Project overview
Human reproduction is inefficient and abnormal implantation of the embryo into the mother's womb (or 'uterus') is a leading cause of maternal and foetal morbidity and mortality worldwide. After fertilisation of the egg, the embryo maintains a continuous reciprocal communication with the mother. The embryo implants into the lining of the mother's womb, also known as the 'endometrium' at the start of pregnancy. Failure in the orchestration of this process leads to reproductive failures including subfertility (inability to conceive for >1year), recurrent miscarriages (>2 consecutive early pregnancy losses), and recurrent implantation failure (>1 failed in-vitro fertilisation cycles despite good quality embryos replaced). Reproductive failures and later pregnancy complications, including low birth weight, preterm delivery, and pre-eclampsia are thought to result from poor implantation/ placental development. Current management options for these women are ineffective and prevention strategies are limited.
Natural killer (NK) cells are cells of the innate immune system and are key regulators of implantation. During implantation, the outer layer of cells in the developing embryo (fetal trophoblast cells) invade the endometrium to gain access to nutrients. NK cells within the womb have surface receptors, called Killer Cell Immunoglobulin-like Receptors (KIRs), which interact with Human Leukocyte Antigen (HLA) receptors on fetal trophoblast cells, maintaining fine control of the depth of invasion into the mother's womb. HLA is a complex that helps the immune system distinguish the body's own proteins from foreign proteins (such as viruses and bacteria). Specific combinations of KIRs and HLA pairs have been shown to impact pregnancy outcomes. For example, the combination of KIR2DS1 (an activating receptor for uterine NK cells) in the mother, in association with fetal HLA-C has been shown to be protective against pregnancy complications. This suggests that pregnancy success is determined by the interaction between NK cells within the mother's womb and fetal tissue.
The objective of this project is to assess how activating receptors, such as KIR2DS1, expressed on NK cells in the endometrium contribute to successful pregnancy. Endometrium will be obtained from women known to suffer from reproductive failures during the 'implantation window', a specific time point during a menstrual cycle in which the womb is programmed to respond and prepare for a possible pregnancy. These samples will be processed in the laboratory to characterise activating and inhibitory receptors on NK cells, and understand their function. Their potential to secrete various cytokines (small proteins important in cell-to-cell communication) will also be assessed. Work from the Khakoo lab has also shown that naturally occurring small biological molecules (or 'peptides') derived from certain proteins are displayed on the cell surface by HLA, which has the potential to activate NK cells by binding specifically to KIRs. We will examine whether interactions of activating KIR on NK cells in the womb with fetal trophoblast cells are modulated by peptides to influence pregnancy success.
For the first time, we will be able to understand the interactions between the mother's NK cells in the womb and specific peptides on the fetal trophoblast. This will help us understand the immunological mechanisms of healthy implantation and placental development and may help in the development of new therapies or target patients to specific treatments. This project will take place at the University of Southampton led by Professor Cheong, a specialist in reproductive medicine and Professor Salim Khakoo, an expert in NK cells in collaboration with Professor Ashley Moffett's group at the University of Cambridge, who are world leaders in immunology research within pregnancy. A MRC Clinical Research Training Fellowship has provided funding for Dr. Ng to work on this project as a MRC PhD Research Fellow.
Natural killer (NK) cells are cells of the innate immune system and are key regulators of implantation. During implantation, the outer layer of cells in the developing embryo (fetal trophoblast cells) invade the endometrium to gain access to nutrients. NK cells within the womb have surface receptors, called Killer Cell Immunoglobulin-like Receptors (KIRs), which interact with Human Leukocyte Antigen (HLA) receptors on fetal trophoblast cells, maintaining fine control of the depth of invasion into the mother's womb. HLA is a complex that helps the immune system distinguish the body's own proteins from foreign proteins (such as viruses and bacteria). Specific combinations of KIRs and HLA pairs have been shown to impact pregnancy outcomes. For example, the combination of KIR2DS1 (an activating receptor for uterine NK cells) in the mother, in association with fetal HLA-C has been shown to be protective against pregnancy complications. This suggests that pregnancy success is determined by the interaction between NK cells within the mother's womb and fetal tissue.
The objective of this project is to assess how activating receptors, such as KIR2DS1, expressed on NK cells in the endometrium contribute to successful pregnancy. Endometrium will be obtained from women known to suffer from reproductive failures during the 'implantation window', a specific time point during a menstrual cycle in which the womb is programmed to respond and prepare for a possible pregnancy. These samples will be processed in the laboratory to characterise activating and inhibitory receptors on NK cells, and understand their function. Their potential to secrete various cytokines (small proteins important in cell-to-cell communication) will also be assessed. Work from the Khakoo lab has also shown that naturally occurring small biological molecules (or 'peptides') derived from certain proteins are displayed on the cell surface by HLA, which has the potential to activate NK cells by binding specifically to KIRs. We will examine whether interactions of activating KIR on NK cells in the womb with fetal trophoblast cells are modulated by peptides to influence pregnancy success.
For the first time, we will be able to understand the interactions between the mother's NK cells in the womb and specific peptides on the fetal trophoblast. This will help us understand the immunological mechanisms of healthy implantation and placental development and may help in the development of new therapies or target patients to specific treatments. This project will take place at the University of Southampton led by Professor Cheong, a specialist in reproductive medicine and Professor Salim Khakoo, an expert in NK cells in collaboration with Professor Ashley Moffett's group at the University of Cambridge, who are world leaders in immunology research within pregnancy. A MRC Clinical Research Training Fellowship has provided funding for Dr. Ng to work on this project as a MRC PhD Research Fellow.