Allogeneic murine pregnancy models for assessing the developmental effects of immune‐stimulating antibodies: Challenges in reproducibility

Abstract

Literature suggests that murine allogeneic pregnancy models are an alternative approach for evaluating the developmental toxicity of immune-stimulating agents. In this study, multiple syngeneic and allogeneic murine pregnancy models were used to assess the potential embryo-fetal effects of four different murine antibodies (IgG 1 or IgG 2 ) that activate the immune system by binding to T-cell receptors (PD-L1, LAG-3, and GITR).The pregnancy models were generated by within and between matings of five different inbred strains of mice (CBA/CaJ, DBA/2J, BALB/c, C57BL/6, and CBA/J). The antibodies were administered every 2-3 days by intraperitoneal injection (n = 12-29/group) during gestation days 6 to 14. There were no differences in embryo-fetal endpoints between the allogeneic and syngeneic pregnancies. Additionally, treatment with the antibodies had no effect on mean postimplantation loss in either the syngeneic or allogeneic pregnancies despite confirmation of pharmacologically-relevant systemic exposures.These results suggest that allogeneic murine pregnancy models need further validation and testing before they can be reliably used as an alternative approach for assessing the developmental effects of agents that stimulate the immune system. K E Y W O R D S allogeneic pregnancy, developmental effects, immune stimulation, maternofetal tolerance, monoclonal antibodies, T-cells

Immune checkpoint molecules in pregnancy: Focus on regulatory T cells

“…For CTLA‐4, Tim‐3 and PD‐1, their involvement and possible roles in maternal immune response have been confirmed by different approaches such as animal and human experiments. Most in vivo data show PD‐1, CTLA‐4, and Tim‐3 signaling deficiency in abortion‐prone mice and increased fetal loss was observed in allogeneic pregnant mice that were administered with blocking PD‐1, CTLA‐4, and Tim‐3 antibodies . The combination blockade of two types of immune checkpoint molecules lead to more serious pregnancy outcome over single intervention by highly inhibiting the production of anti‐inflammatory cytokines .…”