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Problem:  IVIG prepared from plasma of stored human blood can be efficacious in improving pregnancy success in a selected subgroup of patients but RCTs using an IVIG showing inferior suppression of NK activity in vitro have been negative (J Assist Reprod Genet 2006). A significant component of NK suppression by IVIG appears to be due to CD200 released into plasma from PBL during storage at 4C. CD200 receptors (CD200R) are expressed at the fetomaternal interface prior to onset of abortion; CD200R1 mediates direct effects on gamma-delta T cell development and suppresses alpha-beta T cell responses in vitro, whereas CD200R2 alters DC so as to facilitate development of alpha-beta Treg cells. Which receptor(s) mediate NK cell suppression?

Methods:  Purified human PBL or the CD56+ NK cell subset of PBL were used to lyse 51Cr-labeled K562 cells in vitro. Different IVIG preparations were tested for suppressive ability, and suppression was blocked by either anti-huCD200 mAb or rabbit anti-huCD200R1 or R2 antibodies.

Results:  CD200-dependent IVIG NK suppressive potency differed among IVIG types (Gammagard>Gamunex>>Gamimmune). CD200-dependent suppression was blocked by anti-CD200R antibody able to react with the type 2 receptor. K562 cells did not express receptor, and purified CD56+ NK cells were suppressed effectively without the need for non-NK cells.

Conclusions:  IVIG may directly express NK cell activity via CD200 binding to CD200R2.