Production and characterization of mice transgenic for the A and B isoforms of human FcgammaRIII.
Fcgamma receptor (FcgammaR) 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) FcgammaRIII 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 hFcgammaR. The present report characterizes the phenotypic and functional expression of hFcgammaRIII in transgenic mice derived by crossing hFcgammaRIIIA and hFcgammaRIIIB transgenic mice. Interleukin-2 (IL-2) induces hFcgammaRIII expression by myeloid cells and their precursors, and these transgenic receptors promote in vitro cytotoxicity and anti-hFcgammaRIII antibody internalization. Splenocytes from untreated and IL-2-treated hFcgammaRIIIA, hFcgammaRIIIB, and hFcgammaRIIIA/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 hFcgammaRIII. These results indicate that hFcgammaRIII transgenes are expressed on relevant murine cellular subsets, exhibit inducible up-regulation patterns similar to those seen in humans, and code for functional proteins. hFcgammaRIII transgenic mice exhibiting specific cellular subset expression will permit the examination of strategies designed to enhance hFcgammaRIII-dependent immunological effector functions and will provide a model system in which to evaluate preclinically potential candidate molecules that recognize hFcgammaRIII for the immunotherapy of cancer.
Amoroso
A R
AR
Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA.
Alpaugh
R K
RK
Barth
M W
MW
McCall
A M
AM
Weiner
L M
LM
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D000938:Antigen-Presenting Cells / Q000276:immunology; D001853:Bone Marrow / Q000378:metabolism; D001947:Breeding; D004705:Endocytosis; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016513:Mice, SCID; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D020033:Protein Isoforms; D017452:Receptors, IgG