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The Mechanism of Rh-Immune Globulin Prophylaxis Involves Significant Increases in the Immunosuppressive Cytokines TGFβ and PGE2.

For more than 40 years, hemolytic disease of the newborn (HDN) caused by anti-Rh(D) antibody produced by a pregnant mother to her Rh(D) + baby has been prevented by Rh(D)-immune globulin prophylaxis. Surprisingly, although a number of theories have been proposed, the mechanism of action of this immunosuppressive treatment remains completely unknown (Kumpel BM, Immunol Lett.2002;82:67–73). One potential mechanism of action is the production of one or several strongly immunosuppressive cytokines capable of blocking a primary immune response. Thus, to begin to unravel the possible mechanism(s) of the immunosuppression induced by administration of Rh(D)-immune globulin, we have examined production of a number of immunomodulatory cytokines following administration of Rh(D)-immune globulin. After informed consent, we measured levels of 17 different cytokines pre- and 48 hours post-administration of 300 μg of anti-Rh(D)(WinRhoSDF) in 10 healthy women candidates for Rh(D)-immune globulin prophylaxis. We used platelet-poor plasma from citrated whole blood and quantitative ELISA having the most sensitive detection limits. We observed no striking changes in levels of the cytokines IL-1 sRII, IL-12 p40, IL-16, or MCP-1. Levels of IL-4, IL-5, IL-10, IL-13, IL-17, MIP-1α, GM-CSF, TNFβ, and IFNγ remained below detection levels both pre- and post-testing. However, IL-1ra levels showed a slight to moderate decrease in 7 of 10 women after Rh(D)-immune globulin administration. In contrast, levels of TGFβ-1 increased, >1.3-fold in 7 of 10 women and >2-fold in 4 of 10 women. In one instance, the increase in TGFβ-1 (42, 855 pg/mL) was >5-fold and this woman also had a significant increase in TGFβ-2 (352 pg/mL). In addition to TGFβ, 4 of 10 women had increases of >1.5-fold in PGE 2 . Statistical analyses using ANOVA, paired Student’s t -test, and Wilcoxon signed-rank, for the combined results of all 10 women receiving Rh(D)-immune globulin indicated that only TGFβ and PGE 2 were significantly elevated post administration of Rh(D)-immune globulin. These results indicate that Rh(D)-immune prophylaxis can induce high levels of the strongly immunosuppressive cytokines TGFβ and PGE 2 . Both of these molecules have been shown to induce profound immunosuppression including prevention of primary immune responses (Ludviksson BR, et al., Eur J Immunol.2000;30:2101–2111; Zhou H, Lamont SJ, Int J Fertil.1986;31:305–310). Our findings represent the first clear evidence for a mechanism of action of Rh(D)-immune prophylaxis.