Modulation of the immune response to treat various infectious and allergic diseases as well as certain forms of cancer has been employed since William B. Coley injected a mixture of bacteria into patients with large inoperable tumors over 100 years ago. The imidazoquinoline compounds are nucleoside analogs with strong type I interferon inducing activity. Recently, these compounds have been found to mediate their effects through a subset of the Toll-like receptor (TLR) family. A topical cream containing imiquimod, a member of the imidazoquinoline family, is currently employed in humans for the treatment of genital warts caused by the human papilloma virus, against actinic keratosis as well as for topical treatment of primary superficial basal cell carcinoma. The goal of the present study was to determine the potential of imidazoquinolines in the treatment of other infectious and allergic diseases as well as their mechanism of action. Furthermore, the role of possible modulators of response to these chemicals has been studied. We show that imidazoquinoline treatment can increase mycobactericidal activity in mice carrying a resistant (wild type) allele of SLC11A1 (formerly natural resistance associated macrophage protein 1 (NRAMP1)). NRAMP1 affected responsiveness to imidazoquinolines in macrophages by modulating P38 MAPK activation as well as atypical PKC activity both of which are required for optimal immunodulatory activity by these TLR ligands. Imidazoquinoline treatment also prevented development of atopic allergic asthma in mice sensitized and challenged with ovalbumin by preventing inflammatory cytokine production as well as eosinophil infiltration in the lungs. Interestingly, this drug when used as a therapeutic agent against allergic asthma was equally efficient in mice carrying the wild type (resistant) or the susceptible allele of the Nramp1 gene. This suggests that NRAMP1 modulates response to imidazoquinoline treatment in models dependent on macrophage subsets which require NRAMP1 function to become activated to an appropriate degree. Taken together, the presented study broadens the possible applicability of imidazoquinolines to the treatment of mycobacterial infections as well as to allergic asthma treatment and defines an important role for NRAMP1 in regulating responses to this family of pharmaceutical compounds.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.100659 |
| Date | January 2005 |
| Creators | Moisan, Jacques. |
| 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 (Division of Experimental Medicine.) |
| Rights | © Jacques Moisan, 2005 |
| Relation | alephsysno: 002326281, proquestno: AAINR25213, Theses scanned by UMI/ProQuest. |
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