Proinflammatory cytokines by Th1 cells and macrophages are involved in the pathogenesis of several organ-specific autoimmune diseases. Clinically, cytokine therapy has the potential of influencing disease outcome by altering the balance between proinflammatory versus immunosuppressive cytokine profiles. Somatic cytokine gene therapy is an attractive alternative to cytokine immunotherapy, because it eliminates the need for frequent protein injections, and generates more constant cytokine levels in vivo which may reduce toxicity and increase therapeutic efficacy. To study the immunoregulatory effects of TGF-beta1 and IL-4 in vivo, we used a novel method of i.m. cytokine gene therapy in 2 experimental models of Th1 cell-mediated autoimmune diseases: murine diabetes and EAE. In our first model, i.m. TGF-beta1 gene administration is effective at suppressing a DTH response, and at protecting NOD mice from autoimmune insulitis and diabetes. In this model, disease protection was associated with a decreased intrapancreatic IL-12 and IFNgamma mRNA expression. In our second model, TGF-beta1 and IL-4-IgG1 gene therapy resulted in anti-encephalitogenic effects in mice with MBP-induced EAE. TGF-beta1 gene delivery had pronounced downregulatory effects on MBP-stimulated T cell proliferation and production of IFN-gamma and TNF-alpha. IL-4-IgG1 gene delivery also suppressed these responses and enhanced endogenous secretion of IL-4. Cytokine gene therapy resulted in a decrease in the severity of CNS inflammatory lesions. With either treatment, CNS IL-12 and IFNgamma mRNA expression was significantly diminished, while IL-4 and TGF-beta1 mRNA levels were increased compared to control mice. In summary, i.m. delivery of cytokine plasmid vectors suppressed pathogenic Th1 responses, while enhancing the production of protective, regulatory cytokines in peripheral lymphoid and/or target tissues. Somatic cytokine gene therapy proved to be an effective therapeutic strategy of cytokine deliv
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35476 |
| Date | January 1998 |
| Creators | Piccirillo, Ciriaco A. |
| Contributors | Prud'homme, Gerald 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 | Doctor of Philosophy (Department of Pathology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001652387, proquestno: NQ50237, Theses scanned by UMI/ProQuest. |
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