The Role of Antigen Presenting Cells in the Generation of Allergen Specific Th2 Cells in the Mouse Allergic Asthma Model

Allergic asthma is a serious disorder with rising incidence and prevalence in industrialized countries. It is mediated by pathogenic CD4 Th2 cells that produce cytokines, recruit inflammatory cells to the lungs, and promote airway hyperreactivity, mucus hypersecretion, and IgE. We have addressed questions about the underlying mechanisms behind the induction and maintenance of Th2-type cells in allergic lung inflammation. We focused first on the dendritic cell as an important antigen presenting cell in allergic disease and found that upon transfer, antigen- pulsed dendritic cells initiate an allergic response, but that this response is not entirely polarized towards a Th2- type response and they induce lung tissue damage reminiscent of emphysema. In other studies, we developed clinically relevant disease models representing relapse and overt allergic asthma and showed that there are distinct phases of disease that respond differentially to treatment with corticosteroids. In additional studies, we discovered that long-lived Th2 memory cells within lung inflammatory infiltrates contribute to disease exacerbations and have been focusing on memory CD4 Th2 cell survival. Our approach has been divided between investigating the inherent properties of memory cells and the environmental factors influencing them to elucidate the cellular and molecular basis for the generation and maintenance of Th2 immunological memory. Our established model of allergic asthma in mice has demonstrated that there is a rapid response to secondary aerosol challenge in the lungs up to 3 years after disease recovery. We presently are addressing the role of DCs in the maintenance of memory in this model. Elucidating the mechanisms underlying the generation and maintenance of CD4 memory has implications for effective immunity against pathogens and tumours, vaccine development, and inhibitory strategies for transplantation, autoimmunity, and allergy.