Testing the efficacy of regulatory dendritic cell treatment in the prevention of preeclampsia

Project Summary/Abstract Preeclampsia is a complex disease of pregnancy involving cardiovascular, immune, and placental dysfunction. It is the leading cause of maternal-fetal morbidity and mortality. Preventative options are poor and the only effective treatment is the delivery of the often pre-term fetus and the dysfunctional placenta. The current proposal aims to investigate the potential of personalized medicine in the form of cellular immunotherapy as a novel preventative measure for the prevention of preeclampsia. Elevated secretion of arginine vasopressin precedes the development of physiological symptoms of preeclampsia in humans, and infusion of vasopressin throughout gestation into wild-type mice is sufficient to initiate the cardiovascular, renal, and immune dysregulation observed in human preeclampsia. Although vascular and renal complications are observed clinically in preeclampsia, immune dysfunction is central to the pathogenesis of preeclampsia. Regulatory dendritic cells have been shown to induce immune tolerance and are a current cellular immunotherapy in ongoing clinical trials for several other immune mediated diseases. The proposed study will test the hypothesize that treatment with regulatory dendritic cells will prevent the cardiovascular, renal, and immune features of preeclampsia. The overall objective of this proposal is to determine if DCreg administration is a potential preventative for preeclampsia. In the following aims, utilizing the chronic AVP infusion mouse model of preeclampsia and primary human mononuclear cells, we will investigate 1) the potential of DCreg to prevent the cardiovascular, renal, and immune features of preeclampsia in mice and 2) the ability of human mononuclear cells obtained from women with chronic hypertension and/or preeclampsia to differentiate into functional DCreg. The vision for my career is to develop an independent, NIH-funded research program that transforms women’s cardiovascular healthcare through innovative scientific discovery and the education of future scientists. To continue to grow as an independent investigator and to achieve my career goals, the objective of the career plan is to develop skills in the following areas: 1) training in assessment of vascular function as it relates to models of preeclampsia; and 2) developing skills in translational clinical research. These will be accomplished through both didactic coursework and experiential training through direct interactions with my mentors and colleagues. If regulatory dendritic cells prevent preeclampsia in the present study, this data will identify a novel cellular immunotherapy for preventing preeclampsia. Future studies would be aimed at further understanding the mechanism(s) of regulatory dendritic cell action and the potential of regulatory dendritic cells in preventing preeclampsia. This project is innovative as it proposes a powerful, novel treatment as a possible prevention for preeclampsia: personalized cellular immunotherapy.