Research

Main research interests:

1. Investigation of the cellular and molecular mechanisms involved in the generation and suppressive function of activin-A-induced regulatory T cells in Th2-cell mediated allergic responses.
   
   The mucosal immune system and, specifically, that of the lung has the challenging task of mounting effective responses towards pathogenic agents, while suppressing inflammation against harmless airborne allergens. In health, the latter process is achieved through induction of immunological tolerance that controls inflammatory responses to allergens and prevents airway damage. In allergies and asthma, however, a failure of tolerogenic mechanisms is observed which results in excessive T helper type -2 (Th2) driven allergic responses, chronic inflammation and decline in lung function.
   

   The research of our laboratory is focused on understanding the cellular and molecular mechanisms that govern immune tolerance in the context of allergic inflammation. Our previous studies have uncovered the TGF-β superfamily member, activin-A, as a novel inducer of CD4+Foxp3-IL-10-producing regulatory T cells that suppress Th2 cell-driven allergic responses in vivo (Semitekolou et al JEM 2009). Activin-A-induced regulatory T cells also protect against experimental asthma upon transfer in vivo.  This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells (DCs). We are interested in elucidating the mechanisms involved in the generation and suppressive function of activin-A-induced regulatory T cells; the roles these cells play in the induction of tolerogenic DCs and the maintenance of immune homeostasis in the respiratory mucosa, and their effects on the development of other regulatory T cell subsets (‘infectious tolerance’). Understanding of the mechanisms that induce regulatory T cell suppression may offer critical insight into how their function may be exploited in vivo for the design of effective immunotherapies.

   For these studies, our laboratory employs a wide range of immunological analyses including in vitro cellular techniques and in vivo animal models of allergic diseases. In addition, biochemical and molecular biology approaches along with genomics (such as RNA-Seq analyses), proteomics and mass spectrometry analyses are utilized.
    

2. Elucidation of the role of activin-A in the induction of human regulatory T cells suppressive against allergic responses in asthmatics.
   
   Another research area of our group is investigating the role of activin-A in the induction of functional human regulatory T cells. Our ongoing studies reveal that activin-A drives the generation of a strongly suppressive ICOS+IL-10-producing human regulatory T cell population that mitigates allergen-driven Th2 cell responses. Importantly, in vivo administration of activin-A-induced regulatory T cells into humanized mice confers protection against experimental asthma manifestations. Of high relevance to clinical settings, activin-A-induced regulatory T cells can restrain robust allergen-driven Th2 cell effector responses in individuals with severe, steroid-refractory, asthma. Our findings may have important implications for the therapeutic use of activin-A-induced regulatory T cells in cell-transfer regimes aiming at resolving overexuberrant inflammation and re-establishing immune tolerance in the airways.
   
    
3. Examination of the effects of activin-A on allergen-driven airway remodeling and angiogenesis in severe asthma.

Asthma is a serious chronic disease characterized by airway hyperresponsiveness (AHR) and inflammation. Current therapeutic approaches fail to provide a cure, mainly in individuals with severe asthma associated with established airway remodeling. Vascular changes are central components of airway remodeling and relate to increased airway wall thickness, AHR and asthma severity. Hence, factors that can effectively control airway vascular remodeling represent essential therapeutic targets. We have previously shown that activin-A is increased in a mouse model of chronic airway remodeling and in the lungs of asthmatics at baseline and following pulmonary allergen challenge in vivo (Kariyawasam HH et al J Allergy and Clin Immunol 2009, Kariyawasam HH et al, Am J Respir Crit Care Med, 2008). In addition, activin-A promotes human airway epithelial cell repair and decreases inflammatory cytokine and chemokine release in vitro. Our current research aims to elucidate the role of activin-A and its downstream signaling pathways in the regulation of airway remodeling and angiogenic processes in chronic allergic airway disease in vivo and in severe asthmatics.