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Objective: Tokishakuyakusan (TSS) is a traditional herbal medicine that has been used empirically to prevent recurrent pregnancy loss. Its mode of action remains unclear. With their potent capacity to produce cytokines, invariant natural killer (iNKT) cells are involved in the control of fetomaternal immunity in early gestation. This study aimed to clarify the effect of TSS on iNKT cell activities in a well‐studied murine miscarriage model. Methods: Pregnant mice were fed 1% TSS‐containing or control diet from the day of vaginal plug formation. Alpha‐galactosylceramide (AGC) was administered intraperitoneally to the pregnant mice at day 9.5 postcoitus (pc) to stimulate iNKT cells. Peripheral cytokine levels were evaluated using cytokine arrays. The percentage of iNKT cells among splenocytes was examined by flow cytometric analysis. The incidence of pregnancy loss was assessed at day 12.5 pc. Results: The ratio of fetal resorptions to total conceptuses was significantly higher in the group exposed to TSS (34%) than in controls (78%). A rapid and robust surge in inflammatory cytokines, including IFN‐γ and TNF‐α, was detected in the peripheral blood of control animals 2 hours after AGC administration. This peripheral cytokine induction was significantly attenuated in the TSS‐fed group compared with the control. The percentage of iNKT cells among total splenocytes was lower in the TSS‐fed group than in controls. Conclusion: The findings in this study suggest that the inhibitory effects of TSS on pregnancy loss may involve immune modulation of iNKT cells during early pregnancy. Pregnancy Loss After AGC Administration. Pregnant mice were fed a regular diet supplemented by TSS or a control diet without TSS from day 0.5 pc. Pregnant mice were injected intraperitoneally with AGC at a dose of 40 μg/kg on day 9.5 pc. Uteri were collected at 72 h after AGC administration and pregnancy loss evaluated. A, Macroscopic images of representative pregnant uteri from control (upper) and TSS‐fed dams (lower). Pregnancy loss sites are indicated by arrows. B, Microscopic findings of pregnancy loss sites. Uteri containing fetuses were fixed and were sectioned. Sections at representative at sites of pregnancy loss (left) and live fetuses (right) were stained with hematoxylin and eosin. Fetal tissue is indicated by arrows and placental tissues by arrowheads [ABSTRACT FROM AUTHOR]

The cover image, by Takeshi Nagamatsu et al., is based on the Original Article Tokishakuyaku‐san, a Japanese herbal medicine mitigates iNKT cell mediated pregnancy loss in mice, DOI: 10.1111/aji.13021. [ABSTRACT FROM AUTHOR]