The infiltration and accumulation of eosinophils in solid tumors has been recognized as a correlative clinical feature of several tumor types, including colon, pancreatic, and breast cancers. This eosinophil recruitment also occurs in many mouse models of tumorigenesis. Despite the abundance of clinical studies and the availability of mouse models, eosinophil effector functions in general are poorly understood and, indeed, questions remain as to the role(s), if any, of these leukocytes. Studies of tumor associated eosinophils in the mouse have remained equivocal, in part, due to the lack of specific reagents and models with which to define unequivocally mechanisms of effector function. The goal of this proposal is to bridge this gap by exploiting our extensive experience examining eosinophil activities using allergen provocation models of lung disease. For example, we have created several specific antibodies that allow unambiguous detection of infiltrating eosinophils and the release of granule proteins (i.e., activation leading to degranulation). In addition, we have developed several knockout mice deficient of the predominant granule proteins that will permit assessments of degranulation. We have also developed a novel line of transgenic mice congenitally devoid of eosinophils. The ablation of eosinophils in these transgenic animals was accomplished through the expression of a suicide gene (i.e., Diphtheria Toxin A) exclusively in eosinophil-lineage cells and provides a unique opportunity to define eosinophil responses to tumors. This proposal utilizes these novel models and reagents to test the hypothesis that eosinophils modulate tumor onset/growth. Our objectives will be achieved by completing the following Specific Aims: (1) To define the kinetics of eosinophil recruitment to solid tumors as well as the extent of eosinophil activation/degranulation within tumors to which they have been attracted; (2) To determine the extent to which eosinophil-associated host responses modulate mammary gland tumor onset, growth kinetics, or rate of metastasis; (3) To determine whether eosinophil degranulation (i.e., the release of toxic cationic secondary granule proteins) has direct effects on mammary gland tumors. ? ?
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