Research in the Reproductive Immunology group centres on three related themes:
• Cytokine and leukocyte control of conception and early pregnancy.
• Maternal immune regulation of success and quality of embryo implantation, placental development and reproductive outcome.
• Male seminal fluid signalling in the female reproductive tract.
1. Role of seminal fluid signalling in the female reproductive tract
We are interested in the female genital tract response to insemination, and its significance in fertility and reproductive tract health. Seminal fluid has a profound effect on the female tract immune environment and is a key factor in establishing local immune adaptations that allow receptivity to pregnancy. This is mediated by paternal transplantation antigens also shared by the conceptus, as well as immune-deviating cytokines that promote immune tolerance as opposed to rejection. Importantly the immune changes induced by seminal fluid can impact infection with sexually transmitted infections such as HIV and Chlamydia, as well as progression of tumorigenesis and potentially other disease states including endometriosis. We aim to unravel the molecular identity of the sperm and seminal plasma signalling molecules, and characterise the nature of the cytokine and chemokine response and ensuing inflammatory events elicited in the female tissues. The physiological consequences of the female tract response for fertility and embryo development, as well as infection and immune defence, are studied.
2. Uterine leukocytes and the immune response to pregnancy.
Antigen presenting cells (APCs) are essential for initiating immune tolerance for pregnancy and uterine immune responses to infection. Uterine macrophages and dendritic cells are master regulators of tolerance to paternal alloantigens, through generating regulatory T cells that prevent maternal immune rejection of the conceptus. Our current projects using T-cell transgenic models aim to investigate the cytokine regulation and role of professional and non-professional APCs in unique mechanisms for processing paternal MHC antigens at the outset of pregnancy. Additionally, these cells have tissue remodelling functions and communicate with epithelial cells and stromal cells to impact endometrial receptivity for blastocyst implantation. Immune-deviating cytokines including TGFb, IL-10 and IL-6 contribute to these events and their significance is being evaluated in null mutant mouse models.
3. Seminal fluid and reproductive health in women
In women, seminal fluid induces cellular changes and an induction of inflammatory cytokines similar to the response in mice and other animals. The cytokine and chemokine regulation of the cervical and uterine response in women can be modelled in in vitro experiments, where we are aiming to identify the nature of the active signalling factors in human seminal fluid. We are now seeking to investigate the influence of seminal fluid on fertility in women, and to examine the relationship between the seminal fluid content of individual signalling components and fertility status in men. This work has implications for our understanding of the immune response to STDs such as HIV, as well as for reproductive processes.
4. Role of reproductive tract cytokines in embryo development and fertility.
Cytokines originating from the oviduct and uterine epithelium act to regulate the development of the embryo as it traverses the reproductive tract prior to implantation. Through effects on the timing and extent of cell proliferation and differentiation, cytokines synchronise embryo growth with the maternal changes that lead to uterine receptivity. Our studies indicate an important role for GM-CSF in promoting optimal blastocyst development, implantation and placental development, and in programming metabolic health in offspring. In humans, GM-CSF promotes development of healthy blastocysts and application of this discovery to improve implantation success in human IVF is now the subject of clinical trials. Our current studies are exploring the mechanisms through which GM-CSF and other maternal tract cytokines influence gene expression and developmental programming in embryos.