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Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice.

Nanni P, Nicoletti G, De Giovanni C, Landuzzi L, Di Carlo E, Cavallo F, Pupa SM, Rossi I, Colombo MP, Ricci C, Astolfi A, Musiani P, Forni G, Lollini PL - J. Exp. Med. (2001)

Bottom Line: IL-12 treatment strongly increased the cell vaccine efficacy.Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident.In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Section, Department of Experimental Pathology, University of Bologna, Italy.

ABSTRACT
Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor latency, but every mouse eventually succumbed to multiple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu combined with systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185(neu) antigen must be expressed by allogeneic cells. IL-12 treatment strongly increased the cell vaccine efficacy. The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes. Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident. A central role for IFN-gamma in the preventive effect was proven by the lack of efficacy of vaccination in IFN-gamma gene knockout HER-2/neu transgenic Balb/c mice. A possible requirement for IFN-gamma is related to its effect on antibody production, in particular on IgG2a and IgG2b subclasses, that were not induced in IFN-gamma knockout HER-2/neu mice. In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

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Subclasses of antibodies induced in Balb-neuT mice and in IFN-γ knockout Balb-neuT mice. Cytofluorometric analysis of serum binding to Neu/H-2q cells with secondary anti–mouse isotype antibodies is reported. Each bar represents the mean ± SEM of sera (diluted 1:65) from three mice at the fifteenth week of age bled after the second course of the indicated treatment.
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fig10: Subclasses of antibodies induced in Balb-neuT mice and in IFN-γ knockout Balb-neuT mice. Cytofluorometric analysis of serum binding to Neu/H-2q cells with secondary anti–mouse isotype antibodies is reported. Each bar represents the mean ± SEM of sera (diluted 1:65) from three mice at the fifteenth week of age bled after the second course of the indicated treatment.

Mentions: Analysis of Ig subclasses in sera from Balb-neuT transgenic mice treated with the cell vaccine or with the vaccine plus IL-12 is shown in Fig. 10 . The combined treatment with Neu/H-2q cells plus IL-12 significantly (P < 0.05) increased the level of IgG1, IgG2a, and IgG2b. By contrast, in IFN-γ knockout BALB-neuT mice receiving the vaccine plus IL-12 the treatment failed to increase the level of all Ig subclasses except IgG1.


Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice.

Nanni P, Nicoletti G, De Giovanni C, Landuzzi L, Di Carlo E, Cavallo F, Pupa SM, Rossi I, Colombo MP, Ricci C, Astolfi A, Musiani P, Forni G, Lollini PL - J. Exp. Med. (2001)

Subclasses of antibodies induced in Balb-neuT mice and in IFN-γ knockout Balb-neuT mice. Cytofluorometric analysis of serum binding to Neu/H-2q cells with secondary anti–mouse isotype antibodies is reported. Each bar represents the mean ± SEM of sera (diluted 1:65) from three mice at the fifteenth week of age bled after the second course of the indicated treatment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195980&req=5

fig10: Subclasses of antibodies induced in Balb-neuT mice and in IFN-γ knockout Balb-neuT mice. Cytofluorometric analysis of serum binding to Neu/H-2q cells with secondary anti–mouse isotype antibodies is reported. Each bar represents the mean ± SEM of sera (diluted 1:65) from three mice at the fifteenth week of age bled after the second course of the indicated treatment.
Mentions: Analysis of Ig subclasses in sera from Balb-neuT transgenic mice treated with the cell vaccine or with the vaccine plus IL-12 is shown in Fig. 10 . The combined treatment with Neu/H-2q cells plus IL-12 significantly (P < 0.05) increased the level of IgG1, IgG2a, and IgG2b. By contrast, in IFN-γ knockout BALB-neuT mice receiving the vaccine plus IL-12 the treatment failed to increase the level of all Ig subclasses except IgG1.

Bottom Line: IL-12 treatment strongly increased the cell vaccine efficacy.Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident.In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Section, Department of Experimental Pathology, University of Bologna, Italy.

ABSTRACT
Transgenic Balb/c mice expressing the transforming rat HER-2/neu oncogene develop early and multifocal mammary carcinomas. Within the first 5 months of life the tissue-specific expression of HER-2/neu causes a progression in all their 10 mammary glands from atypical hyperplasia to invasive carcinoma. It was previously observed that chronic administration of interleukin (IL)-12 increased tumor latency, but every mouse eventually succumbed to multiple carcinomas. A significant improvement in tumor prevention was sought by administering allogeneic mammary carcinoma cells expressing HER-2/neu combined with systemic IL-12. This treatment reduced tumor incidence by 90% and more than doubled mouse lifetime. For the maximum prevention p185(neu) antigen must be expressed by allogeneic cells. IL-12 treatment strongly increased the cell vaccine efficacy. The mammary glands of mice receiving the combined treatment displayed a markedly reduced epithelial cell proliferation, angiogenesis, and HER-2/neu expression, while the few hyperplastic foci were heavily infiltrated by granulocytes, macrophages, and CD8(+) lymphocytes. Specific anti-HER-2/neu antibodies were produced and a nonpolarized activation of CD4(+) and CD8(+) cells secreting IL-4 and interferon (IFN)-gamma were evident. A central role for IFN-gamma in the preventive effect was proven by the lack of efficacy of vaccination in IFN-gamma gene knockout HER-2/neu transgenic Balb/c mice. A possible requirement for IFN-gamma is related to its effect on antibody production, in particular on IgG2a and IgG2b subclasses, that were not induced in IFN-gamma knockout HER-2/neu mice. In conclusion, our data show that an allogeneic HER-2/neu-expressing cell vaccine combined with IL-12 systemic treatment can prevent the onset of genetically determined tumors.

Show MeSH
Related in: MedlinePlus