FLT3-LIGAND, IMMUNOMODULATION AND THERAPY IN ASTHMA

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DESCRIPTION (provided by applicant): There is a direct association between type 2 T-lymphocyte profiles and allergic airway inflammation in asthma. One strategy for preventing type 2 responses to an allergen is to suppress the pro-allergic signals that antigen presenting cells (APCs) send to T-cells. The most potent APCs in the lung are dendritic cells (DCs), and recent studies have revealed phenotypic variability in this population, which can strongly polarize the developing T cells. FLT3 Ligand (FL) is a growth factor for DCs, and induces a type 1 T-cell response. We recently reported that FL prevented ovalbumin-induced allergic airway inflammation in mice and suppressed late allergic response (LAR) and airway hyperresponsiveness (AHR). Based on these studies, we developed the hypothesis that FL has therapeutic activity for hosts with asthma by the expansion of DC1 cells, production of IL-12 and induction of a type 1 T cell response that inhibits type 2 T-cell stimulation important in asthma. In Specific Aim 1, we will examine the ability of FL to reverse LAR, AHR, and eosinophilia in a mouse model of allergic airway inflammation and augment an antigen-specific, type 1T cell response to the inciting allergen. We will determine the dose-response for FL therapeutic activity and duration of effect. We will also examine the effect of FL on clinical correlates of asthma including baseline AHR in mice sensitized, but not challenged with the allergen. Further, we will examine the levels and isotype of antibodies to the allergen and cytokine levels in serum and lung washings, in addition to non-antigen and antigen-specific type 1 and 2 T cell responses by Elispot assays both systemically (spleen) and regionally (mediastinal lymph nodes and collagenase digested lungs). Non-specific therapeutic effect of FL will be examined in Schistoma mansoni-induced allergic airway inflammation model. In Specific Aim 2, we will investigate the ability of FL to reverse the airway remodeling associated with chronic asthma. We will study the ability of FL to reverse the histopathologic changes, including tracheal and bronchial epithelial thickness and sub-epithelial fibrosis, measure pro-fibrotic cytokines and chemokines and examine smooth muscle hyperplasia. In Specific Aim 3, we will study the mechanisms of FL therapeutic activity for acute and chronic asthma. We will determine the therapeutic activity of FL in wild type and IL-12( knock-out (KO) mice. As KO mice may have pre-existing compensatory mechanisms, we will also undertake studies examining the therapeutic activity of FL in animals given neutralizing antibodies to IL-12 during allergic airway inflammation.