Human asthma is characterized by infiltration of eosinophils and other inflammatory cells into the airways. The pathological events that lead to eosinophilic airway inflammation are a direct result of activation of T lymphocytes. It is therefore important to understand the mechanisms of T cell activation in asthma, how external interventions might alter T cell activation, and what consequences on airway inflammation and function might follow. Activation of T cells is known to require two stimulatory signals. The first is provided by the interaction of antigen receptor with its appropriate antigen in the context of self MHC molecules. The second, non-cognate interaction, involves interaction between ligands on the T cell surface and on antigen presenting cells (called """"""""T cell co- stimulation""""""""). We have found that this non-cognate interaction between the CD28 family of molecules on T cells and B7 molecules on antigen presenting cells and other cells is involved in the pathogenesis of eosinophilic airway inflammation and hyperresponsiveness in S. mansoni soluble egg antigen (SEA) sensitized and challenged mice. Treatment with a soluble CD28/B7 interaction antagonist, CTLA4Ig, at the time of antigen challenge can suppress airway eosinophilia. The overall goal of this study is to elucidate the role of CD28/B7 co-stimulatory interactions in the pathophysiology of allergic asthma.
In Specific Aim #1, we evaluate the individual roles of CD28, B7-1, B7-2, and CTLA4 in SEA-induced airway inflammation and hyperresponsiveness by inhibiting molecular function through administration of soluble antagonists or blocking monoclonal antibodies in vivo, in normal or genetically engineered """"""""knockout"""""""" mice that lack individual molecules along the co-stimulatory pathway. To assess the influence of these interventions, we will measure airway constrictor responsiveness, assess airway inflammation histologically, quantify and characterize BAL fluid cells, and examine the proliferative and cytokine secretory responses of T lymphocytes from these animals after SEA or control challenges. Adoptive transfer experiments will further clarify the molecular mechanisms of the proposed interventions.
In Specific Aim #2, we will use immunohistochemical analyses to determine the spatial and temporal evolution of T cell activation in relation to the sensitization/challenge process, and in relation to the development of airway inflammation and constrictor hyperresponsiveness.
In Specific Aim #3, we will test whether modulating T-cell activation or secretion by local overexpression of B7-1, B7-2, CTLA4Ig, IFNg, or IL-4 within airways will prevent or enhance airway inflammation and hyperreactivity in S. mansoni sensitized and challenged mice in a fashion predicted by the results of Specific Aims #1 and #2. We will use replication-deficient adenoviral vectors encoding these immunoregulatory molecules to effect gene transfer and overexpression within airway epithelium. Together, these studies should elucidate the role of T cell costimulation in allergic airway inflammation and hyperresponsiveness. The knowledge gained will suggest potential new therapeutic interventions for asthma.
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