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Abstract

Julia Kargl, Otto Loewi Research Center, Division of Pharmacology; Medical University of Graz, Austria

Supervisor: Julia Kargl
Availability: This position is available.
Offered by: Medical University of Graz
Application deadline:Applications are accepted between February 04, 2019 00:00 and March 31, 2019 23:59 (Europe/Zurich)

Description

Background:

Pregnancy is an immunological challenge for mother and fetus, and the establishment of immune tolerance at the fetal-maternal interface is essential. The semi-allogeneic setting of trophoblast invasion and decidua development is highly regulated and accompanied by leukocyte infiltration. Innate and adaptive leukocyte accumulation and localization within the placenta is highly organized to maintain normal development. Especially the function and phenotype of macrophages has been well described (1, 2). However other leukocyte populations have been identified to play a crucial role in placenta homeostasis, including neutrophils, cytotoxic and regulatory T-cells. Neutrophils form an essential part of the innate immune responses and are the first inflammatory cells migrating towards acute infections. Their role in regulating adaptive immunity is less well understood but has been described in the setting of cancer (3, 4). Further, neutrophils have been implicated in the establishment of maternal tolerance through the induction of regulatory T-cells and neutrophil depletion led to abnormal development of the fetal-maternal unit in mouse models (5). Imbalance of leukocyte infiltration and localization within the placenta has been linked to complications in pregnancy, including gestational diabetes mellitus, preeclampsia and preterm labor, however a detailed picture of leukocyte dysfunction is missing.

Hypothesis and Objectives:

We hypothesize that innate and adaptive leukocyte infiltration, function and localization within the placenta is altered in health and disease and that immune cell interactions play a crucial role in maintaining immune tolerance at the fetal-maternal interface.

The purpose of this study is to evaluate leukocyte composition and localization within the placenta in health and disease including innate (neutrophils, monocytes, macrophages, innate lymphoid cells) and adaptive (CD8, CD4 T-cell, B-cell subsets) immune cells. Further, we will evaluate neutrophil function and focus on lymphocyte/neutrophil, trophoblast/neutrophil and macrophage/neutrophil interactions.

Methodology:

The PhD candidate will comprehensively characterize the immune landscape in healthy and diseased placenta tissue samples using multicolor flow cytometry (18-plex), next-generation sequencing and multiplex fluorescence microscopy (3, 6). Functional analysis of neutrophils will be investigated in assays of shape change, chemotaxis and Ca2+ signaling and levels of neutrophil specific enzymes will be assessed by ELISA and western blots. Lymphocyte/neutrophil, trophoblast/neutrophil and macrophage/neutrophil interactions will be studied using in vitro co-culture systems. In this study, we will make use of established cell culture models, primary cells and tissue from consented patients.

References:

  1. Svensson-Arvelund J, Ernerudh J. (2015) The role of macrophages in promoting and maintaining homeostasis at the fetal-maternal interface. Am J Reprod Immunol, 2015; 74(2):100-109
  2. Schliefsteiner C, Peinhaupt M, Kopp S, Lögl J, Lang-Olip I, Hiden U, Heinemann A, Desoye G, Wadsack C. (2017) Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus. Front Immunol. doi: 10.3389/fimmu.2017.00888
  3. Kargl J, Busch SE, Yang GHY, Kim KH, Hanke ML, Metz HE, Hubbard JJ, Madtes DK, McIntosh MW, Houghton AM. (2017) Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nature Commun.8, 14381 doi: 10.1038/ncomms14281
  4. Coffelt SB, Wellenstein MD, deVisser KE. (2016) Neutrophils in cancer: neutral no more. Nat Rev Cancer.;16(7):431-46(2016)
  5. Nadkarni S, Smith J, Sferruzzi-Perri AN, Ledwozyw A, Kishore M, Haas R, Mauro C, Williams DJ, Farsky SHP, Marelli-Berg FM, Perretti M. (2016) Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy. PNAS  doi:10.1073/pnas.1611944114
  6. Mark NM*, Kargl J*, Busch SE, Yang GHY, Metz HE, Zhang H, Hubbard JJ, Pipavath SNJ, Madtes DK, Houghton AM. (2017) COPD alters immune cell composition and immune checkpoint inhibitor efficacy in NSCLC. AJRCCM. doi:10.1164/rccm.201704-0795OC (* Equally contributing authors)