPLEX ; RESPONSES ; COMPLEXES ; SERA ; REDUCTION ; DENDRITIC CELLS ; BINDING ; SEQUENCE ; antibodies ; NEUTRALIZING ANTIBODIES ; PARTICLES ; ASSAY ; ESCHERICHIA-COLI ; GLUTATHIONE ; LYMPHOCYTES ; VIRUS-LIKE PARTICLES ; HPV ; HPV16 ; VACCINE ; IMMUNE-RESPONSE ; vaccination ; L1 ; SEQUENCE-ANALYSIS ; glutathione-S-transferase ; HPV PSEUDOVIRIONS ; NASAL IMMUNIZATION
    Abstract: We analyzed capsomeres of human papillomavirus type 16 (HPV16) consisting of the L1 major structural protein for their ability to trigger a cytotoxic T-cell (CTL) response. To this end, we immunized C57BL/6 mice and used the L1(165-173) peptide for ex vivo restimulation of splenocytes prior to analysis (Cr-51 release assay and enzyme-linked immunospot assay [ELISPOT]). This peptide was identified in this study as a D-b-restricted naturally processed CTL epitope by HPV16 L1 sequence analysis, major histocompatibility complex class I binding, and Cr-51 release assays following immunization of C57BL/6 mice with HPV16 L1 virus-like particles (VLPs). HPV16 L1 capsomeres were obtained by purification of HPV16 L1 lacking 10 N-terminal amino acids after expression in Escherichia coli as a glutathione S-transferase fusion protein (GST-HPV16 L1DeltaN10). Sedimentation analysis revealed that the majority of the purified protein consisted of pentameric capsomeres, and assembled particles were not observed in minor contaminating higher-molecular-weight material. Subcutaneous (s.c.) as well as intranasal immunization of C57BL/6 m ice with HPV16 L1 capsomeres triggered an L1-specific CTL response in a dose- dependent manner as measured by ELISPOT and Cr-51 release as say. Significant reduction of contaminating bacterial endotoxin (lipopolysaccharide) from the capsomere preparation did not diminish the immunogenicity. Antibody responses (serum and vaginal) were less robust under the experimental conditions employed. In addition, s.c. vaccination with HPV16 L1 capsomeres induced regression of established tumors expressing L1 determinants (C3 tumor cells). Our data demonstrate that capsomeres are potent inducers of CTL responses similar to completely assembled T=7 VLPs. This result is of potential relevance for the development of (combined prophylactic and therapeutic) HPV-specific vaccines, since capsomeres can be produced easily and also can be modified to incorporate heterologous sequences such as early HPV proteins
    Type of Publication: Journal article published
    PubMed ID: 12663770
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  • 2
    Keywords: CANCER ; EXPRESSION ; CLINICAL-TRIAL ; Germany ; human ; INFORMATION ; PROTEIN ; PROTEINS ; PATIENT ; RESPONSES ; INFECTION ; T cell ; T-CELLS ; E7 ; IMMUNE-RESPONSES ; antibodies ; antibody ; PARTICLES ; TRIAL ; NEOPLASIA ; HUMANS ; WOMEN ; cervical cancer ; cervical intraepithelial neoplasia ; CERVICAL-CANCER ; EFFICACY ; FUSION ; LYMPHOCYTES ; VIRUS-LIKE PARTICLES ; HPV ; VACCINE ; SAFETY ; immune response ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; intraepithelial neoplasia ; T-LYMPHOCYTES ; vaccination ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; L1 ; T lymphocyte ; DOUBLE-BLIND ; PREVALENCE ; T lymphocytes ; glutathione-S-transferase ; YOUNG-WOMEN ; IMMUNIZATION ; ONCOLOGY ; PERSISTENT ; RECOMBINANT ; END ; GRADE ; RECIPIENTS ; development ; EVENTS ; PERSISTENCE ; USA ; HUMAN PAPILLOMAVIRUSES ; IMPROVEMENT ; immune responses ; clinical trial ; CIN
    Abstract: Persistent infection with human papillomaviruses (HPV) is a prerequisite for the development of cervical cancer. Vaccination with virus-like particles (VLP) has demonstrated efficacy in prophylaxis but lacks therapeutic potential. HPV16 L1E7 chimeric virus-like particles (CVLP) consist of a carboxy-terminally truncated HPV16L1 protein fused to the amino-terminal part of the HPV16 E7 protein and self-assemble by recombinant expression of the fusion protein. The CVLP are able to induce L1- and E7-specific cytotoxic T lymphocytes. We have performed a first clinical trial to gain information about the safety and to generate preliminary data on the therapeutic potential of the CVLP in humans. A randomized, double blind, placebo-controlled clinical trial has been conducted in 39 HPV16 mono-infected high grade cervical intraepithelial neoplasia (CIN) patients (CIN 2/3). Two doses (75 mu g or 250 mu g) of CVLP were applied. The duration of the study was 24 weeks with 2 optional visits after another 12 and 24 weeks. The vaccine showed a very good safety profile with only minor adverse events attributable to the immunization. Antibodies with high titers against HPV16 L1 and low titers against HPV16 E7 as well as cellular immune responses against both proteins were induced. Responses were equivalent for both vaccine concentrations. A trend for histological improvement to CIN I or normal was seen in 39% of the patients receiving the vaccine and only 25% of the placebo recipients. Fifty-six percent of the responders were also HPV16 DNA-negative by the end of the study. Therefore, we demonstrated evidence for safety and a nonsignificant trend for the clinical efficacy of the HPV16 L1E7 CVLP vaccine. (c) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17721997
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  • 3
  • 4
    ISSN: 0890-8508
    Keywords: Human papillomavirus type 16 ; antibodies ; type-specificity
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1433-0415
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Durch molekulare und epidemiologische Studien wurde bewiesen, daß die humanpathogenen Papillomviren (HPV) Typ 16 und 18 ursächlich an der Entstehung des Zervixkarzinoms beteiligt sind. Diese Aussage gilt auch in bisher noch eingeschränktem Maße für andere sog. High-risk-HPV-Typen wie HPV 31, 33, 35, 39, 45, 51, 52, 56 und 58. Etwa 1/2 Mio. Frauen erkranken jährlich weltweit am Zervixkarzinom und zwischen 1–4% aller jüngeren Frauen leiden an einer Präkanzerose der Cervix uteri. Das Wissen um die virale Genese anogenitaler Neoplasien wird jedoch bisher nicht für die primäre und sekundäre Prävention dieser Erkrankungen eingesetzt. Dies liegt vor allem daran, daß die Infektion mit genitalen HPV-Typen bei jungen Frauen hoch prävalent ist, jedoch nur selten zum Karzinom führt. In der folgenden Übersicht werden daher die wichtigsten vorliegenden epidemiologischen Daten zum Zervixkarzinom und seinen Vorstufen auf ihre Assoziation mit HPV analysiert. Im weiteren werden die molekularbiologischen Daten von HPV für die ano- genitale Karzinogenese dargestellt. Abschließend wird auf die Bedeutung von HPV für die Prävention des Zervixkarzinoms eingegangen.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1433-0393
    Keywords: SchlüsselwörterZervixkarzinom ; Epidemiologie ; Humane Papillomviren ; Karzinogenese ; Prävention ; Key wordsCarcinoma of the cervix ; Epidemiology ; Human papillomavirus ; Carcinogenesis ; Prevention
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Molecular and epidemiological studies have confirmed that human pathogenic papillomaviruses (HPV)types 16 and 18 are causally involved in the developement of carcinoma of the cervix. This statement is also true, albeit with reservations as yet, of other so-called high-risk HPV types, such as HPV 31, 33, 35, 39, 45, 51, 52, 56 and 58. Around 500,000 women throughout the world become ill with carcinoma of the cervix every year, and 1–4% of all younger women have a precancer of the cervix uteri. This knowledge of the viral origin of anogenital neoplasms has not yet been exploited for primary and secondary prevention of these illnesses, however. This is mainly because infection with genital HPV types is very prevalent in young women but seldom leads to carcinoma. In this review, therefore, the most important epidemiological data available on cervical carcinoma and its preliminary stages are analysed with reference to an association with HPV. In addition, the molecular biological data on HPV as it relates to anogenital carcinogenesis are presented. In conclusion, the significance of HPV for the prevention of carcinoma of the cervix is discussed.
    Notes: Zusammenfassung Durch molekulare und epidemiologische Studien wurde bewiesen, daß die humanpathogenen Papillomviren (HPV) Typ 16 und 18 ursächlich an der Entstehung des Zervixkarzinoms beteiligt sind. Diese Aussage gilt auch in bisher noch eingeschränktem Maße für andere sog. High-risk-HPV-Typen wie HPV 31, 33, 35, 39, 45, 51, 52, 56 und 58. Etwa 1/2 Mio. Frauen erkranken jährlich weltweit am Zervixkarzinom und zwischen 1–4% aller jüngeren Frauen leiden an einer Präkanzerose der Cervix uteri. Das Wissen um die virale Genese anogenitaler Neoplasien wird jedoch bisher nicht für die primäre und sekundäre Prävention dieser Erkrankungen eingesetzt. Dies liegt vor allem daran, daß die Infektion mit genitalen HPV-Typen bei jungen Frauen hoch prävalent ist, jedoch nur selten zum Karzinom führt. In der folgenden Übersicht werden daher die wichtigsten vorliegenden epidemiologischen Daten zum Zervixkarzinom und seinen Vorstufen auf ihre Assoziation mit HPV analysiert. Im weiteren werden die molekularbiologischen Daten von HPV für die anogenitale Karzinogenese dargestellt. Abschließend wird auf die Bedeutung von HPV für die Prävention des Zervixkarzinoms eingegangen.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-8798
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary.  The “high-risk” human papillomavirus type 16 (HPV 16) is associated with the development of cervical cancer. Although the viral gene products E6 and E7 are constitutively expressed in HPV 16-associated lesions and therefore appear as candidate antigens for a specific immune response, the immune system fails to produce an efficient defence against tumor outgrowth in affected patients. Keratinocytes are the natural target cells of HPV infection. To investigate the E7-specific immune response in vivo, we used transgenic mice expressing the oncogenes E6 and E7 of HPV 16 under the control of the keratin 10 promoter in the suprabasal layers of the epidermis. This expression pattern closely reflects the viral early gene transcription that is observed in low grade cervical intraepithelial lesions (CIN). The transgene product E7 does not induce an immune response in these transgenic mice. However, upon vaccination anti-E7 antibodies were produced without causing signs of autoimmune disease. In contrast, E7-specific cytotoxic T lymphocytes (CTL) were not detected after immunization. From these results we conclude that in K10 HPV 16 E6/E7 transgenic mice the E7 transgene expression induces specific immunological tolerance on the CTL level.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-8798
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The low expression of major histocompatibility complex (MHC) class I antigens on human papillomavirus (HPV)-infected cervical carcinoma cells may be responsible for an insufficient cytotoxic T cell response against these cells. To investigate in vitro whether the HPV type 16 early gene product E7 influences cell surface expression of MHC class I and II molecules the HPV negative keratinocyte cell line HaCaT was either stably transfected with the E7 gene or infected with E7-recombinant vaccinia viruses. No difference in MHC class I transcription was detected between E7-transfected and untransfected HaCaT cells. MHC class I cell surface expression as determined by FACS analysis was stronger in some of the transfectants and less intensive in others when compared to untransfected HaCaT cells. In wildtype as well as in E7-recombinant vaccinia virus infected HaCaT cells downregulation of MHC class I molecules on protein and transcriptional level was observed. The alterations in MHC class I expression were independent of the presence and amount of E7-specific transcripts. None of the transfectants or infected HaCaT cells had MHC class II molecules on their cell surface. Hence, our data did not show a correlation between HPV 16 E7 and MHC expression in vitro.
    Type of Medium: Electronic Resource
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