title: IL-12 immunotherapy of minimal residual disease in murine models of HPV16-associated tumours: induction of immune responses, cytokine production and kinetics of immune cell subsets.
abstract: We have established animal models of HPV16-associated tumours with distinct levels of MHC class I expression. This model was used for examination of immune responses, production of cytokines and kinetics of immune cell subsets after IL-12 therapy of minimal residual tumour disease induced by CBA-4A (cyclophosphamide derivative) treatment. Upregulation of cytokine production was detected, compared to control animals without tumours. No differences in Th1/Th2 polarization of the immune responses after immunotherapy in animals bearing tumours with different surface expression of MHC class I molecules were observed. In the spleens of TC-1 (MHC class I+) but not of TC-1/A9 (MHC class I-) treated tumour-bearing animals, the cytotoxic CD8+ cells detectable in 51Cr microcytotoxicity assay, were found. In the spleens of TC-1/A9 but not of TC-1 tumour-treated animals, the NK activity measured as the lysis of NK-sensitive YAC-1 targets was detected. Down-regulation of the CD4+ and CD8+ subpopulations in spleens of tumour-bearing animals were not restored after therapy. The percentage of CD25+/CD4+ T regulatory (Treg) cells in lymph nodes remained unchanged. The cytoreductive chemotherapy led to strong upregulation and accumulation of immunosuppressive immature myeloid Gr-1+/CD11b+ cells (IMC) in the spleens of treated animals. The accumulation of Gr-1+/CD11b+ cells was significantly decreased after subsequent IL-12 immunotherapy. These data suggest that elimination of IMC after IL-12 immunotherapy may be responsible for the improvement of antitumour responses after adjuvant IL-12 vaccination for the treatment of CMRTD.
authors.affiliation: Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague 4, Czech Republic. indrova@img.cas.cz
authors.forename: Marie
authors.initials: M
authors.lastname: Indrová
authors.forename: Jana
authors.initials: J
authors.lastname: Bieblová
authors.forename: Jan
authors.initials: J
authors.lastname: Bubeník
authors.forename: Milan
authors.initials: M
authors.lastname: Reinis
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D052162:Human papillomavirus 16 / Q000378:metabolism*; D007107:Immune System / Q000276:immunology* / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000737:chemistry* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007700:Kinetics; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000821:virology*
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D018664:Interleukin-12