Immunoregulation by Mycobacterium vaccae : effects on CD11c+ antigen-presenting cells in a mouse model of pulmonary inflammation
Throughout evolution, mammals have co-existed with many harmless organisms such as saprophytic mycobacteria. These "Old Friends" have helped the hosts' immune system to evolve immunoregulatory mechanisms that prevent inappropriate immune responses. Exposure, once a common occurrence has now become increasingly rare. A revised version of the hygiene hypothesis proposes that this reduced exposure may be a contributing factor to the recent increase in allergic diseases in developed countries. In models of allergic pulmonary inflammation, treatment with M. vaccae inhibits airway hyperreactivity and induces allergen specific regulatory T cells (Tregs), which secrete IL-10 and depend upon production of IL-10 and TGF-p in vivo. Since Treg-induction is dependent on antigen presenting cells (APCs) such as CD11c+ cells, this thesis addresses the effects that M. vaccae has on CD11c+ APCs, in a mouse model of allergic pulmonary inflammation. M. vaccae treatment reduces pulmonary allergic inflammation by decreasing type-2 responses such as eosinophilia and IL-4 expression. Rather than an increase in type-1 cytokines, IL-10 is elevated in the lungs, both at the protein and message level. Characterization of pulmonary CD11c+ APCs by ELISA, FACS and real time RT-PCR, shows an immunoregulatory cytokine profile with increased expression of IL-10, TGF-fJ and IFN-oc. In passive transfer experiments, CD11c+ cells appear not play a role as regulatory cells themselves, but may be involved in the induction of Treg through their cytokine release. In vitro studies show these CD11c+ APCs are capable of inducing naive T cells to become Tregs, as measured by increased production of IL-10 and Foxp3 expression. M. vaccae has been used in clinical trials of asthma and eczema, with encouraging results. This thesis goes some way to understanding one mechanism behind a potentially valuable form of immunotherapy.