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anti-RhD antibodies modulate NK cell activity
reported to be expressed on 1106mel cells.32 Further studies are required to decipher this differential killing by NK cells. A possible mechanism arising from our work is that anti- RhD antibodies increase NK-cell activation, resulting in increased killing of iDC. This may, in turn, lead to decreased antigen presentation and a decreased humoral response. In the context of an RhD- individual exposed to RhD+ erythrocytes, this effect could diminish the produc- tion of anti-RhD antibodies, which is the clinical outcome observed upon anti-RhD prophylactic treatment. Previous studies have demonstrated that impaired killing of DC by cytotoxic T lymphocytes and NK cells can lead to continu- ous antigen presentation and exaggerated immune activa- tion,33,34 as seen in hemophagocytic lymphohistiocytosis.35 We can therefore speculate that in the inverse case, activa- tion of NK by anti-RhD antibodies can contribute to AMIS via killing of DC. If administration of the anti-RhD antibod- ies indeed leads to the killing of DC, a general immune sup- pression would be expected in these women. This should
be investigated in the future in a clinical study.
Although the mechanism we describe here is unrelated to ADCC of erythrocytes (anti-RhD-mediated lysis of ery- throcytes by CD16 on NK cells), ADCC, if significant, could potentially also contribute to the mechanism of action of anti-RhD antibodies. Several studies have shown that NK cells are capable of lysing erythrocytes via ADCC (mainly in the context of Plasmodium falciparum infected ery- throcytes)36. Only a small fraction, however, have researched this effect with human allo-antibodies, let alone anti-RhD. Furthermore, these studies rarely employ direct, reliable measurements of erythrocyte lysis.37 Therefore, this important question should be comprehensively addressed
In summary, we provide new insights into the activity of polyclonal anti-RhD antibodies which are in clinical use. These findings could contribute to the clinical efficiency of these preparations or imply that these antibodies carry unique features meriting further study.
Disclosures
No conflicts of interest to disclose.
Contributions
SE and IK designed and performed experiments, analyzed results, and wrote the paper; SK performed experiments; OZ pro- vided reagents and contributed professional advice; RA, MZ and DM assisted in the dendrtic cell experiments; UE was responsible for the human samples and OM supervised the project.
Acknowledgments
The authors thank Yulia Gendler and Dr. Shulamit Metsger from the Hadassah Blood Bank (Jerusalem, Israel) for their fruitful discussions and assistance with the erythrocyte experiments, Suhair Abdeen from Hadassah Medical Center (Jerusalem, Israel) for the isotype analysis and Natan Stein from The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research (Jerusalem, Israel) for language editing.
Funding
This work was supported by the ISF-China program and by the ISF Moked grant. Further support came from the ICRF pro- fessorship grant, by the MOST-DKFZ grant, by the GIF grant. The study was also supported by the Israel Science Foundation (grant 502/15), the Kass Medical Research Award and the Israeli Society of Hematology and Transfusion Medicine research grant (to S.E).
by future studies.
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