Title

The role of regulatory T cells in the development and resolution of a mouse model of ovalbumin-induced allergic airway disease

Date of Completion

January 2007

Keywords

Biology, Cell|Health Sciences, Pathology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Asthma is a serious health concern in developed countries and urban centers, with the morbidity and mortality remaining high despite many recent advances in our understanding of its pathogenesis. Utilizing an ovalbumin (OVA)-induced mouse model of allergic airway disease (AAD), mice sensitized to OVA develop AAD in response to short-term (3–10 days) aerosol exposure, characterized by airway hyperresponsiveness (AHR), allergen-specific serum IgE antibody titers, lung inflammation, and elevated bronchoalveolar lavage (BAL) levels of TH2 cytokines and inflammatory cells. OVA-sensitized mice that are chronically exposed to OVA-aerosol challenge (42 days) exhibit a resolution of airway inflammation (Local Inhalational Tolerance, LIT) with a significant decrease in lung eosinophilia and a reversal of AHR. In contrast, systemic OVA-specific IgE remains elevated over naïve levels, suggesting that suppression of inflammation in the local lung environment occurs with the persistence of systemic OVA-specific responses. Therefore, it is hypothesized that the immunosuppressive function of regulatory T cells (Tr) is responsible for the resolution of inflammation in response to long-term aerosol antigen challenge in this model of allergic airway disease. ^ The development of LIT response in this OVA model is unaffected by adult thymectomy, IgE, B cell, and IL-10 deficiency, but is partially dependent on T cell responsiveness to TGF-β. At the LIT stage, total numbers of T and B lymphocytes were elevated in the hilar lymph node (HLN) above naïve levels, indicating a local retention of lymphocytes at LIT. Total numbers of T and B cells in systemic lymph nodes were unaffected at AAD and LIT, indicating that this retention of lymphocytes was a local phenomenon. Finally, putative Tr (phenotype and function) were increased and retained in the BAL and HLN during LIT, suggesting either local expansion or recruitment to the lung, where they may play a role in the resolution of airway inflammation. In addition, in vivo disruption of Tr function through studies utilizing Tr-suppression resistant Cbl-b −/− mice and mice treated with Tr-depleting antibody demonstrated renewed airway inflammation at LIT. Taken together, these results indicate that Tr populations in the local lung environment are integral for the resolution of chronic inflammation in this OVA model. ^