Research Interests

Keywords: reproductive immunology; uterine endometrium; conception; embryo implantation; female reproductive function; female response to seminal fluid; seminal plasma; pregnancy complications; female infertility; recurrent pregnancy loss; preterm birth; preeclampsia.

Research in the Reproductive Immunology group centres on four related themes:
• Mechanisms of immune control of female reproduction and pregnancy
• The impact of pregnancy tolerance perturbation on embryo implantation, placental development, pregnancy progression and offspring outcomes
• Defining immune causes of infertility and pregnancy complications, and developing diagnostic tools and immune-targeting interventions; 
• Male seminal fluid factors that influence female pregnancy tolerance and cryptic female choice.

Research projects

1. The immune response and endometrial receptivity

Certain types of immune cells are essential for female immune tolerance of implantation and pregnancy, while others can suppress implantation and pregnancy. Uterine macrophages and dendritic cells are master regulators of tolerance, through generating regulatory T cells that suppress inflammation, prevent maternal immune rejection of the conceptus, and facilitate robust placental development. Our projects use mouse models to investigate the functions and behavior of regulatory T cells, macrophages and dendritic cells in unique mechanisms for generating tolerance at the outset of pregnancy. Additionally, these cells have tissue remodelling functions and communicate within cell networks to impact endometrial receptivity for decidualisation and embryo implantation, and placental development. Specific immune-regulatory agents including cytokines, microRNAs and TLR ligands contribute to these events and their significance is evaluated in genetic mouse models.

2. Understanding and treating immune causes of infertility and pregnancy loss

With our clinical partners, we evaluate the relationship between immune status and fertility, and are identifying T cell signatures associated with recurrent implantation failure and early pregnancy loss in women. A focus is to distinguish different subtypes of immune disorder that constrain conception and healthy pregnancy, based on peripheral blood markers that indicate impaired tolerance, elevated inflammation, and/or immune dysfunction secondary to altered metabolic status. A specific challenge is to identify and evaluate immune interventions that boost immune tolerance, such as low dose IL-2, with potential for safe and effective use in women where an impaired immune response is implicated in reproductive and pregnancy disorders.  Although various immune interventions are proposed to be useful in human infertility, our studies and others demonstrate these are often ineffective when used in unselected patient populations - so a key challenge is to develop the tools to better match treatments to individual patient needs in a precision medicine approach.

3. Priming the female immune response for conception and pregnancy

We are interested in the female response to seminal fluid, and its significance for fertility and reproductive health. Seminal fluid has a profound effect on female tract immune parameters and is a key factor in establishing local immune adaptations that allow conception, receptivity to embryo implantation and progression of pregnancy. This is mediated by male transplantation antigens and immune-regulatory factors that promote generation of regulatory T cells. The immune changes induced by seminal fluid are critical for fertility and pregnancy health, and can also impact sexually transmitted infection, and conditions including infertility, recurrent miscarriage, and endometriosis. We focus on defining the molecular identity of sperm and seminal plasma signalling molecules, and characterising the immune response elicited in female tissues. The physiological consequences of the female tract response for fertility and embryo development, as well as infection and immune defence, are studied. 

4. Seminal fluid factors 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, or studied in tissue biopsies. We are identifying the active signalling factors in human seminal fluid, and investigating how these impact fertility and pregnancy outcomes in the human IVF setting. We are also examining the relationship between the seminal fluid content of individual signalling components, fertility and health status, and age and lifestyle factors in men. This work has potential to deliver new immune-based diagnostics and treatment interventions for male infertility.

5. Cytokine regulation of embryo development

Cytokines originating from the maternal oviduct and uterine epithelium act to regulate the development of the embryo as it traverses the reproductive tract prior to implantation. Cytokines modulate gene expression, and cell survival and differentiation, to synchronise embryo growth and development with uterine receptivity. Some years ago we discovered an important role for GM-CSF in promoting blastocyst development, implantation and placental formation, to ultimately affect fetal growth and offspring health after birth. In humans, we showed GM-CSF suppresses cell stress and promotes development of healthy blastocysts. In partnership with Origio A/S, we conducted clinical trials in IVF patients to show GM-CSF improves implantation success especially after prior miscarriage. Our work resulted in the product Embryogen, now sold in 50 countries worldwide. Our current studies are exploring how specific maternal tract cytokines exert both positive and negative effects on preimplantation embryos, to program implantation competence, fetal development and health of offspring after birth.