V. ZAITSEV
26.06.2003, 00:46
Уважаемый AlexT!
Т.к. я отказался участвовать в дискуссии по ВПЧ на форуме урология, привожу здесь некоторые зарубежные работы, проясняющие ряд моментов разгоревшегося там спора. Надеюсь, д-р Яков не будет возражать против продолжения этой темы на этом форуме.
Сначала, для вступления небольшой абзац:
Innate Immunity and Vaccinology Return to the Forefront of Infectious Disease Study
Disclosures
David R. Haburchak, MD, FACP
If I had to come up with a theme for the 40th Annual Meeting of the Infectious Diseases Society of America (IDSA), held October 24-27, 2002 in Chicago, Illinois, it would be "A Change of Perspective." Certainly since the founding of the IDSA, the focus on infectious disease management has been prevention of infection and, failing that, chemotherapy, specifically antibiotic therapy. Unfortunately, attendees could not help notice the continuing march of antimicrobial resistance by legions of bacteria, fungi, and viruses, elegantly depicted in scores of epidemiologic posters and presentations. The gloom was not broken by reports of new antibiotic breakthroughs. Only a few scattered opportunities exist for holding actions with "me too" antibiotics tweaked to provide a little better activity against certain pathogens. Just as the sun appeared to be setting on the antibiotic era, however, there were rays of hope coming from an old direction -- enhancement of the immune system, both innate and adaptive. Clinicians should be heartened.
…………………………………………………………………………………………………
Теперь сами работы.
1. HPV innate immunity.
Woodworth CD.
Biology Department, Science Center, Clarkson University, Potsdam, NY 13699, USA. [Ссылки могут видеть только зарегистрированные и активированные пользователи]
HPV infections of the epidermis and anogenital tract occur frequently in healthy individuals, and 'high risk' HPV types are a major risk factor for cervical cancer. The first line of defense against HPV is the innate immune system, which provides non specific protection against a variety of pathogens and also enhances the adaptive immune response. However, HPV-infected cells often evade innate immune recognition and elimination. HPV gene expression and release of virus occur in superficial squamous cells where virus antigens are not readily detected, and keratinocytes are not lysed during HPV infection so there is no inflammatory response. In addition, HPV early proteins inhibit specific components of the innate immune system. E6 and E7 inhibit signaling by type I interferons and decrease expression of multiple interferon-inducible genes. E5 and E7 inhibit expression of major histocompatibility complex class I proteins on the cell surface. HPV-infected cells are resistant to lysis by natural killer (NK) cells, but are sensitive to cytokine-activated NK cells. Activated macrophages also kill HPV-infected cells and control malignant development. Thus, innate immunity is important for prevention of HPV infections, but HPV often persists due to evasion or inactivation of innate defenses.
PMID: 12165480 [PubMed - indexed for MEDLINE]
2.Frequent display of human papillomavirus type 16 E6-specific memory t-Helper cells in the healthy population as witness of previous viral encounter.
Welters MJ, de Jong A, van den Eeden SJ, van der Hulst JM, Kwappenberg KM, Hassane S, Franken KL, Drijfhout JW, Fleuren GJ, Kenter G, Melief CJ, Offringa R, van der Burg SH.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Genital human papillomavirus (HPV) infection is common and the majority of infected individuals successfully deal with this virus. Clearance of HPV is presumably mediated by T cells but HPV-16-specific T-cell memory was usually detected in patients with progressive disease and not in healthy subjects, suggesting that HPV-immunity comes too late. We now show the presence of HPV-16 E6-specific memory T-helper (Th) responses in a major fraction (12 of 20) of healthy individuals by application of the IFN-gamma-ELISPOT assay. Although nearly all E6-peptides were recognized, the majority of the responders targeted peptide sequences of the COOH-terminal half (E6(81-158)) of HPV-16 E6. In a direct comparison, the presence of HPV-16 E6-specific T cells coincided with HPV-16 E2-specific T-cell reactivity in healthy individuals, whereas hardly any HPV-16 E7-specific Th immunity was found. This indicates that the induction of T-cell reactivity against HPV-16 E7 is suboptimal during infection when compared with that against HPV-16 E2 and HPV-16 E6. In conclusion, the presence of HPV-16 E6-specific Th memory in the healthy population demonstrates that HPV infection leads to T-cell immunity against immediate early proteins expressed during infection. Because this HPV-16 E6-specific T-cell immunity was frequently detected in healthy subjects, our data suggest that the observed IFN-gamma-producing proliferating T cells circulating in the peripheral blood play a role in protection against persistent HPV infection and associated development of malignancies.
PMID: 12566307 [PubMed - indexed for MEDLINE]
3. [Ссылки могут видеть только зарегистрированные и активированные пользователи]
4. Cancer Immunity, Vol. 3 Suppl. 1, p. 25 (6 February 2003)
Immunotherapy for HPV associated pre-cancer
Ian H. Frazer1*, G.J. Leggatt1, K. Matsumoto1, R. De Kluyver1, M. Quinn2, J. Nicklin3, J. Tan2, L. Perrin3, P. Ng4, V. O'Connor5, O. White1, N. Wendt1, J. Martin1, S.V. Mitchell6, A. McKenzie6, J. Crowley6, S. Edwards6, and D. Maher6
1Centre for Immunology and Cancer Research, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland
2Royal Women's Hospital, Parkville, Victoria
3Royal Women's Hospital, Brisbane, Queensland
4Mater Mother's Hospital, Brisbane, Queensland
5Queen Elizabeth II Jubilee Hospital, Brisbane, Queensland
6CSL Limited, Parkville, Victoria, Australia
*Presenting author
Abstract
Cervical pre-cancer is associated with, and develops from, infection of cervical epithelium by one of a range of oncogenic papillomaviruses. To model the immunology of papillomavirus infection, we have grafted skin transgenic for the E7 major transforming protein of HPV16 to naive recipient mice (1). We examined the nature of the immune response to E7 developed following grafting, the effect of E7 specific immunotherapy on graft outcome, and the nature of the immune response, which can result in graft destruction. Grafting to transgenic skin in which E7 or hGH is expressed in epithelial cells from a keratin 14 promoter to a naive animal induces active tolerance of the graft antigen, and this tolerance is not broken by immunization. Co-administration of a strong pro-inflammatory signal at the time of grafting E7 transgenic skin results in graft rejection, and animals that have rejected one E7 graft will specifically reject a further E7 transgenic graft without further immune manipulation. Graft rejection requires both CD4 and CD8 T cells, and antigen specific rejection response can be determined either by CD4 cells or by CD8 cells.
To establish the safety, tolerability and immunogenicity of HPV16 specific immunotherapy for CIN in patients with CIN, we conducted a double blind trial using CerVax16™, a fusion protein of E6 and E7 from HPV16 combined with ISCOMs, a saponin based adjuvant. 31 women with CIN 1-3 were randomly allocated to receive active treatment (n = 24) with one of three dose levels of antigen (20 µg, 60 µg, or 200 µg), or placebo (n = 7). Up to three injections were given intramuscularly over 6 weeks. Subjects were assessed for adverse events, immunogenicity, and HPV16 viral load in cervical biopsies taken before and after treatment. Local site reaction (mild n = 11, moderate n = 11, severe n = 2) and systemic symptoms (mild n = 11, moderate n = 8, severe n = 3) were observed in active and placebo groups. Specific antibody was induced for all 24 subjects given active vaccine. 12 of 20 evaluable subjects given active vaccine demonstrated a gamma-interferon response. CTL responses were detected in some subjects. In general, responses increased with multiple vaccinations. No major changes in colposcopic appearance or in cervical histology were observed. Of 14 HPV16 +ve subjects treated, 13 had lower mean HPV copy number per cell after treatment. Mean viral load fell from 50 ± 22 viral copies per cell pre-treatment to 12 ± 8 post-treatment (P<0.05; paired t test). Mean viral load did not fall significantly in women given placebo (P=0.34). CerVax16™ is thus safe and immunogenic in patients with HPV16-associated CIN, and may reduce the load of HPV16 in infected cervical tissue.
Т.к. я отказался участвовать в дискуссии по ВПЧ на форуме урология, привожу здесь некоторые зарубежные работы, проясняющие ряд моментов разгоревшегося там спора. Надеюсь, д-р Яков не будет возражать против продолжения этой темы на этом форуме.
Сначала, для вступления небольшой абзац:
Innate Immunity and Vaccinology Return to the Forefront of Infectious Disease Study
Disclosures
David R. Haburchak, MD, FACP
If I had to come up with a theme for the 40th Annual Meeting of the Infectious Diseases Society of America (IDSA), held October 24-27, 2002 in Chicago, Illinois, it would be "A Change of Perspective." Certainly since the founding of the IDSA, the focus on infectious disease management has been prevention of infection and, failing that, chemotherapy, specifically antibiotic therapy. Unfortunately, attendees could not help notice the continuing march of antimicrobial resistance by legions of bacteria, fungi, and viruses, elegantly depicted in scores of epidemiologic posters and presentations. The gloom was not broken by reports of new antibiotic breakthroughs. Only a few scattered opportunities exist for holding actions with "me too" antibiotics tweaked to provide a little better activity against certain pathogens. Just as the sun appeared to be setting on the antibiotic era, however, there were rays of hope coming from an old direction -- enhancement of the immune system, both innate and adaptive. Clinicians should be heartened.
…………………………………………………………………………………………………
Теперь сами работы.
1. HPV innate immunity.
Woodworth CD.
Biology Department, Science Center, Clarkson University, Potsdam, NY 13699, USA. [Ссылки могут видеть только зарегистрированные и активированные пользователи]
HPV infections of the epidermis and anogenital tract occur frequently in healthy individuals, and 'high risk' HPV types are a major risk factor for cervical cancer. The first line of defense against HPV is the innate immune system, which provides non specific protection against a variety of pathogens and also enhances the adaptive immune response. However, HPV-infected cells often evade innate immune recognition and elimination. HPV gene expression and release of virus occur in superficial squamous cells where virus antigens are not readily detected, and keratinocytes are not lysed during HPV infection so there is no inflammatory response. In addition, HPV early proteins inhibit specific components of the innate immune system. E6 and E7 inhibit signaling by type I interferons and decrease expression of multiple interferon-inducible genes. E5 and E7 inhibit expression of major histocompatibility complex class I proteins on the cell surface. HPV-infected cells are resistant to lysis by natural killer (NK) cells, but are sensitive to cytokine-activated NK cells. Activated macrophages also kill HPV-infected cells and control malignant development. Thus, innate immunity is important for prevention of HPV infections, but HPV often persists due to evasion or inactivation of innate defenses.
PMID: 12165480 [PubMed - indexed for MEDLINE]
2.Frequent display of human papillomavirus type 16 E6-specific memory t-Helper cells in the healthy population as witness of previous viral encounter.
Welters MJ, de Jong A, van den Eeden SJ, van der Hulst JM, Kwappenberg KM, Hassane S, Franken KL, Drijfhout JW, Fleuren GJ, Kenter G, Melief CJ, Offringa R, van der Burg SH.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Genital human papillomavirus (HPV) infection is common and the majority of infected individuals successfully deal with this virus. Clearance of HPV is presumably mediated by T cells but HPV-16-specific T-cell memory was usually detected in patients with progressive disease and not in healthy subjects, suggesting that HPV-immunity comes too late. We now show the presence of HPV-16 E6-specific memory T-helper (Th) responses in a major fraction (12 of 20) of healthy individuals by application of the IFN-gamma-ELISPOT assay. Although nearly all E6-peptides were recognized, the majority of the responders targeted peptide sequences of the COOH-terminal half (E6(81-158)) of HPV-16 E6. In a direct comparison, the presence of HPV-16 E6-specific T cells coincided with HPV-16 E2-specific T-cell reactivity in healthy individuals, whereas hardly any HPV-16 E7-specific Th immunity was found. This indicates that the induction of T-cell reactivity against HPV-16 E7 is suboptimal during infection when compared with that against HPV-16 E2 and HPV-16 E6. In conclusion, the presence of HPV-16 E6-specific Th memory in the healthy population demonstrates that HPV infection leads to T-cell immunity against immediate early proteins expressed during infection. Because this HPV-16 E6-specific T-cell immunity was frequently detected in healthy subjects, our data suggest that the observed IFN-gamma-producing proliferating T cells circulating in the peripheral blood play a role in protection against persistent HPV infection and associated development of malignancies.
PMID: 12566307 [PubMed - indexed for MEDLINE]
3. [Ссылки могут видеть только зарегистрированные и активированные пользователи]
4. Cancer Immunity, Vol. 3 Suppl. 1, p. 25 (6 February 2003)
Immunotherapy for HPV associated pre-cancer
Ian H. Frazer1*, G.J. Leggatt1, K. Matsumoto1, R. De Kluyver1, M. Quinn2, J. Nicklin3, J. Tan2, L. Perrin3, P. Ng4, V. O'Connor5, O. White1, N. Wendt1, J. Martin1, S.V. Mitchell6, A. McKenzie6, J. Crowley6, S. Edwards6, and D. Maher6
1Centre for Immunology and Cancer Research, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland
2Royal Women's Hospital, Parkville, Victoria
3Royal Women's Hospital, Brisbane, Queensland
4Mater Mother's Hospital, Brisbane, Queensland
5Queen Elizabeth II Jubilee Hospital, Brisbane, Queensland
6CSL Limited, Parkville, Victoria, Australia
*Presenting author
Abstract
Cervical pre-cancer is associated with, and develops from, infection of cervical epithelium by one of a range of oncogenic papillomaviruses. To model the immunology of papillomavirus infection, we have grafted skin transgenic for the E7 major transforming protein of HPV16 to naive recipient mice (1). We examined the nature of the immune response to E7 developed following grafting, the effect of E7 specific immunotherapy on graft outcome, and the nature of the immune response, which can result in graft destruction. Grafting to transgenic skin in which E7 or hGH is expressed in epithelial cells from a keratin 14 promoter to a naive animal induces active tolerance of the graft antigen, and this tolerance is not broken by immunization. Co-administration of a strong pro-inflammatory signal at the time of grafting E7 transgenic skin results in graft rejection, and animals that have rejected one E7 graft will specifically reject a further E7 transgenic graft without further immune manipulation. Graft rejection requires both CD4 and CD8 T cells, and antigen specific rejection response can be determined either by CD4 cells or by CD8 cells.
To establish the safety, tolerability and immunogenicity of HPV16 specific immunotherapy for CIN in patients with CIN, we conducted a double blind trial using CerVax16™, a fusion protein of E6 and E7 from HPV16 combined with ISCOMs, a saponin based adjuvant. 31 women with CIN 1-3 were randomly allocated to receive active treatment (n = 24) with one of three dose levels of antigen (20 µg, 60 µg, or 200 µg), or placebo (n = 7). Up to three injections were given intramuscularly over 6 weeks. Subjects were assessed for adverse events, immunogenicity, and HPV16 viral load in cervical biopsies taken before and after treatment. Local site reaction (mild n = 11, moderate n = 11, severe n = 2) and systemic symptoms (mild n = 11, moderate n = 8, severe n = 3) were observed in active and placebo groups. Specific antibody was induced for all 24 subjects given active vaccine. 12 of 20 evaluable subjects given active vaccine demonstrated a gamma-interferon response. CTL responses were detected in some subjects. In general, responses increased with multiple vaccinations. No major changes in colposcopic appearance or in cervical histology were observed. Of 14 HPV16 +ve subjects treated, 13 had lower mean HPV copy number per cell after treatment. Mean viral load fell from 50 ± 22 viral copies per cell pre-treatment to 12 ± 8 post-treatment (P<0.05; paired t test). Mean viral load did not fall significantly in women given placebo (P=0.34). CerVax16™ is thus safe and immunogenic in patients with HPV16-associated CIN, and may reduce the load of HPV16 in infected cervical tissue.