Anakinra and etanercept prevent embryo loss in pregnant nonobese diabetic mice

Abstract

Bacteria and viruses activate the host innate immune response via Toll-like receptor (TLR)-involved signaling and potentially cause pregnancy failure. TLR7 and TLR9 respond to single-stranded RNA (a viral intermediate) and hypomethylated CpG DNA motifs (specific molecular constituents of bacteria) respectively. In this study, we treated murine RAW264.7 cells with R837, CpG1826, or a combination of the two. RT-PCR was performed to detect cytokines, Tlr7, and Tlr9. WT and nonobese diabetic murine embryo resorption models were established by i.p. injections of TLR7 and TLR9 ligands. Neutralizing antibodies and the IL1b and TNFa inhibitors were used. The specific inhibitors anakinra and etanercept effectively prevented TLR7 and TLR9 ligand-induced embryo loss. Notably, this effect was not observed in decidual NK cell-depleted mice. Our findings suggest that anakinra and etanercept may have potential for preventing TLR7 or TLR9 ligand-induced abortion in the presence of decidual NK cells.

Five successful pregnancies with antenatal anakinra exposure

“…The miscarriage rate was 30% for pregnancies not on anakinra vs 10% for pregnancies on anakinra in the aforementioned cryopyrin-associated periodic syndromes study [3]. An additional study looking at murine models with an elevated IL-1 environment found that when these mice were given IL-1 inhibition, it prevented pregnancy loss [10]. A common theme among prior case exposures is flaring disease activity when taken off anakinra, but good response after the medication is restarted.…”

Mechanisms of Key Innate Immune Cells in Early- and Late-Onset Preeclampsia

“…This suggests that TLR9 is capable of suppressing angiogenesis (127) and that aberrantly activated ligand binding to different TLRs may significantly influence pregnancy outcomes. In a relatively recent study, it was demonstrated that inhibition of TLR activation and thus inhibition of downstream signaling, could not prevent embryo resorption in the absence of dNK cells (105,128). Differential expressions of TLRs throughout pregnancy and in preeclampsia, suggest that these receptors might represent potential therapeutic targets.…”

Association of Intron-2 Variable Numbers of an 86-bp Tandem Repeat- Polymorphisms of Interleukin-1 Receptor Antagonist Gene and Idiopathic Recurrent Spontaneous Abortion

“…A more general correlation between IL1RN*2 allele and presence of autoinflammatory disease strongly supports a role in the control of the inflammatory response, and iRSA may be included within this group of diseases 15,35 . New evidence from murine models has shown prevention of miscarriage by blocking IL-1β 36 .…”