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Ferrata Storti Foundation
Haematologica 2021 Volume 106(7):1846-1856
Cell Therapy & Immunotherapy
Anti-RhD antibody therapy modulates human natural killer cell function
Shlomo Elias,1,2* Inbal Kol,1* Shira Kahlon,1 Rajaa Amore,3 Mariam Zeibak,3 Dror Mevorach,3 Uriel Elchalal,4 Orly Zelig2 and Ofer Mandelboim1
1The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC); 2Department of Hematology; 3Rheumatology Research Center, Department of Medicine and 4Department of Obstetrics and Gynecology, Hadassah – Hebrew University Medical Center, Jerusalem, Israel.
* SE and IK contributed equally as co-first authors.
ABSTRACT
Anti-RhD antibodies 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 the 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. Mechanistically, we demonstrate that NK cell degranula- tion 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 this CD16 activation is dependent upon glycosylation of the anti-RhD anti- bodies. Furthermore, we show that anti-RhD antibodies induce NK cell degranulation in vivo in patients who receive this treatment prophylacti- cally. Finally, we demonstrate that the anti-RhD drug KamRho enhances the killing of dendritic cells. We suggest that this killing leads to reduced activation of adaptive immunity and may therefore affect the production of anti-RhD antibodies
Introduction
Anti-RhD immunoglobulins are polyclonal antibodies which are commonly used in clinical practice. These antibodies are produced from human sera, and are mainly administered to prevent endogenous production of anti-RhD antibodies in case of exposure to the RhD antigen.1 This prophylactic treatment is commonly used in RhD- women pregnant with an RhD+ fetus. As such, they are at risk of developing anti- RhD antibodies which can cause hemolytic disease of the fetus and newborn (HDFN). Paradoxically, anti-RhD antibodies are also used as prophylactic treatment for this condition. Anti-RhD antibodies are administered not only as a preventive therapy, but can also be used for treating immune thrombocytopenic purpura,2 an autoimmune disease characterized by peripheral destruction of platelets.
Despite over five decades of use, the mechanism behind anti-RhD’s effect remains unclear.3 Several hypotheses have been raised to explain the clinical impact of these antibodies, but none has been definetely proven.1-5 One of the leading notions is that anti-RhD antibodies can cause antibody-mediated immune suppression (AMIS), even though a mechanism to explain this has not been established yet. One of the possibilities to explain AMIS is that anti-RhD antibodies lead to macrophage-medi- ated destruction of RhD+ erythrocytes.6 A second theory hypothesizes that the anti- RhD antibodies mask the RhD antigen on erythrocytes. Such masking could prevent the RhD antigen from being recognized by the immune system. It is estimated, how- ever, that most of the RhD antigen sites remain unbound by the anti-RhD antibodies, and therefore should generate an immune response.4 Additional reported effects of these preparations include an increase of the cytokines transforming growth factor-β (TGF-β) and prostaglandin E2.7 It has also been suggested that anti-RhD antibodies might cross-link the B-cell receptor and the inhibitory fragment crystallizable receptor
Correspondence:
OFER MANDELBOIM
oferm@ekmd.huji.ac.il
Received: September 13, 2019. Accepted: May 27, 2020. Pre-published: May 28, 2020.
https://doi.org/10.3324/haematol.2019.238097
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