Abstract
Disclosure: A. Yasuda: None. T. Seki: None. H. Kashiwagi: None. N. Kitajima: None. Y. Kametani: None. Immune tolerance to a semi-allogeneic fetus is crucial for a successful pregnancy. However, the mechanisms of tolerance to semi-allografts in the co-existence with normal defenses against cancer and pathogens is not clear. During pregnancy, levels of pregnancy-related proteins and hormones such as progesterone (P4), estrogen, testosterone, and glucocorticoids (GC) increase. We hypothesized that the most abundant pregnancy related hormone in the placenta, P4, might play an important role in the local tolerance in the placenta. Thus, we aimed to compare the effects of P4 and cortisol (COR) on human lymphocytes in vivo, to clarify their role in the systemic regulation of immunity during pregnancy. Healthy donor peripheral blood mononuclear cells (PBMCs) were treated with P4 or COR for 6 h. These PBMCs were washed and transplanted intravenously into 8- to 9-week-old NOG-hIL-4-Tg (formal name, NOD.Cg-PrkdcscidIl2rgtm1Sug/Tg(CMV-IL4)/Jic) mice. Human epidermal growth factor receptor-2 (HER2) peptide was emulsified in complete Freund's adjuvant and administered intraperitoneally to these PBMC-NOG-hIL-4-Tg mice at the same day. As a negative control, an equal volume of PBS was added to the culture and transplanted into NOG-hIL-4-Tg mice. Boosters were administered using incomplete Freund's adjuvant 2 weeks after the primary immunization. Peripheral blood was collected 4 weeks after transplantation and 2 weeks after booster administration. T and B cell profiles were analyzed using FCM 28 days later. The results revealed that significantly higher numbers of human CD45+ cells engrafted in the spleens of P4-treated mice compared to COR-treated mice 4 weeks post-transplantation. Transplanted human CD45+ cells included T and B cells, and CD8+ T cells were significantly higher in P4-treated mice compared to both control and COR-treated mice. Moreover, antigen-specific IgG production was maintained in the P4-treated mice, suggesting that the T cell/B cell function was maintained in the mice. Compared to control and P4-treated mice, COR-treated mice tended to engraft fewer human CD45+ cells. Moreover, B cell engraftment tended to be lower in COR-treated mice than in control mice. Antigen-specific IgG production was not maintained. There results suggest that lymphocytes which experienced a high P4 environment maintain engraftment and function of human lymphocytes in the NOG-hIL-4-Tg mice, while high COR environment rather dampens the engraftment and function of them. The high-P4 environment limited in the placenta may support pregnant immunity to protect the semi-allogeneic fetus from pathogen-induced infectious disease or cancer. Presentation: Friday, June 16, 2023