The prevalence of childhood asthma is increasing dramatically in industrialized societies. The reasons for this are not completely understood, although persistent indoor aeroallergen challenge, exposure to industrial pollutants and tobacco smoke, and infant bronchiolitis have all been implicated. From these studies, the concept emerges that asthma is the result of a preponderance of accumulated risk factors occurring in a critical sequence, at a critical time in development. Primary prevention of asthma will result from elimination or interruption of any of these risks. One such risk may be the balance between oxidative stress and antioxidants, particularly in the lung. Recent evidence has suggested that oxidative stress may influence the polarization of T cell responses in mice. The effects of oxidative stress on the development of Th2 responses in humans are unknown, as are the effects of antioxidants.
The Specific Aims of this Project are: 1. To determine how exposure to oxidative and nitrosative stress affects the function of various antigen presenting cells. 2. To test whether oxidative stress alters the Th1/Th2 balance of a T cell response to antigen. 3. To determine whether antioxidant treatment of antigen presenting cells, and/or T cells, will alter the type of T cell response to antigen. Different types of antigen presenting cells, including monocytic cell lines and primary cells (e.g., dendritic cells) will be subjected to relevant stressors and tested for their ability to modulate the expression of co-stimulatory molecules, cytokines, and chemokines. The APC that are generated under different conditions of oxidative stress will then be tested for the ability to support or modulate the polarization of T cell responses to Th1 or Th2. Finally, the ability of thiol and non-thiol antioxidants to modulate the induction of Th1 or Th2 responses will be determined. These experiments will both answer fundamental questions about the development of immune responses, but also provide a framework for rational clinical trials of specific antioxidants used at critical times for the primary prevention of asthma.
| King, Miranda R; Ismail, Anisa S; Davis, Laurie S et al. (2006) Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype. J Immunol 176:2765-72 |
