Stem Cell and Biological Interventions to treat Allergic Airway Disease
Kavanagh, Heather (2010) Stem Cell and Biological Interventions to treat Allergic Airway Disease. PhD thesis, National University of Ireland Maynooth.
The aim of this work was to investigate immune modulation with a particular focus on airway inflammation and allergic pathogenesis. This was probed in a model of pathogen driven immunomodulation (B. pertussis), and two models of therapeutic intervention namely immunisation (attenuated B. pertussis, BPZE1) or using a candidate cell therapy approach (mesenchymal stem cells, MSC). This work demonstrated that, in contrast to virulent B. pertussis, an attenuated, candidate vaccine strain of B. pertussis, BPZE1, did not enhance but rather reduced allergendriven airway pathology supporting findings that suggest allergic asthma is linked not just to a CD4+ T cell profile, but also to the degree of airway damage at the time of priming. The second approach sought to ascertain whether a candidate stem cell therapy could modulate immunity in vivo to a degree that was sufficient to suppress allergic lung inflammation. The work presented here demonstrated that adult bone marrow-derived allogeneic MSC actively prevent the induction of allergen driven pathology in a murine model. Prior stimulation of MSC with IFN-γ increased their protective effect. An increase in IL-10 as a result of MSC delivery suggested a role for MSC in Treg induction. The immune mechanisms by which MSC confer protection in this model were probed and demonstrated that MSC generate the expansion of Treg subsets, CD4+FoxP3 and CD8+ γ/δ T cells, in the lung. Moreover, expansion of Treg was proven to exert a functional effect as depletion of these cells resulted in a negation of the protective effect of MSC. In an experimental asthma model, where mice devoid of naturally occurring Treg, delivery of MSC fails to impair the development of allergic airway pathology and class switching to IgE. A reduction in airway eosinophilia in the absence of regulatory T cells suggested an alternative mechanism of protection employed by MSC. Pre-incubation with MSC inhibited the expression of important adhesion markers on eosinophils which most likely affected their ability to migrate as demonstrated by the inhibitory effect on their chemotactic migration. These data suggests a critical role for soluble factor secretion by MSC contributing to the reduction of airway eosinophilia. Collectively, these data provides a fundamental insight into novel therapeutic approaches that can profoundly influence the allergic airway response.
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