ABSTRACTS

SPEAKERS’ ABSTRACTS OPENING SESSION

OS.01

Vaccines and reproduction: where are we heading? IH Frazer The University of Queensland, TRI, Brisbane, Australia

If the aim of reproductive health care is a healthy mother and a healthy baby, then the immune system’s role cannot be ignored. Anogenital, transplacental, intrapartum and post partum infections each have the potential to compromise both mother and baby and many can be prevent by immunisation. Control of reproductive fitness through immune manipulation can increase or deliberately decrease fertility. My address will examine the role of vaccines and immunotherapy in control of STIs and of other infections that threaten maternal or neonatal health, and the challenges of delivering these equitably across the global community.

OS.02

Angiogenesis revisited: endothelial cell metabolism as a target? P Carmeliet Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Leuven Belgium, Department of Oncology, KU Leuven, Leuven, Belgium

Angiogenesis, the growth of new blood vessels, plays a crucial role in numerous diseases, including cancer. Anti-angiogenesis therapies have been developed to starve cancer cells from nutrients. Clinically approved anti-angiogenic drugs prolong the survival of cancer patients, but their success is limited by intrinsic refractoriness and acquired resistance. New strategies are thus needed to block tumor angiogenesis via alternative mechanisms. We recently reported that PFKFB3-driven glycolysis regulates the endothelial tip cell function during vessel sprouting, even capable of overruling the potent pro-stalk activity of Notch, and that its loss in endothelial cells causes vascular hypobranching defects. Moreover, partial and transient reduction of glycolysis by blocking PFKFB3 reduced pathological

angiogenesis in several disease models. Ongoing studies explore the role of lipid and amino acid metabolism in vessel sprouting, and assess the therapeutic potential of targeting these metabolic pathways for anti-angiogenic therapy.

S.01-1

Decidual natural killer cells: key regulators in early pregnancy JE Cartwright Cardiovascular and Cell Sciences Research Institute, St. George’s, University of London, London, UK

Problem: Decidual natural killer (NK) cells have been implicated in the regulation of invasion of trophoblast cells from the semi-allogeneic fetal placenta. Additionally they may have roles in regulating the remodelling of uterine spiral arteries. Disruption of these processes has been associated with the pathology of pregnancy disorders, including pre-eclampsia. This has been an area that is difficult to study in early human pregnancy but where advances are now being made by combining screening modalities with culture models of isolated primary cells. Methods of Study: We have used uterine artery Doppler resistance indices (RI) as a proxy measure of the extent of spiral artery remodelling. This allows us to study first trimester cells isolated from pregnancies with impaired spiral artery remodelling (high RI) and a higher incidence of pregnancy disorders and compare these to cells isolated from pregnancies with a normal RI. Decidual NK cell interactions with trophoblast and vascular cells were investigated. NK cell expression of inhibitory and activating receptors and their secretion of pro- and anti-angiogenic factors were profiled. Results: Decidual NK cell receptor expression is altered in pregnancies with impaired vascular remodelling and a higher risk of pre-eclampsia. In addition cells from these pregnancies are less able to induce trophoblast invasion or chemoattraction. Decidual NK cells from normal RI pregnancies were able to induce changes in vascular cells which are

American Journal of Reproductive Immunology 73 (Suppl. 2) (2015), 15–33 ª 2015 The Authors. American Journal of Reproductive Immunology © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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seen during spiral artery remodelling however cells from high RI pregnancies were less able to do this. Conclusions: Investigation of the phenotype of decidual NK cells from this high-risk group of pregnancies compared to pregnancies where placentation is occurring normally is providing an insight into maternal immune cell-mediated effects on trophoblast behaviour and the uterine vasculature.

in pregnancy. The pathways by which KIR2DL4HLA-G interactions induce the cellular senescence of NK cells and the role of the resulting proangiogenic and proinflammatory senescence associated secretory phenotype (SASP) in vascular remodeling will be discussed in the context of reproduction.

S.02-1

Epigenetics of decidual inflammation S.01-2

Natural killer and other innate lymphoid cells in the uterus F Colucci University of Cambridge, Cambridge, UK

No organ is richer in NK cells than the uterus. During pregnancy, uterine NK cells regulate local vascular adaptation, placental development and fetal growth. The development of NK cell populations is intertwined with that of other groups of innate lymphoid cells, which contribute to tissue homeostasis, repair and barrier immunity. We will discuss the various populations of uterine NK cells and innate lymphoid cells in the context of reproductive immunology.

S.01-3

HLA-G mediated NK cell senescence promotes vascular remodeling: implications for reproduction S Rajagopalan Laboratory of Immunogenetics NIAID/NIH Rockville, USA

The uterus in early pregnancy is a non-lymphoid organ that is enriched in natural killer (NK) cells. Studies to address the role of these abundant human NK cells at the maternal fetal interface have focused on their response to the major histocompatibility complex (MHC) molecules on fetal trophoblast cells that they contact. The interaction of maternal NK cell receptors belonging to the killer cell Ig-like receptor (KIR) family with trophoblast MHC class I molecules in pregnancy can regulate NK cell activation for secretion of proangiogenic factors that promote placental development. KIR2DL4 (CD158d) is a KIR family member that is uniquely poised to play a role in pregnancy due to the restricted expression of its ligand, HLA-G by fetal trophoblast cells early 16

A Erlebacher1,2, C Clementi1, J Siewiera1, P Nancy1 1 Department of Pathology, NYU School of Medicine, NYU Langone Medical Center; 2NYU Cancer Institute, New York, USA

Successful pregnancy requires delicate control over the maternal immune cells that reside at the maternal/fetal interface. On the one hand, immune cell-mediated inflammation at the maternal/fetal interface is likely to be a major instigator of preterm birth, while immunogenic recognition of fetal/placental antigens by professional antigen presenting cells runs the risk of inducing T cell responses that might induce fetal demise. On the other hand, inadequate immune surveillance of the maternal/fetal interface might be expected to increase the risk of fetal and placental infection. We will discuss recent our recent work on the molecular and cellular pathways that regulate immune cell trafficking and inflammation within the pregnant mouse uterus. This work points to the seminal importance of the decidua, i.e. the specialized endometrial stromal tissue that directly encases the implanted embryo, and in particular an epigenetic program active in decidual stroma cell is that transcriptionally silences expression of genes that regulate inflammation and leukocyte trafficking. For example, as a result of this program, effector T cells are unable to accumulate within the maternal/fetal interface even under conditions of local inflammation. We are currently attempting to elucidate the breadth and overall significance of the silencing program towards reproductive success, and to determine the exact molecular pathways that induce its activity in decidual stromal cells. Together, our results have major implications for the immunology of pregnancy its complications. Supported by grants from the NIH, The American Cancer Society, and The March of Dimes.

American Journal of Reproductive Immunology 73 (Suppl. 2) (2015), 15–33 ª 2015 The Authors. American Journal of Reproductive Immunology © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

ABSTRACTS

S.02-2

From pregnancy and the immune boundaries between individuals to insights into the lineage commitment of regulatory T cells AG Betz MRC Laboratory, Cambridge, UK

Arguably, the immune system not only protects ‘self-integrity’ by defending the organism from invasion by pathogens, but defines ‘self’ in the first place. The evolution of histocompatibility allowed stationary organisms to define themselves as individuals, preventing fusion with other members of the same species. This boundary between self and nonself was key to the propagation of successful genetic changes in stationary organisms fighting for limited resources. In higher, more complex organisms the focus of defence shifted from the definition of self to protection from parasites and invading microorganisms and viruses. The evolution of the immune system culminated in the adaptive immune system of mammals, which has the ability to retain memories of prior encounters with pathogens. In mammals, the major histocompatibility complex is actually used for antigen presentation to immune effector cells. This passive retention of histocompatibility poses a real problem for the immune system during invasive placentation, as the mother has to tolerate the implantation of a fetus that carries highly immunogenic paternal histocompatibility antigens. To this end a mechanism had to evolve to allow the maternal immune system to specifically suppress the rejection of the fetus, without unduly increasing the risk of infections. We were able to demonstrate that regulatory T cells not only prevent autoimmunity, but are also key to maternal fetal tolerance. Intriguingly, a single lineage factor Foxp3 necessary and sufficient for the development and maintenance of regulatory T cells.Yet very little is known about the mechanisms involved. Comparative genomics suggest that the evolution of Foxp3 and, thus regulatory T cells, facilitated the evolution of invasive placentation. We used the insights obtained in these analyses to dissect the function of Foxp3 on a molecular level. Our findings suggests that Foxp3 acts as a bridge between DNA binding interaction partners and proteins with effector function permitting it to regulate a large number of genes. We directly used the insights gained from reproductive immunology and the

evolution of regulatory T cells to inform our functional studies of Foxp3.

S.02-3

The chemokine network at the maternal-fetal interface in the early pregnancy MR Du, SC Wang, DJ Li Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University, Shanghai, China

Problem: Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation, directed migration, and immune regulation. Methods of Study: Analyzing the expression of chemokine and its receptor in the villious trophoblast cells and decidual cells. Then studying the function of chemokine and chemokine receptor at the maternal-fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells. Results: Chemokines and their receptors are widely expressed at the maternal-fetal interface. The interactions of chemokine and its receptor induce selective trafficking of leukocyte subsets to the decidua, inducing maternal-fetal immune tolerance and placental development. Conclusions: The gestational uterine microenvironment is characterized by the differential expression and secretion of chemokines that induce multiple events closely associated with normal pregnancy so as to form a fetus-supporting milieu during pregnancy.

American Journal of Reproductive Immunology 73 (Suppl. 2) (2015), 15–33 ª 2015 The Authors. American Journal of Reproductive Immunology © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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S.03-1

Parallel studies of mucosal immunity in the reproductive and gastrointestinal mucosae of HIV-infected women U Shanmugasundaram1, JW Critchfield1, J Pannell2, J Perry3, J Terdiman4, LC Giudice3, K SmithMcCune3, RM Greenblatt2,5,6, BL Shacklett1 1

Department of Medical Microbiology and Immunology, University of California, San Francisco, USA; 2Department of Clinical Pharmacy, University of California, San Francisco, USA; 3Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, USA; 4Division of Gastroenterology, Department of Medicine, University of California, San Francisco, USA; 5 Department of Internal Medicine, University of California, San Francisco, USA; 6Department of Biostatistics and Epidemiology, University of California, San Francisco, USA

Problem: The effects of HIV on the gastrointestinal tract (GIT), including CD4+ T-cell depletion, epithelial disruption, and collagen deposition, are well documented and only partially reversed by combination antiretroviral therapy (cART). However, the effects of HIV on the female reproductive tract (FRT) are less well understood, and most studies have focused on the ectocervix and vagina without assessing the upper tract. Here, we investigated CD4+ T-cell frequency, phenotype, and HIV-specific T-cell responses, in the endocervix and endometrium of HIV-positive women, comparing these tissues to the gastrointestinal mucosa. Method of Study: Samples from terminal ileum, sigmoid colon, endometrium, endocervix and blood were obtained at mid-luteal phase from women who were natural controllers??(VL

'Innovations in Reproductive Immunobiology', ASRI 35th Annual Meeting, June 2 - 5, 2015, Queen's University, Kingston, Ontario, Canada.

'Innovations in Reproductive Immunobiology', ASRI 35th Annual Meeting, June 2 - 5, 2015, Queen's University, Kingston, Ontario, Canada. - PDF Download Free
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