Immune modulation is one treatment modality which is being explored in the context of human diseases and disorders. Methods of such manipulation which use gene therapy have an advantage in the treatment of chronic diseases such as autoimmunity because they are less invasive and more persistent. Furthermore, naked plasmid has advantages as a vector over other methods: it is more persistent and less immunogenic and cytotoxic than viral vectors, and simpler than DNA-conjugate vectors. Thus, naked plasmid is a viable alternative treatment to study in the context of an autoimmune disease such as diabetes mellitus, despite it's disadvantages of low transfection and expression rates. Here, we demonstrate that treatment of an autoimmune model, the non-obese diabetic (NOD) mouse, with an autoantigen to which a signal sequence had been added was protective, even in the apparent absence of secretion of that gene product. In contrast, treatment with the native cDNA of the same antigen was not protective. Furthermore, we show by immunohistochemistry that gene expression is still detectable in the muscle 22 weeks after injection. Other experiments demonstrate that multiple vaccinations with the altered form of the antigen were essentially as protective as a single vaccination following by multiple injections of blank plasmid, suggesting an important role for immunostimulatory sequences in bacterial DNA in causing surveying dendritic cells to migrate out of the tissue and present antigen in draining lymph nodes. Attempts to study the results of DNA vaccination by comparing immunization via different routes were inconclusive. / We have demonstrated that DNA vaccination of an autoimmune model with a autoantigen can delay disease. The simplicity and economy of such vectors and the benefits they have for the treatment of chronic disease in contrast to more inflammatory viral vectors, support future research into their use in the treatment of autoimmune diseases.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.31218 |
| Date | January 2001 |
| Creators | De Pooter, Renee. |
| Contributors | Prud'homme, G. J. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Pathology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001804710, proquestno: MQ70410, Theses scanned by UMI/ProQuest. |
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