title: Anti-HER-2/neu immune responses are induced before the development of clinical tumors but declined following tumorigenesis in HER-2/neu transgenic mice.
abstract: HER-2/neu oncogene products have been implicated as a potential target of T cell-mediated immune responses to HER-2/neu-induced tumors. Using HER-2/neu transgenic mice (oncomice), we investigated whether, and if so how, anti-HER-2/neu immune responses are induced and modulated in these oncomice from birth to tumor initiation. Female oncomice carrying the activated HER-2/neu oncogene displayed apparent hyperplasia in mammary glands at 10 weeks of age and developed mammary carcinomas around an average age of 26 weeks. Unfractionated spleen cells from 10- to 15-week-old oncomice that were cultured without any exogenous stimuli exhibited cytotoxicity against the F31 tumor cell line established from an HER-2/neu-induced mammary carcinoma mass. The final antitumor effectors were a macrophage lineage of cells. However, this effector population was activated, depending on the stimulation of oncomouse CD4(+) T cells with oncomouse-derived antigen-presenting cell (APC) alone or with wild-type mouse APC in the presence of F31 membrane fractions, suggesting the presence of HER-2/neu-primed CD4(+) T cells and HER-2/neu-presenting APC in 10- to 15-week-old oncomice. These antitumor cytotoxic responses were detected at approximately 5 weeks of age and peaked at age 10 to 15 weeks. However, the responses then declined at tumor-bearing stages in which the expression of target proteins could progressively increase. This resulted from the dysfunction of CD4(+) T cells but not of APC or effector macrophages. These results indicate that an anti-HER-2/neu CD4(+) T cell-mediated immune response was generated at the pretumorigenic stage but did not prevent tumorigenesis and declined after the development of clinical tumors.
authors.affiliation: Department of Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Noritami
authors.initials: N
authors.lastname: Takeuchi
authors.forename: Shin-Ichiroh
authors.initials: S
authors.lastname: Hiraoka
authors.forename: Xu-Yu
authors.initials: XY
authors.lastname: Zhou
authors.forename: Masakazu
authors.initials: M
authors.lastname: Nagafuku
authors.forename: Shiro
authors.initials: S
authors.lastname: Ono
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsujimura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hamaoka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases