Defining T cell-placenta immune mechanisms in chronic villitis

PROJECT SUMMARY Chronic villitis of unknown etiology (CVUE) is diagnosed in 10-15% of all term placentas and is characterized by the infiltration of maternal T lymphocytes into the chorionic villi with corresponding trophoblast necrosis. This inflammation accompanies 40-60% of fetal growth restriction (FGR) cases, 20-30% of stillbirths, and infants with a CVUE diagnosis are 4 times more likely to be neurodevelopmentally delayed. Importantly, approximately 55% of patients with a CVUE diagnosis will have recurrent disease, making this a clinically significant placental finding. However, consequences of this diagnosis are rarely considered clinically due to the paucity of data surrounding the biologic mechanisms promoting CVUE. These gaps have resulted in our inability to predict and/or prevent new and recurrent disease. CVUE is hypothesized to be either a maternal alloimmune response to the fetus or an undiagnosed infection, both of which would have shared immune mechanisms but different antigen targets. We previously showed that CVUE placenta downregulate immune checkpoint receptors and upregulate major histocompatibility complex (MHC) to promote T cell activation. We also demonstrated that expansion of T cell clones occurs during CVUE, but not in response to common viruses. Preliminary data presented in this application demonstrates that patients with CVUE have elevated proinflammatory cytokines and chemokines in the blood and placenta and these maternal T cells may be responding to a common placental antigen. Still, there remains no definitive explanation as to the antigen specificity or local mechanisms at the maternal fetal interface that control or amplify this abnormal immune response. Therefore, this study is significant as it will define whether CVUE is an infectious or alloimmune pathology and describe changes in placental MHC and co-stimulatory receptor expression which leads to activation and cytotoxicity by maternal T cells against these antigens. Access to unique institutional resources, multidisciplinary expertise, and novel approaches makes our application highly innovative. Our hypothesis is that increased major histocompatibility complex (MHC) expression on antigen presenting cells (APCs) in the periphery and trophoblast cells of the placenta promotes maternal T cells to recognize and respond to fetal antigens, leading to CVUE. We will address this hypothesis in two specific aims by: 1) assessing the impact of CVUE inflammation on MHC and co-stimulatory receptors in the placenta to promote T cell mediated cytotoxicity and 2) identifying mechanisms of maternal T cell activation and expansion in response to fetal-specific antigens during CVUE. This study will create the most comprehensive immunologic understanding of systemic- and tissue-mediated mechanisms of CVUE pathogenesis to date. These data are critical for future studies that address diagnosis of CVUE in utero and test therapeutic strategies, such as immune modulating agents, for prevention of CVUE and its associated fetal morbidity and mortality.