Production and characterization of mice transgenic for the A and B isoforms of human FcγRIII

Fc gamma receptor (Fc gamma R) engagement is pivotal for many effector functions of macrophages, polymorphonuclear neutrophils (PMN), and natural killer (NK) cells. Mice transgenic for the A and B isoforms of human (h) Fc gamma RIII on macrophages, PMN, and NK cells were constructed to permit the study of mechanisms and potential in vivo strategies to utilize the cytotoxic effector and antigen-presenting functions of cells expressing the hFc gamma R. The present report characterizes the phenotypic and functional expression of hFc gamma RIII in transgenic mice derived by crossing hFc gamma RIIIA and hFc gamma RIIIB transgenic mice. Interleukin-2 (IL-2) induces hFc gamma RIII expression by myeloid cells and their precursors, and these transgenic receptors promote in vitro cytotoxicity and anti-hFc gamma RIII antibody internalization. Splenocytes from untreated and IL-2-treated hFc gamma RIIIA, hFc gamma RIIIB, and hFc gamma RIIIA/B mice exhibited enhanced in vitro cytotoxicity toward HER-2/neu-overexpressing SK-OV-3 human ovarian carcinoma cells when incubated with the murine bispecific mAb 2B1, which has specificity for HER-2/neu and hFc gamma RIII. These results indicate that hFc gamma RIII transgenes are expressed on relevant murine cellular subsets, exhibit inducible up-regulation patterns similar to those seen in humans, and code for functional proteins. hFc gamma RIII transgenic mice exhibiting specific cellular subset expression will permit the examination of strategies designed to enhance hFc gamma RIII-dependent immunological effector functions and will provide a model system in which to evaluate preclinically potential candidate molecules that recognize hFc gamma RIII for the immunotherapy of cancer.