Modulation of Natural Killer Cells by Therapeutic Antibody Preparations.

Abstract 3680

Poster Board III-616

Therapeutic antibody preparations are used in the treatment of several diseases. Thus, human immunoglobulin is administered as high dose intravenous immunoglobulin (IVIg) to patients suffering from a wide range of disorders. Moreover, various monoclonal antibodies (MoAbs) are approved for therapy in cancer and immune diseases. Natural Killer (NK) cells exert important immune effector functions. As these cells express the IgG receptor, CD16 (FcγRIIIa), it is of clinical importance to investigate how these cells react to therapeutic antibody preparations. We found that cytotoxic effector functions of NK cells were significantly inhibited by therapeutic antibody preparations in vitro. Natural cytotoxicity and antibody dependent cell-mediated cytotoxicity (ADCC) were inhibited by treating peripheral blood mononuclear cells (PBMCs) with the polyclonal immunoglobulin preparation Beriglobin, as well as the MoAb preparation Rituximab, prior to standard 51Cr-release assays compared to untreated cells. Moreover, our data showed that freshly isolated NK cells had IgG bound to the cell surface. The level of bound IgG increased following short-time exposure to both therapeutic antibody preparations, and the level of CD16, which is the key receptor for inducing ADCC, decreased. To investigate whether the NK-inhibitory effects of IVIg were demonstrable in vivo too, we analyzed blood from patients diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP), a disorder in which high-dose IVIg as monotherapy has shown striking effects. Comparing peripheral blood samples obtained from patients before treatment and 3 days following high-dose IVIg using multiparameter flow cytometry, we demonstrated a substantial decrease in the number of CD56+/CD3- NK cells. Moreover, as shown in vitro, the expression of CD16 on the NK cells was markedly reduced following high-dose IVIg treatment due to IgG engaged by the FcγRIIIa receptor (CD16). Finally, we found that NK mediated cytotoxicity decreased significantly when comparing peripheral blood samples from patients before and 3 days following IVIg treatment. In conclusion, our data presented in this study show that high-dose immunoglobulin therapy induces NK inhibitory effects in vitro as well as in vivo and thus may have important consequences for the overall therapeutic efficiency.