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Background:Human immune system (HIS)-engrafted mice are new tools to investigate human immune responses. Here, we used HIS mice to study human immune responses against human HER-2-positive cancer cells and their ability to control tumour growth and metastasis.Methods:BALB/c Rag2−/−, Il2rg−/− mice were engrafted with CD34+ or CD133+ human cord blood hematopoietic stem cells (HSC) and vaccinated with human HER-2-positive cancer cells SK-OV-3 combined to human IL-12.Results:Both CD34+ or CD133+ human HSC gave long-term engraftment and differentiation, both in peripheral blood and in lymphoid organs, and production of human antibodies. Vaccinated mice produced specific anti-HER-2 human IgG. An s.c. SK-OV-3 challenge was significantly inhibited (but not abolished) in both vaccinated and non-vaccinated HIS mice. Tumours were heavily infiltrated with human and murine cells, mice showed NK cells and production of human interferon-γ, that could contribute to tumour growth inhibition. Vaccinated HIS mice showed significantly inhibited lung metastases when compared with non-vaccinated HIS mice and to non-HIS mice, along with higher levels of tumour-infiltrating human dendritic cells.Conclusion:Anti-HER-2 responses were elicited through an adjuvanted allogeneic cancer cell vaccine in HIS mice. Human immune responses elicited in HIS mice effectively inhibited lung metastases. [ABSTRACT FROM AUTHOR]

The aim of this paper is to discuss biological and computational models of tumor-immune system interactions. To this end we provid first a short introduction to the field of general immunology, then a more in-depth exposition of cancer immunology. Finally we discuss a first approach to vaccine that prevent tumor onset from a biological point of view and we describe how to reproduce this phenomenon from a computational model. [ABSTRACT FROM AUTHOR]

The HER-2/neu proto-oncogene is overexpressed in 2030% of human breast cancers and is associated with high recurrence risk. The oncogenic potential of HER-2/neu, together with its elevated expression in tumors, cell surface localization, and immunogenicity in some patients, make this oncoprotein an ideal target for immunotherapeutic approaches. To test the efficacy of immune-based strategies in eliciting an antitumor response, we used the N#202 transgenic mouse model engineered to overexpress the rat neu proto-oncogene under the control of the mouse mammary tumor virus promoter; females of this line develop spontaneous focal mammary tumors by 6 months of age. Transgenic mice immunized intramuscularly with a HER-2 cDNA ligated into the VR1012 (VICAL) expression vector under the control of the cytomegalovirus promoter developed significantly fewer spontaneous tumors as compared with mice injected with the empty vector (P < 0.0001) or not injected (P = 0.0006). However, this protection was observed only when immunization was started in 3-month-old but not in 6month-old mice. These data suggest that the xenogeneic HER-2 DNA sequence can break immune tolerance to rat neu in transgenic N#202 mice and induce protective immunity that impairs the neu oncogene-driven progression of mammary carcinogenesis. The preventive effect achieved by our immunological approach appeared not to be based on anti-neu specific B and T cell immune attacks but was more possibly based on different mechanisms including aspecific and inflammatory immunological responses. [ABSTRACT FROM AUTHOR]

The in vitro cytotoxic response against H-2 and H-2 SV40-transformed fibroblasts was studied in a 40-h H-proline assay. A very low response against SV40 TASA is associated with the H-2 antigens on target cells: however, SV40-transformed H-2 cells are as immunogenic as SV40-transformed H-2 cells and prime against H-2 target cells. The data concerning in vitro amplification of the anti-SV40 TASA response and the involvement of cyclophosphamide-sensitive suppressor populations confirm the comparable immunogenicity of SV40-transformed H-2 and H-2 cells and cannot account for the haplotype-related behavior observed with SV40-transformed target cells. The study of the response against allogeneic SV40-transformed cells shows the reverse situation: the lower cytotoxic response is now associated with the H-2 antigens on SV40-transformed cells. As suggested by the data presented here, an interaction between SV40 TASA and H-2 antigens might be postulated. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor x (TNE) is a multipotent cytokine which affects many biological properties of both normal and neoplastie cells. Mere we show that treatment with TNF reduces B16-A melanoma cell susceptibility to normal and in vivo- and in vitro-activated NK cell mediated killing. This resistance is associated with an enhancement of B16-A metastatic potential in normal syngeneic mice, but not in anti-asialo GMI-treated animals, further supporting the NK dependence of TNF-induced enhancement of metastatic ability. A significant increase of MHC class I expression on B16-A murine melanoma cells is observed after TNE treatment, in all these effects TNF interacts positively with interferon γ (IFN γ). Taken together, these results indicate that TNF treatment negatively affects the susceptibility of B16-A murine melanoma to NK effectors in vivo and in vitro. This decreased susceptibility may be related, at least in part, to enhanced expression of MHC class I antigens on tumour cells. [ABSTRACT FROM AUTHOR]