Angiotensin-converting enzyme (ACE) is a peptidase responsible for the conversion of angiotensin I to angiotensin II. We used gene targeting in mice to substitute control of the ACE locus from the endogenous promoter to a macrophage specific promoter. These new mice, called ACE 10/10, express high ACE levels in macrophage and macrophage-like cells. Challenge of ACE 10/10 mice with the aggressive mouse melanoma cell line B16-F10 showed that these mice are remarkably resistance to tumor growth. Tumor resistance is associated with an enhanced T cell response, as determined by tetramer analysis. Preliminary data also suggest enhanced nitric oxide and cytokine production by ACE 10/10 macrophages. We also studied the response of ACE 10/10 mice to infection by clone 13 of the lymphocytic choriomeningitis virus (LCMV). This stain of LCMV results in a chronic viral infection. ACE 10/10 mice mount a much more vigorous and effective immune response to this infection. This is characterized by increased numbers of T cells sensitive to the virus, a much faster clearing of virus from sera, and the complete elimination of chronic viral infection from organs such as the kidney. These data support our hypothesis that ACE 10/10 mice have enhanced immune function. Here, we propose studies to compare ACE 10/10 immune function to that of wild-type mice. Ultimately, we seek the specific biochemical mechanisms by which ACE changes the behavior of the immune response. In the first two Specific Aims, we start with simple, in vitro characterizations of ACE 10/10 macrophages and then advance to more complex in vitro and in vivo studies of T cell/macrophage interactions.
Specific Aim 3 will study the transfer of ACE over-expressing macrophages as a model for developing eventual human treatment protocols. ACE 10/10 mice are resistant to both B16 melanoma (a tumor) and LCMV (a systemic virus). This suggests that we have discovered something that is not only very new, but very broad in its potential applications. Our discovery offers a new approach to enhance natural immunity, and it may lead to new therapeutic avenues for the control of infectious disease and malignancy quite complementary to standard therapy.
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