Human IgG1 and mouse IgG3 but not monomeric IgM or IgE facilitate antibody-dependent cell-mediated cytotoxicity by human natural killer cells.

Antibody-dependent cell-mediated cytotoxicity depends upon the interaction of target-cell-bound immunoglobulins with the Fc receptor expressed on different effector cells, notably natural killer (NK) cells. Here, we first generated over 1,500 mouse monoclonal antibodies against Raji, an NK-resistant human target cell. We confirmed IgG3 as the most efficient mouse immunoglobulin for the mediation of human NK ADCC and demonstrated pentameric IgM to be a nonmediator. Since the inability of IgM to mediate ADCC could have been due to steric hindrance secondary to the large size of IgM, we reduced and alkylated pentameric IgM and obtained a high percentage of monomers. These monomers did not mediate ADCC either, although they too promoted binding between NK cells and the Raji targets. Further, IgE anti-trinitrophenyl (TNP) antibodies were unable to mediate human NK ADCC of TNP-coated Raji cells. Next, we selected highly sensitized renal patients whose sera contained high titers of HLA and non-HLA antibodies. We demonstrated that human IgG1 facilitated the mediation of ADCC by human NK cells whereas human IgG3 and IgM did not.