The establishment of pregnancy and placentation require a dynamic interplay of immune cell signaling at the maternal-fetal interface. Deficits in immune cell function compromise pregnancy. The specific pathogen-free (SPF) laboratory mouse has been the animal model of choice for investigating immune cell dynamics and functions during the establishment of pregnancy. However, there are two significant issues with the SPF laboratory mouse and its use to model the hemochorial maternal-fetal interface: i) placentation is shallow; ii) the SPF conditions used to maintain laboratory animals, including the mouse and rat, hinder immune system maturation and are inadequate for accurately modeling the complexities of human pathophysiology. Consequently, we have adapted a strategy of normalizing the SPF laboratory rat immune system through exposure to rats maintained in an environment of robust pathogen exposure (?dirty rats?). We utilize this strategy with the goal of humanizing laboratory animal immune responses. We hypothesize that uterine immune cell composition, pregnancy-dependent trafficking, and function are affected by the maturation state of the immune system, which collectively impact pregnancy success. In this research project, we will utilize the rat as an animal model for hemochorial placentation and test the hypothesis that the maturation state of its immune system will impact uterine immune cell dynamics and function during the establishment of pregnancy.
Two aims are proposed: i) explore the effects of immune system maturation on uterine immune cell composition, trafficking and function during rat pregnancy; ii) investigate the effects of immune system maturation on responses to stressors during the establishment of pregnancy. Experimental dissection of immune mechanisms controlling placentation will provide new insights into the etiology of pregnancy-associated diseases and the identification of new efficacious diagnostic and therapeutic strategies.
(RELEVANCE STATEMENT) Disorders of hemochorial placentation are a significant human health issue. The immune system has an important regulatory role in placental development and its dysfunction is associated with placental pathology and pregnancy-related diseases. Experimental dissection of immune mechanisms controlling placentation require the use of appropriate animal models, including those with a mature immune system, and will provide new insights into the etiology of pregnancy-associated diseases and the identification of new efficacious diagnostic and therapeutic strategies.