Acute lymphoblastic leukemia model for the study of immune-mediated tumour rejection and the study of potential therapeutic protocols.
Published: 2005
Language: eng
Number of pages: 177
Description: 70Z/3 is a murine pre-B cell leukemia line that has been used extensively in the study of signalling pathways in B cells. As a tumour, 70Z/3 cells were initially found to cause widespread disease upon injections in animals. We have isolated 70Z/3 variants divergent in their capacity to lead to morbidity after injections. One variant, 70Z/3-NL, elicits an immune response capable of eliminating the tumour. Another variant, 70Z/3-L, is not rejected and causes morbidity. I found that an immune response generated against 70Z/3-NL cells protects against a challenge with 70Z/3-L cells. I further observed, through the isolation of subclones from 70Z/3-NL, that immune recognition of only a portion of the cells is sufficient to protect against the tumour.Finally, I used 70Z/3-L to test an anti-tumour therapy based on the use of low doses of IL-12. I established a protective therapy against an intraperitoneal challenge with 70Z/3-L cells with doses of IL-12 ranging from 500 to 1000 ng/kg. IFN-gamma has been associated in many IL-12-based therapies with both therapeutic effects and toxicity. This protocol of daily injections of IL-12 led to protection of challenged animals but did not induce IFN-gamma when mice received only injections of IL-12. Serum levels of IFN-gamma increased only when both tumour cells and IL-12 were administered to the animals. I determined that CD4+ and CD8+ T cells were required for the IL-12 therapy while NK cells were not necessary. I conclude that we can use a dose of IL-12 that does not directly induce IFN-gamma. In this context, although IFN-gamma is ultimately needed for the rejection, it is not an initiating event of low dose IL-12 therapy.The ability of 70Z/3-NL cells to initiate immune rejection is of clinical relevance, especially if we can find the gene, or genes, responsible for the initiation of the immune response. I have used both serial analysis of gene expression (SAGE) and microarrays to compare gene expression between 70Z/3-NL and 70Z/3-L. I have confirmed differential expression of two genes, TSA-1 and SPARC.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5310.

Thesis (Ph.D.)--University of Toronto, 2005.

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