There are currently no ideal treatments or acceptable vaccines for cutaneous leishmaniasis, a worldwide health problem caused by infection with a number of species of the dimorphic protozoa Leishmania. Therefore, there is an urgent need to search for simple, safe, effective, and affordable treatments. Imiquimod is an immune-response modifying agent. Recently, 5% imiquimod cream (Aldara(TM)) received approval by the Food and Drug Administration in the United States and is currently available for the treatment of external genital and perianal warts caused by human papillomavirus infection. The antiviral activity of this drug is mediated through stimulation of cytokine release from many cell types including macrophages resulting in a local immune response at the site of application. Moreover, imiquimod has been shown to enhance cell-mediated immune responses (CMIR). Since imiquimod activates macrophages, the exclusive host cells of Leishmania, and stimulates CMIR which are required for host defence against Leishmania, we have investigated the potential of using imiquimod and its related compound, S-28463, as agents for treating leishmaniasis. It is demonstrated within that imiquimod and S-28463 effectively stimulated leishmanicidal activity both in vitro in macrophages and in vivo in a mouse model. These compounds also stimulated signal transduction associated with the induction of nitric oxide synthesis in macrophages. Imiquimod and S-28463 induced leishmanicidal activity in macrophages in the absence of any other cell types. We have demonstrated that S-28463 generated macrophage leishmanicidal activity by inducing genes involved in macrophage activation and inflammatory responses. Finally, we have also performed an analysis on the influence of L. donovani on macrophage gene expression using a cDNA array analysis, a similar methodology to study the effect of S-28463 on macrophage gene expression. Intramacrophage infection with L. donovani was shown to cause general
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.36878 |
| Date | January 2001 |
| Creators | Buates, Sureemas. |
| Contributors | Matlashewski, Greg (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 (Institute of Parasitology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001808391, proquestno: NQ69974, Theses scanned by UMI/ProQuest. |
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