Investigation of Immunomodulatory Concepts in a Murine Model of Airway Mucosal Sensitization to Innocuous Antigen

Abstract

<p>The epidemic rise in the prevalence of allergy and asthma, primarily in the "developed" world, has impelled prolific nodes of inquiry into the epidemiology, aetiology, immunology and management of these syndromes. While studies in human patients have revolutionized pharmacological treatment of asthma and allergy, and have also intimated some of the environmental agents and conditions conducive to disease expression in susceptible populations, only animal models of asthma afford the experimental flexibility upon which detailed in vivo analysis of immunology and pathogenesis depends. Because asthma arises through airway mucosal contact with allergens, chemical pollutants and/ or infectious agents, an authentic animal model of asthma should preserve the airway as the interface of incipient contact with antigen and, by extension, as the immune microenvironment that conditions allergic sensitization. This heuristic is particularly relevant when considering questions about the immunomodulatory effects of local, anti-inflammatory intervention. The research documented in this thesis investigates several immunomodulatory concepts- including pharmacological intervention (Chapter 2), costimulatory molecule blockade (Chapter 3) and chemokinetic manipulation of cell trafficking (Chapters 4 and 5)-in a murine model of airway mucosal sensitization to an innocuous antigen. The salient message informed by these studies is that the outcome of an immune-inflammatory response is very much a reflection of the airway microenvironment in which the immune system initially processes antigen. Of substantive clinical interest, these data indicate that the efficacy of acute, therapeutic intervention must be reconciled with the status of the antigen-specific response once treatment has ceased.</p>