Oral Presentation ESA-SRB-APEG-NZSE 2022

Prevention of miscarriage in mice by boosting maternal Treg cells in pregnancy with an IL2-antibody complex (#58)

Kerrie Foyle 1 , Peck Yin Chin 1 , Carsten Merkwirth 2 , Jasmine Wilson 1 , Mei Chong 1 , Bihong Zhang 1 , Lachlan Moldenhauer 1 , Shanna Hosking 1 , Ella Green 1 , Greg Ferguson 2 , Gerald Morris 3 , James Karras 2 , Alison Care 1 , Sarah Robertson 1
  1. The Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, SA, Australia
  2. Ferring Research Institute, San Diego, CA, USA
  3. Department of Pathology, University of California, San Diego, CA, USA

T regulatory (Treg) cells are essential for maternal immune tolerance in healthy pregnancy. They are generated at conception and act to suppress effector responses against fetal alloantigens and facilitate uterine vascular adaptations required to support placental development. Treg cell insufficiency in women is associated with infertility, recurrent miscarriage, and preeclampsia. In the present study, we utilised an abortion-prone mouse model to evaluate the efficacy of IL-2 complexed with JES6-1 anti-IL-2 antibody (IL-2/JES6-1) to increase uterine Treg cells and improve reproductive success. CBA/J female mice were mated with DBA/2 males to generate abortion-prone pregnancies, which were treated with three injections of IL-2/JES6-1 at 24h intervals on days 0.5-2.5 post coitum (pc). Treg cells, measured as the proportion of CD4+ T cells expressing Foxp3, were increased >3-fold and >2-fold on day 3.5 pc in the uterus and draining lymph nodes following treatment with IL-2/JES6-1 but not IL-2/IgG or PBS control (all 9-16 dams/group), and the ratio of Foxp3+ Tregs to Foxp3- Tconv cells was increased in both tissues. Elevated expression of Ki67 and suppressive function markers CTLA4, CD25, and Foxp3 were observed for both thymic-derived and peripheral Treg cells. IL-2/JES6-1 treatment reduced fetal loss from 31% to 10%, a rate comparable to non-abortion prone CBA/J female x Balb/c male matings (all P<0.05, ANOVA). A small decline in fetal weight at day 18.5 pc after IL-2/JES6-1 treatment was partly attributable to larger litter size, while no abnormalities were observed in placenta development or spiral artery remodelling. These experiments demonstrate the efficacy of boosting uterine Treg cells through targeting IL-2 signaling for mitigating immune-mediated fetal loss. The results are relevant for designing clinical interventions targeting Treg cells to manage immune-mediated infertility and pregnancy disorders in women.