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The American Society for Reproductive Immunology's Second Clinical Reproductive Immunology Symposium: ‘Using Reproductive Immunology to Improve Clinical Practices’ was held on October 27th to 28th 2012, in New Haven, Connecticut. The objective of this symposium was to disseminate up-to-date clinical reproductive immunology information and how it relates to current clinical practices, diagnostics, and therapeutics for women's reproductive and pregnancy-related issues, with a view to bridging the distance between clinicians and translational researchers. It provided a common platform to physicians and physician scientists to facilitate the application of research outcomes into current medical practice. This symposium highlighted the current status of health issues during pregnancy including preeclampsia, preterm birth, maternal obesity and diabetes, autoimmunity and infection. In addition, a session was dedicated toward demystifying laboratory techniques of reproductive immunology for clinicians. This symposium was attended by approximately 50 delegates along with the 16 invited speakers and included 17 presentations that addressed key issues in the immunology of maternal–fetal well-being. This report will summarize the highlights of the meeting.
The symposium began with a welcome and opening address from the meeting chair, Dr. Vikki Abrahams (Yale University), followed by greetings from the President of the American Society of Reproductive Immunology, Dr. Udo Markert (Friedrich-Schiller-Universität). Dr. Surendra Sharma (Brown University) chaired the first session on ‘Preeclampsia’, a late gestational complication that affects approximately 5–8% of pregnancies and is associated with maternal hypertension and proteinuria. The objective of this session was to recognize current and novel ways to diagnose, identify biomarkers for, and develop treatments for preeclampsia by harnessing the innate and adaptive immune response. Dr. Mana Parast (University of California San Diego) discussed the role of T regulatory cells (Tregs) in maintaining maternal tolerance in normal and preeclamptic pregnancies. Using human tissue samples, she showed that the proportion of cytotoxic T lymphocytes (CTL) is higher in preeclampsia. She also showed that specifically in early onset preeclampsia, the number of decidual Tregs is reduced, which along with the increased proportion of CTLs, likely results in elevated trophoblast apoptosis. She suggested that the identification of changes in T cells subpopulations, including Tregs, could potentially be applied in clinical settings to determine the onset of disease. Dr. Errol Norwitz (Tufts Medical Center) stressed the use of biomarkers for the risk assessment of preeclamptic patients early in pregnancy. He provided an insight into the etiology of preeclampsia and highlighted currently used biomarkers. The last talk in this session came from Dr. Michael Paidas (Yale University) who talked about the pleiotropic molecule, antithrombin, that inhibits serine proteases and does not cross placenta. The maternal syndrome during preeclampsia includes renal dysfunction, systemic inflammation and placental hypoxia. He described a current clinical initiative using antithrombin as a therapy for preeclampsia: ‘A Prospective Randomized Evaluation of the Safety and Efficacy of Recombinant Antithrombin in Very Preterm Preeclampsia (PRESERVE-1)’. Preliminary outcomes from prior studies have suggested favorable maternal outcomes, benefit to neonates and evidence of pharmacological activity.
Dr. Silvia Daher (São Paulo Federal University) chaired the second session entitled ‘Maternal Obesity and Diabetes’ that focused on reviewing new concepts of the impact of obesity and diabetes on obstetrical outcomes and on the current diagnostic and therapeutic options. In this session, Dr. Jane Norman (Queen's Medical Research Institute) shared her research findings that link adverse pregnancy outcomes to obesity. Moreover, she talked about the ongoing clinical initiative, EMPOWaR: Efficacy of Metformin in Pregnant Obese Women, a Randomized Controlled Trial. The question of this study is does metformin reduce excess birth weight in offspring of pregnant women with a raised BMI? Dr. Silvia Daher concluded the session with an interesting talk on profiling inflammatory mediators in gestational diabetes mellitus. She talked about mechanism of insulin resistance and factors such as adiponectin and leptin. Moreover, her data suggest that the levels of leptin, adiponectin and resistin change across gestation and may be used as a biomarker in gestational diabetes.
Dr. Charles Wira (Dartmouth University) chaired the third session focused on ‘The microbiome and reproduction’. This session illustrated the contributions that the female reproductive tract microbiome has on reproductive health and pregnancy outcomes and reviewed the potential benefits of probiotics. Dr. Raina Fichorova (Brigham & Young Women's Hospital) talked about the regulation of the vaginal microflora and its impact on reproductive health. As approximately 50% of placentas from preterm births contain culturable microbes, she suggested that the maternal microbe has the potential to shape the fate of the newborn. As an example, she highlighted that maternal microbes can induce systemic inflammation in the newborn as demonstrated in ‘ELGAN STUDY’. Moreover, her research findings suggested that vaginal bacteria could modulate hormonal action. Dr. Roberto Romero (National Institute of Health) provided a deep insight into the relationship between the vaginal microbiome and spontaneous preterm labor. He suggested that baby's microflora is dependent on the mode of delivery. Moreover, he suggested that birth by cesarean could have long-term health implications in the baby, such as asthma. He also shared a case study that suggested that the vaginal microbiome of reproductive age females from different ethnicity is mostly conserved in terms of the presence of one or more species of lactobacillus. However, there is large difference in the abundance of individual microorganisms in non-pregnant women from different ethnicity. Finally, he talked about the identification of non-culturable genus of firmicutes bacteria, megasphera-like bacteria in higher concentration in women with bacterial vaginosis. Dr. Gregor Reid (University of Western Ontario) addressed the importance of probiotics in reproductive health and pregnancy outcome. He presented an interesting perspective on how we are essentially bacteria inside a human skeleton, and probiotics have a potential to be used as a therapy to maintain a healthy pregnancy. He indicated this could be particularly important in resource disadvantaged regions of the world where pregnancy too often ends in maternal or infant death. In support of this idea, he shared an information on an initiative in Africa related to the use of probiotics in community kitchens. The probiotic yogurt produced there has been shown to provide benefits to people, including pregnant women and people with HIV/AIDS.
Dr. Raina Fichorova (Brigham & Young Women's Hospital) chaired the next session that was titled ‘Demystifying laboratory techniques of Reproductive Immunology for the Clinician’. The focus of this session was to showcase reproductive immunology-based laboratory techniques and describe how they can be applied to improving patient care and management. Dr. Udo Markert (Friedrich-Schiller-Universität) talked about the application of cutting-edge technologies such as microarray (miRNome) and SELDI-TOF. As these technologies provide an enormous amount of data, Dr. Markert questioned ‘Do we really need so much data’. Then, he shared his recent findings related to the identification of a microRNA cluster that is induced in trophoblast cells when treated with leukemia inhibitory factor (a major trophoblast function regulator). In addition, he also shared data from proteomic analysis (SELDI-TOF) of follicular fluid from normal pregnant and preeclamptic patients. Moreover, his findings illustrated that in terms of protein levels, follicular fluid is different from serum. Dr. Evangelos Ntrivalas (Foundation of Blood Research) discussed the use of multicolor flow cytometry to quantitate immune cells that might be involved in preeclampsia. He showed data which suggest that in normal pregnancy, the number of T regulatory cells is increased. In contrast, during preeclampsia the number of TH17 cells is increased. The last speaker in this session, Dr. Elizabeth Bonney (University of Vermont), gave a spectacular historical review about the animal models available for studying adverse pregnancy outcomes and highlighted the advantages and disadvantages of each.
On last day of the symposium, the meeting started with the session ‘Infection, Inflammation and Preterm Birth’. Dr. Elizabeth Bonney (University of Vermont) chaired this session which set out to describe the recent advances in the prediction and treatment of women at risk of infection-associated preterm birth. Clinically, approximately 40% of the preterm births are associated with infections. Based on experimental and clinical studies, it is currently believed that untoward activation of the immune system by pathogens is one of the key factors in infection-induced preterm births. In his talk, Dr. Gil Mor (Yale University) emphasized the importance of the presence of immune cells at the maternal–fetal interface for a normal pregnancy. Moreover, the interaction between immune cells and the trophoblast at the maternal–fetal interface can be modulated by the microenvironment. As viruses and bacteria can both infect pregnant women, Dr. Mor shared his recent findings focused on understanding the mechanisms behind ascending infection during pregnancy. He showed that prior exposure to a viral infection in mice facilitates bacterial entry by inhibiting the antibacterial response in the cervix. He also proposed a double-hit hypothesis, which suggests that viral infection of the placenta/decidua alters the expression of innate immune sensors such as Toll-like receptors (TLRs) and promotes a strong inflammatory response toward bacterial products. The next speaker, Dr. Shigeru Saito (University of Toyama), introduced a novel method for detecting infection as a way to predict the prognosis of the preterm birth. He suggested using amniotic fluid to identify microbes using real time quantitative PCR. Moreover, he elucidated the importance of using eukaryote-made thermostable Taq DNA polymerase to avoid contamination of DNA of Escherichia coli while performing highly sensitive quantitative PCR. As the last speaker of this session, Dr. Roberto Romero (National Institute of Health) introduced the use of molecular imaging and the application of nanomedicine to prevent infection/neuroinflammation-induced cerebral palsy. He highlighted the influence of prematurity on cerebral palsy and suggested that intrauterine infection can have detrimental effect on brain development of neonates. He showed that administration of endotoxin in the pregnant rabbits affects newborn's ability to move compared to untreated controls. Finally, he demonstrated the use of therapeutic drug linked to dendrimer, tree-like polymers, to specifically target inflammatory cells in the brain such as microglia for treating cerebral palsy in animal model of cerebral palsy.
The final session of the symposium was chaired by Dr. Joanne Kwak-Kim (Rosalind Franklin University of Medicine and Science). This session was entitled ‘Autoimmunity and Pregnancy’. Antiphospholipid syndrome (APS) and lupus are autoimmune disorders that are associated with pregnancy complications, such as preeclampsia. The aim of this session was to evaluate the current methods for diagnosing and treating pregnant women with lupus and APS and to integrate new concepts of immune cell and autoantibody profiles in these patients. Dr. Michael Lockshin (Hospital of Special Surgery) discussed APS-associated pregnancy complications and the mechanisms involved. However, the focus of his talk was mainly about using antiphospholipid antibodies to predict adverse pregnancy outcomes, and he highlighted the PROMISSE (Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus and Antiphospholipid Syndrome) study. The purpose of this study is to determine whether complement split products that can injure healthy organs and elevated levels of circulating anti-angiogenic factors can be used to predict poor pregnancy outcome in patients with lupus and APS. The next speaker, Dr. Clare Tower (Manchester University), talked about the role of Tregs in lupus and pregnancy. Based on several studies, she highlighted that the number of Tregs in lupus patients decreases during pregnancy. Moreover, it is possible that these Tregs are functionally defective and are making women more prone for pregnancy complications. Finally, she hypothesized the role of TGFβ in maintaining the number of Tregs during pregnancy. Lastly, Dr. Joanne Kwak-Kim (Rosalind Franklin University) talked about the current and potential management of pregnant patients with APS. She emphasized the inflammatory role of antiphospholipid antibodies (APA) and differences of clinical and laboratory findings between women with recurrent pregnancy losses and APA and patients with classical APS. She concluded that it might be beneficial if lupus and APS patients are treated with combination therapy instead of heparin alone.
The meeting concluded with closing remarks from the meeting chair, Dr. Vikki Abrahams, where she thanked all the speakers, participants and the sponsors for supporting the 2nd Clinical Reproductive Immunology Symposium. Overall, this meeting has provided a tremendous opportunity for clinician and researchers to collaborate and disseminate scientific knowledge in developing better ways to identify and treat women's reproductive and pregnancy-related issues. Future meetings on these topics will further address the missing links and help patients suffering from pregnancy disorders.