31-OR

Abstract

Objectives Natural Killer (NK) cells are key regulators of normal placental development. In contrast to peripheral blood NK (pNK) cells, NK cells located at the maternal-fetal interface constitute the main local lymphocyte population in early pregnancy, are non-cytotoxic and pro-angiogenic. Decidual NK cells (dNK) regulate remodeling of uterine spiral arteries (SA), a process leading to increased blood supply to the developing fetal–placental unit. When SA remodeling is impaired, reduced placental perfusion results in elevated plasma sFlt1 levels, triggering preeclampsia systemic symptoms, (hypertension, edema and proteinuria). We aim to model a NK cell based therapy for preeclampsia. Methods Ex vivo manipulation of human pNK cells by a combination of hypoxia, TGFb-1 and 5-aza-2′-deoxycytidine (AZA) yields cells, termed idNK cells, with phenotypic and in vitro functional similarities to dNK cells including expression of dNK cell surface markers and chemokine receptors, proangiogenic capacity and reduced cytotoxicity. idNK cells were further characterized by microarray gene expression profiling, and their capacity to remodel SA was evaluated in immunodeficient mice presenting narrow SA. Results Although distinct from dNK cells, idNK cells acquired the gene expression signature that differentiates dNK cells from pNK cells. Most importantly, i-dNK cell injection increased placental perfusion in a mouse model with narrow SA as evidenced by decreased uterine artery resistance evaluated by Doppler ultrasound, and ameliorated SA remodeling. Conclusions Ex vivo conversion of peripheral blood NK cells into i-dNK cells may be a potential approach for the prevention or treatment of preeclampsia and related disorders. Disclosures R. de Carvalho Cavalli: None. A. Cerdeira: None. H. Korkes: None. S. Burke: None. A. Rajakumar: None. M. Bhasin: None. S. Karumanchi: Consultant, Commercial Interest: Aggamin LLC. H. Kopcow: None.