Tolerance & Immunity Through the Lens of Pregnancy
Why is pregnancy an interesting immunologic problem?
The immune system, composed of cells, proteins and molecules, distinguishes self from non-self to prevent harmful responses against the body while defending against pathogens. Although organ transplant rejection aligns with this principle, the lack of maternal rejection of the genetically distinct placenta and fetus challenges it. Unfortunately, we have only begun to scratch the surface of understanding the beautiful “immunologic paradox” of pregnancy.
The Rizzuto lab investigates this mystery. We leverage mouse models and immunologic tools in clever ways to define and dissect maternal immune responses during pregnancy.
The anatomy of pregnancy is extraordinary…
The placenta develops from the outer blastocyst to facilitate gas and nutrient exchange between maternal and fetal circulations. Maternal and fetal blood are not in direct contact. Rather, molecules (including maternal antibodies), transit across placental epithelial cells, called trophoblasts, which are positioned in the maternal bloodstream and invade into the uterus (decidua & myometrium). We know that trophoblasts express many antigens foreign to maternal immune cells, including some which elicit rejection in the transplant setting. But pregnancy is often successful, even in the face of anti-placental immunity. We hypothesize that multiple immune tolerance mechanisms protect the placenta & fetus while preserving immunity to foreign pathogens.
Figure modified from: Rizzuto 2025, PMID 39264989.
Our motivation
Our wish to understand the basic science of pregnancy immunology is partly motivated by Dr. Rizzuto’s long-term interest in alleviating devastating and poorly understood pregnancy syndromes, including pre-eclampsia. Additional motivation stems from an interest in developing novel immunotherapies to invigorate or dampen immunity. For example, there is an intriguing and relatively unexplored parallel between pregnancy immunology and tumor immunology. The placenta exhibits many of the “hallmarks of cancer”, including invasiveness, accessing vasculature, genomic instability, and immune evasion. Notably, the placenta and fetus are seemingly impervious to treatments that can elicit rejection of tumors, supporting our hypothesis that novel immune tolerance mechanisms operate in concert to safeguard pregnancy. By unraveling the immunologic paradox of pregnancy, we will push forward the field’s understanding of the fundamental nature of immune tolerance and in doing so, discover new ways to manipulate responses for benefit.