SL3-3 murine leukemia virus (SL3) is a highly T-cell lymphomagenic retrovirus that reliably induces tumors when inoculated into newborn mice. An important genetic determinant for cell-type specificity and tumorigenic potential is shared with feline leukemia virus (FeLV). A recombinant virus, termed FS-LC, was constructed in which the determinant from FeLV was substituted for the corresponding region of SL3. FS-LC was shown to induce T-cell tumors with kinetics comparable to SL3. Thus, we concluded that the FeLV enhancer sequence can functionally substitute for that of SL3. Known oncogenes were identified as targets of insertional mutagenesis in 10% of FS-LC-induced tumors. To identify the proto-oncogenes involved in the remaining tumors, a recombinant library was constructed from DNA of an FS-LC-induced tumor. Ribosomal protein L4 was identified as a site of clonal retroviral integration using this library but no evidence was obtained that it functions as an oncogene. Finally, the immune interactions that occur during acute and chronic MuLV infection and lymphomagenesis were examined, in order to understand how malignant tumors avoid immune recognition and destruction. The role of cytokines was investigated during lymphomagenesis. Our studies indicated the presence in tumors of cytokines known to down-regulate a cell-mediated anti-tumor immune response, and the absence of cytokines known to enhance it. Data indicated that the pattern of cytokine mRNA expression seen in the end stage tumors is generated by the tumor cells. Analysis of animals infected with SL3 or with a non-tumorigenic mutant of SL3, termed Myb5, were examined longitudinally during infection in order to distinguish the immune consequences of retroviral infection per se from those associated uniquely with the malignant process. The results showed little or no difference in cytokine response to infection with SL3 or Myb5. Most interesting was the observation that IFN-gamma expression is elevated in virally-infected animals between 2 and 4 weeks post-inoculation. We concluded from this finding that the host responds immunologically to the virus, although that response uniformly fails to clear infection. The detection of IL-10 mRNA in target tissues longitudinally during infection suggested further that cytokines may provide a hospitable environment for the developing tumor / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_24051 |
| Date | January 1999 |
| Contributors | Beaty, Robert McFaddin (Author), Levy, Laura S (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Rights | Access requires a license to the Dissertations and Theses (ProQuest) database., Copyright is in accordance with U.S. Copyright law |
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