| Abstract |
Allergic asthma is a chronic inflammatory disease of the airways with significantly increased prevalence in industrialized countries the past 2 decades. Asthma is characterized by variable and recurring symptoms, which include wheezing, coughing, chest tightening and breathlessness. It is associated with aberrant T helper type 2 (Th2) immune responses against inhaled harmless environmental antigens (allergens). Dysregulated allergen-specific Th2 responses in the airways lead to pulmonary eosinophillic infiltration, mucus hypersecretion, reversible airway obstruction and airway hyperreactivity (AHR). Current treatments only ameliorate certain clinical features of the disease without providing a cure. Importantly, a significant group of patients has severe, treatment-refractory asthma, requires regular hospitalization and represents a major health-care problem. Hence, factors that can induce and/or enhance immunosuppression are essential therapeutic targets for asthma.
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Immunoregulatory mechanisms, including suppressive cytokines and regulatory T cells (Tregs), attenuate aberrant Th2-mediated allergic responses in experimental asthma models. Immunoregulatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor- β1 (TGF-β1), are critical for the induction and suppressive function of Tregs. Nevertheless, the expression and/or function of Tregs and immunosuppressive mediators are impaired in individuals with allergic asthma. Activin-A is a cytokine member of the TGF-β superfamily involved in a variety of essential biological processes. It is increased in the sera of asthmatics and in mice during acute and chronic allergic airway inflammation. Our group has recently shown that activin-A is an immunosuppressive cytokine as it inhibits allergen-specific Th2 responses and protects against the development of AHR and allergic airway disease in mice. Furthermore, our data have revealed that activin-A exerts suppressive function through induction of allergen-specific Tregs that suppress Th2 responses in vitro and upon adoptive transfer in vivo. However, the role of activin-A in human allergic asthma remains elusive. In this study we hypothesized that activin-A can suppress human Th2-mediated allergic responses and represents a key cytokine for the regulation of allergic airway inflammation and human asthma. Our specific aims were: 1) to investigate the effects of activin-A on the suppression of human Th2 cell-mediated allergic responses in the periphery and the airways 2) to delineate the role of activin-A in the induction of human Treg cells and their effects on the suppression of allergic Th2 responses and 3) to examine whether activin-A can enhance steroid-induced immunosuppression in patients with severe, treatment-refractory asthma. For this purpose, we obtained peripheral blood (PB) CD4+ T cells from age-matched: a) healthy individuals, b) atopics, c) mild/moderate asthmatics and d) severe, treatment-refractory, asthmatics and Bronchoalveolar lavage (BAL) mononuclear cells from severe asthmatics. Subsequently, we cultured CD4+ T cells or BAL mononuclear cells with antigen presenting cells APCs and allergen in the presence, or not, of activin-A and we measured their proliferation and cytokine release.
Our data reveal activin-A as a critical immunosuppressive agent for human allergic asthma. More specifically, we demonstrate that activin-A treatment of PB CD4+ T cells from asthmatic individuals during allergen-specific stimulation in vitro results in significantly decreased
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proliferation and Th effector cytokine (IL-5, IL-13 and IFN-γ) release. Importantly, we show that activin-A also inhibits allergen-specific responses of mononuclear cells in the airways, the active disease site. Notably, our data demonstrate that activin-A-mediated Th suppression is associated with induction of human regulatory T cells that effectively suppress allergen-driven Th2 responses of atopic individuals in vitro. In addition, we demonstrate that activin-A greatly enhances dexamethasone-mediated suppression of allergic Th2 responses from individuals with severe, treatment-refractory asthma. Collectively, our studies show for the first time that activin-A can suppress Th2 allergic responses of atopic and asthmatic individuals, pointing to this cytokine as a critical new therapeutic target for human asthma. Notably, our findings also uncover activin-A as a novel inducer of human Treg cells. Future studies should address the mechanisms through which activin-A induces human Tregs, as well as, the molecular and cellular pathways involved in Th2 cell suppression.
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The role of activin -A in human allergic asthma
