Anti-RhD Antibody Therapy Modulates Human Natural Killer Cell Function

Shlomo Elias ^1,2 Inbal Kol ¹ Shira Kahlon ¹ Rajaa Amore ³ Dror Mevorach ³ Uriel Elchalal ⁴ Orly Zelig ² Ofer Mandelboim ¹

¹The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada (Imric), The Hebrew University Hadassah Medical School, Israel
²Department of Hematology, Hadassah – Hebrew University Medical Center, Israel
³Rheumatology Research Center, Department of Medicine, Hadassah – Hebrew University Medical Center, Israel
⁴Department of Obstetrics and Gynecology, Hadassah – Hebrew University Medical Center, Israel

Anti-RhD immunoglobulins are widely used in clinical practice to prevent immunization against RhD, principally in hemolytic disease of the fetus and newborn. Intriguingly, this disease is induced by production of these very same antibodies, when an RhD negative woman is pregnant with an RhD positive fetus. Despite over five decades of use, the mechanism of this treatment is, surprisingly, still unclear. Here we show that anti-RhD antibodies induce human natural killer (NK) cell degranulation, resulting in enhanced killing of dendritic cells (DCs). Mechanistically, we demonstrate that NK cell degranulation is mediated by binding of the Fc segment of anti-RhD antibodies to CD16, the main Fcγ receptor expressed on NK cells. We found that said CD16 activation is dependent upon glycosylation of the anti-RhD antibodies. We further show that anti-RhD antibodies induce NK cell degranulation in vivo in patients who receive this treatment prophylactically. Taken together, we describe a novel immune property of anti-RhD antibodies, which may contribute to their efficacy in preventing the generation of alloimmune antibodies.

*Shlomo Elias and Inbal Kol contributed equally to this work