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.

Obesity is a growing major public health concern and is associated with various co-morbidities. Given recent evidence of increased bacterial infections in bariatric patients, morbid obesity may adversely affect the immune system. As a pleiotropic pro-inflammatory mediator produced primarily by adipocytes, leptin is a link between metabolism and immunity. Consequently, excessive leptin secretion may hinder the body's ability to defend against bacterial infection. This situation arises in morbid obesity, where chronic hyperleptinemia is observed. We used an in vivo murine model of hyperleptinemia to determine whether abnormal levels of circulating leptin have a detrimental effect on the trafficking of neutrophils, with respect to the number present, their rolling velocity, preadherence, and adherence to the endothelium. / Male CD1 background mice (6-8 weeks) were divided to 3 treatment groups receiving once daily ip injections (1) sham (PBS); (2) low leptin (1mug/g); (3) high leptin (5mug/g). After 7 days of treatment, intravital microscopy was used to visualize post-capillary venule microcirculation of the cremaster muscle in the scrotum. Parameters such as neutrophil rolling, rolling velocity, preadherence, and adherence, were recorded and measured to assess PMN kinetics. / High doses of leptin resulted in increased preadherence and adherence of neutrophils in post-capillary venules. Serum leptin and TNFalpha levels were found not to correlate with this observation; consequently, potential pathways through which leptin increases PMN adhesion could not be elucidated. Conceivably, excessive adhesion could adversely affect neutrophil trafficking by producing a shift towards the marginal pool, limiting their ability to appropriately home into bacterial targets. This could parallel the situation in morbid obesity where high concentrations of leptin are also observed.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0874. Adviser: David M. Kranz. Includes bibliographical references (leaves 184-206) Available on microfilm from Pro Quest Information and Learning.

Thesis (Ph. D.)--University OF MICHIGAN. / CHAIRMAN: STANLEY A. SCHWARTZ.

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN. / CO-CHAIRMEN: GENE I. HIGASHI; DAVID SCHOTTENFELD.

Thesis (Ph.D.)--University of California, San Francisco, 2007. / Source: Dissertation Abstracts International, Volume: 68-12, Section: B, page: 7917. Adviser: Lewis L. Lanier.

Thesis (Ph.D.)--University of California, San Francisco, 2008. / Source: Dissertation Abstracts International, Volume: 69-06, Section: B, page: 3500. Adviser: Jason G. Cyster.

Thesis (Ph.D.)--University of California, San Francisco, 2007. / Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0876. Adviser: Matthew F. Krummel. Includes supplementary digital materials.