NK Cell Function and Tumor Resistance in Mice Transgenic for Antibody to NK Inhibitory Receptors
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Tumor surveillance has been proposed as a means whereby the immune system monitors and eliminates transformed cells before their growth. Transformed cells that survive the immune response are escape variants selected by nature as they have developed mutations in immune recognition components. To boost immune response to these tumors, several types of immunotherapies are being studied but so far have had minimal success when translated into patient studies. Among proposed immunotherapeutic approaches, monoclonal antibody treatments have shown the best efficacy in human clinical trials. NK cells, cytolytic effector cells of the innate immune system, are implicated in tumor surveillance. Inhibitory Ly49 receptors determine the specificity of murine NK cells by recognizing of MHC class I molecules expressed on the target cell. This allows the transmission of inhibitory signals through intracellular signals to block NK cytotoxicity. Many tumors express sufficient levels of self MHC class I and are able to escape lysis by NK cells. Our lab has been studying the inhibitory regulatory pathways in natural killer cells and has developed an approach for enhancing the ability of NK cells to kill tumor cells. We have focused on studying the inhibitory function of the murine Ly49 receptors and provided evidence that blocking of negative signals on two inhibitory receptors, Ly49C and I, with a monoclonal antibody (5E6), allow NK cells to kill syngeneic leukemia cells more efficiently providing an enhanced anti-tumor effect. To study further the effect of Ly49C/I receptor blockade and improve tumor rejection, we developed a transgenic model whereby the 5E6 Fab antibody fragments are constitutively secreted to allow the sustained blockade of the Ly49C/I receptor. These studies detail the generation of these Tg mice and their characterization in relation to NK and T cell receptor development, tolerance, autoimmunity and tumor surveillance. In addition, we demonstrated an effect of blocking inhibitory receptors on NK cells to delay tumor establishment in a nascent tumor model of murine chronic myelogenous leukemia.