Tolerance induction at the early maternal-placental interface trough VIP production by first trimester trophoblast cells

L. FRACCAROLI; E. GRASSO; V. HAUK; G. MOR; C. PÉREZ LEIRÓS; R. RAMHORST

Pecs

Congreso; 11th International Symposium on VIP, PACAP and related peptides; 2013

Pregnancy challenges immune cells and immunomodulatory circuits of the mother and the developing fetus to dynamically adapt to each other in an homeostatic and tolerant environment for fetal growth. From an immunological standpoint, pregnancy was proposed to follow a temporal sequence with a predominantly pro-inflammatory first stage, an immunologically more quiescent, fetal growth promoting second period, and a final cut to a prominent inflammatory environment that precedes labor and delivery. In humans, between weeks 3 and 8 of gestation, a variety of cellular processes are encompassed to ensure proper trophoblast growth and invasion, uterine quiescence, vascularization and tissue remodeling in an immunotolerant microenvironment. The transition points imply redundant immunoregulatory mechanisms to tolerance maintenance. In this sense, the inducible regulatory T cells (iTreg) population is essential for maternal tolerance of the conceptus, performs its suppressive actions in the critical peri-implantation phase of pregnancy. On the other hand, the Vasoactive intestinal peptide (VIP) is synthesized and secreted by trophoblast cells and promotes anti-inflammatory and tolerogenic profiles through specific receptors VPAC1 and VPAC2 on immune cells. Here, we evaluated VIP contribution to the differentiation of maternal iTreg after the interaction with trophoblast cell lines obtained from different stages of human pregnany. We used an in vitro model of maternal leukocyte-trophoblast cell interaction represented by cocultures of fertile women PBMC with human trophoblast cell line from first trimestre (Swan71) and from third trimester (JEG3 and BeWo cell lines). We observed that VIP (10-7M) increased the frequency of maternal CD4+CD25+Foxp3+ cells after 48h of coculture with Swan cells (3.9±0.4 vs 8.3%±0.6, p