Anti-RhD-Mediated Immunosuppression: Can Monoclonal Antibodies Imitate the Action of Polyclonal Antibodies?

Abstract

Passively administered IgG antibodies can temporary prevent the antibody response to the corresponding antigen. This phenomenon of antibody-mediated immune suppression has been successfully applied in clinical practice: administration of polyclonal anti-RhD immunoglobulin to Rh-negative women during and after pregnancy is a very effective measure for the preventing D immunization by D-positive fetal red blood cells and, as a result, the hemolytic disease of the next D-positive fetus or newborn. Anti-D immunoglobulin is derived from sera of immune donors. Plenty of human monoclonal and recombinant anti-D antibodies have been obtained around the world and some of them have passed initial stages of clinical trials; however, none of the monoclonal preparations can be used as a surrogate for polyclonal ones. Evaluation has revealed the two major obstacles that limit the development of an effective monoclonal preparation. They are a low clinical activity of monoclonal anti-D and the lack of a suitable cell line-producer that will be able to provide a correct glycosylation of monoclonal antibodies. Despite a long period of anti-Rh immunoglobulin application we still fail to determine a precise list of the cellular and molecular participants involved in the mechanism for immunosuppression. To date, the overwhelming evidence points to the key role of immune complexes and the peculiarities of their interaction with Fcgamma-receptors (FcγR) on immune cells. The most convincing is the mechanism for a temporal switch-off of the immune response to the antigen due to co-ligation by immune complexes of the B cell receptor and inhibitory low-affinity receptor FcγRIIB on specific B cells (effect of clonal silencing). We investigated in vitro into the interaction of human monoclonal anti-D antibodies with different types of FcγR, as well as into the molecular structure of genes of anti-D antibodies and the composition of the sugar which, as known, does exert a significant influence on the efficiency of interaction between the antibody Fc fragment and FcγR. We have received a series of anti-D antibody counterparts and shown that the effector function crucially varies depending on the nature of the host cells. The original research data provide information valuable for developing a strategy of creation of monoclonal drugs with antiinflammatory properties; moreover, they may help with clarifying some still elusive aspects of regulation of the humoral immune response in general. The data obtained make it possible to speculate that the immunosuppressive activity of polyclonal antibodies and