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Pre-implantation embryo-endometrial signalling

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Title Pre-implantation embryo-endometrial signalling
Period 11 / 2005 - 12 / 2010
Status Completed
Dissertation Yes
Research number OND1317973
Data Supplier ZONMW

Abstract

The paradox of human pregnancy and the fetal allograft continues to challenge immunologists. The apposition and penetration of the blastocyst challenges the maternal immune system, and this immune activation is required for successful implantation and placentation. On the other hand, pregnancy is thought to be a state of immunological allo-tolerance to paternal antigens expressed by the fetus. Thus, fetal-maternal interaction eventually nurtures a balanced environment of controlled local inflammation that leads to a state of peaceful coexistence between allogenic tissue and the maternal endometrium. It has been suggested that an immunological imbalance of the uterine environment at the time of implantation can result in spontaneous abortion, pre-eclampsia, fetal growth restriction and preterm labour. For example, spontaneous abortion has been proposed to be related to dysbalance of expression between pro- and anti-inflammatory cytokines (Blois 2004). In addition, it is thought that pre-eclampsia develops when the local uterine inflammatory response becomes disrupted and triggers the systemic endothelial dysfunction leading to the maternal symptoms (Redman 1999). Thus, implantation and placentation can be considered two aspects of a phenomenon of controlled local inflammation: immunological tolerance and cytokine-mediated trophic activity (Cross 1994). Background It is known that the birth of a healthy infant at term depends upon a coordinated series of events in the development of both embryo and placenta. Failure of one or more key components of placentation may result in a wide range of pregnancy complications varying from embryonic or se We propose that abnormal cytokine and trophic factor expression at the embryo-endometrium interface around the time of implantation is involved in the aetiology of complications of pregnancy related to placental dysfunction. The overall aim of this PhD project is to answer the following questions: This project will be imbedded in the divisional research line 'Periconceptional determinants of pregnancy outcome'. This program focuses on the events preceding and following conception that determine the health of the mother and her newborn. The importance of this period in determining future health has been repeatedly demonstrated in studies supporting the 'Barker Hypothesis' that perinatal events have a major impact on the health of the individual into late adulthood. Implantation is the first event in the fetal-maternal relationship with long-term consequences for mother and child. It is now clear that the complex process of implantation is largely dependent on the immune cross talk between mother and embryo. Our group has developed novel non-invasive tools that open the window on in vivo peri-implantation events. With this unique access to the endometrium at the time of embryo apposition, the large patient population undergoing IVF and care for pregnant women on one side, and the presence of immunology expertise within our division on the other, all the elements required to address this research question are present. By characterizing the immunology of normal and abnormal implantation, and relating this to markers of placental function and clinical outcomes, the first step will be made towards the aim of this collaborative research initiative; that of developing preventive and therapeutic strategies to reduce perinatal morbidity. SUBJECTS AND PATIENT MATERIAL DATABASE 200 women undergoing IVF in the assisted reproduction clinic will be invited to participate in this project. This cohort will be subjected to extensive monitoring before, during and immediately following pregnancy. During frequent outpatient clinic visits various material is collected and stored in collaboration with the RIVM to generate a unique biobank and database based on material collected.

Abstract (NL)

Het baarmoederslijmvlies speelt een belangrijke rol in natuurlijke embryoselectie. Patiƫnten met herhaalde miskramen worden snel zwanger, doordat deze selectie niet (voldoende) functioneert. Dat blijkt uit het proefschrift van Gijs Teklenburg. Menselijke voortplanting is bijzonder ineffectief, stelt Gijs Teklenburg in zijn proefschrift. De kans op een zwangerschap per menstruatiecyclus is slechts twintig procent bij een gezond stel. Dat is niet vreemd, want veel embryo's zijn van abominabele kwaliteit. Ze hebben bijvoorbeeld niet het juiste aantal chromosomen. Teklenburg vroeg zich in zijn promotieonderzoek af hoe het lichaam de juiste embryo's selecteert. Hij analyseerde daarom genetische veranderingen in het baarmoederslijmvlies tijdens het innestelen van embryo's. Wat blijkt: bij goede embryo's zijn weinig veranderingen zichtbaar in het baarmoederslijmvlies. Maar bij slechte embryo's, die later worden afgestoten, juist heel veel. Het lijkt erop alsof het baarmoederslijmvlies klaar staat voor innesteling, maar bij een slecht embryo actief besluit tot afstoting. Het baarmoederslijmvlies selecteert embryo's dus op kwaliteit. Teklenburg bevestigde deze vinding in een onderzoek naar vrouwen die herhaaldelijk miskramen krijgen. Bij hen blijkt het baarmoederslijmvlies inderdaad niet goed te reageren. Door het ontbreken van deze natuurlijke embryoselectie worden deze patiƫnten snel zwanger, maar leiden zwangerschappen vaker tot een miskraam.

Related organisations

Related people

Supervisor Prof.dr. C.J. Heijnen
Supervisor Prof.dr. N.S. Macklon
Doctoral/PhD student Dr. G. Teklenburg

Classification

D21800 Immunology, serology
D23220 Internal medicine

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