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Neutrophil 2016” Inflammation, Immunity and Cancer: Neutrophils and Other Leukocytes The Society For Leukocyte Biology’s 49th Annual Meeting and “Neutrophil 2016” September 15-17, 2016 • University of Verona Congress Center • Verona, Italy Abstract Book www.leukocytebiology.org 1 1. Cytoskeletal adapter proteins Kindlin-3 and Talin- 1 anchor clustered b2-integrins to the cytoskeleton Micro Scale in Vitro Models to Study Neutrophil and facilitate the transition from arrest to diapedesis. Behavior: Past, Present and Future This process represents a gatekeeper mechanism that David J. Beebe, University of Wisconsin regulates the rate and number of neutrophils that across endothelium and gain access to inflamed Microfluidics is now a mature field. The basic tissue. We recently reported that tensile force acts on physics of microfluidics are now well described and LFA-1 (CD11a/CD18) bonds inducing their a plethora of components, devices and systems have colocalization with Orai1, the predominant been demonstrated. The study of cell migration membrane store operated Ca2+ channel that (specifically neutrophils) was one of the first uses of cooperates with the endoplasmic reticulum to elicit microfluidics in cell biology research. I will review cytosolic flux. Employing custom fabricated our history of developing and applying micro scale microfluidic flow channels combined with total phenomena and technology to enable studies of internal reflection fluorescence microscopy, we neutrophil function. While our original focus was to applied defined shear stress to low- or high affinity enable and improve basic studies of cell migration, LFA-1 and imaged the spatiotemporal regulation of our current focus is multifold. First, we strive to bond formation with Kindlin-3 recruitment and make the systems simple and, thus, more accessible Ca2+ influx. We will present a model by which and useable by a broader community. Second, we neutrophils use focal adhesions as mechanosensors have begun to apply the systems in studies involving that convert shear stress–mediated tensile force into human subjects to, for example, understand immune local bursts of Ca2+ influx that catalyze cytoskeletal system regulation in response to various lifestyle engagement and protrusive force to drive a factors (e.g. caffeine, exercise, alcohol, meditation). migratory phenotype. Third, we have begun to build organotypic models that more accurately recapitulate structure/function 3 relationships to study neutrophil trafficking. These models include engineered blood vessels within Microfluidic Chambers to Screen Neutrophil complex 3D microenvironments to study neutrophil Killing of Aspergillus Fumigatus in the Presence migration (and reverse migration) in various of Novel Bifunctional Small Molecules contexts. While, the use of micro scale devices to Caroline N. Jones1,2, Benjamin P. Heithoff1, Kevin study leukocyte biology has a long history (actually Forrest3, Kevin Judice3, Mark C. Poznansky2, James predating the field of microfluidics), the next decade F. Markmann2, Jatin M. Vyas2, Daniel Irimia2 appears to be primed to begin to reap the full 1Virginia Polytechnic Institute and State University; benefits of these now well understood technologies 2Massachusetts General Hospital and Harvard in furthering our understanding of leukocyte Medical School; 3Cidara Therapeutics biology. The contribution of human neutrophils to the 2 protection against fungal infections by Aspergillus fumigatus is essential but not fully understood. On-Chip Phenotypic Analysis of Leukocyte Whereas healthy people can inhale spores of A. Inflammatory Recruitment in Acute and Chronic fumigatus without developing disease, neutropenic Diseases patients and those receiving immunosuppressive Scott I. Simon, University of California, Davis drugs have a higher incidence of invasive aspergillosis. We present a novel microfluidic Neutrophil arrest and migration on inflamed platform in which the interactions between human endothelium involves tethering via selectins and neutrophils and A. fumigatus were observed in real ligation of G-protein coupled receptors, both time, at single-cell resolution, in precisely controlled signaling mechanisms can elicit a conformational microenvironments. The design of the microfluidic shift in the b2-integrins (CD11/CD18) to a high- platform requires neutrophils to migrate along a affinity and clustered state that determines the migration channel to reach nanoliter-sized chambers, strength and lifetime of bond formation with ICAM- where they subsequently interact with A. fumigatus. Time-lapse imaging allows the recording of have implications for the faster diagnosis and start of neutrophil phenotypes including chemotaxis, NET treatment during infections. release, swarming, and phagocytosis, while simultaneously monitoring A. fumigatus growth 4 rates. The platform technology enabled the robust screening of neutrophil trafficking towards and Rapid Microfluidic Immune Cell Migration killing of A. fumigatus in the presence of novel Analysis for Biologically Oriented and Clinically bifunctional small molecules (Cloudbreak Oriented Research technology, C-001 and C-016). The Cloudbreak Francis Lin, University of Manitoba technology (C-001 and C-016) is a bifunctional small molecule utilizing a targeting moiety Directed cell migration is a complex cellular (antifungal agent) that binds to the cell wall of A. function that critically mediates a broad range of fumigatus and is conjugated to an effector moiety physiological and pathological processes such as (chemotactic peptide fMLP) that attracts and immune response and cancer metastasis. Chemical activates neutrophils, directing them to the site of concentration gradient is an important guidance cue infection and priming them for killing. We found for many cell types, particularly the diverse immune that neutrophils alone are weakly attracted to and cell types. Microfluidic devices can precisely modestly control the growth of A. fumigatus hyphae configure cellular microenvironments and therefore (49%). C-001 [100 nM] produced a high influx of have been increasingly employed to investigate the neutrophils and reduced hyphal growth to 5%. mechanism of immune cell migration and Chambers containing C-016 [10 nM] plus chemotaxis. Recently, microfluidics-based immune neutrophils were reduced to <1% hyphal growth. C- cell migration studies have also shown promise for 016 is significantly more effective at priming enabling clinical diagnostic applications. In this talk, neutrophils for effective fungal killing than controls I will discuss our recent work in the development of – fMLP or anti-fungal agent. Neutrophils from new microfluidic devices to study the biological patients receiving immunosuppressive treatment mechanisms of human blood neutrophil migration after kidney transplantation were less effective and chemotaxis. Some of these studies are connected against the fungus than those from healthy donors to disease models such as chronic kidney disease and and broader heterogeneity exists between patients, fibrosis. In addition, I will discuss the development compared with healthy individuals. The fungal of an integrated microfluidic cell migration system killing capacity of neutrophils isolated from to enable rapid all-on-chip human neutrophil immunosuppressed patients was significantly migration analysis for assessing chronic lung increased in the presence of C-001 and C-016 disease. (P<0.01). Bifunctional small molecules represent promising immunotherapies for the treatment of 5 aspergillosis or bacterial and viral infections and further study of these agents is warranted. The Application of Machine Learning Algorithms to microfluidic chamber device will accelerate the Identify Sepsis-Specific Neutrophil Migration study of dynamic host-pathogen interactions and will Signatures facilitate the development of immunomodulating Felix Ellett1, Julianne Jorgensen1, Yuk Ming Liu2, therapies. Currently, we are working on developing Myriam Martinez2, Kathryn Butler2, Daniel Irimia1 integrated multi-sensing platforms to measure 1BioMEMS Resource Center, Department of cytokine secretion rates and to detect levels of ROS Surgery, Massachusetts General Hospital, Harvard at the single cell level in the context of infection and Medical School, Shriners Burns Hospital, Boston, inflammation. The microfluidic platform developed MA 02129 ; 2Department of Surgery, Massachusetts in this study may eventually become a useful tool for General Hospital, Harvard Medical School, measuring the ability of neutrophils from patients to Shriners Burns Hospital, Boston, MA 02129 mount effective immune responses against fungi or other pathogens in vitro. Such tools may be able Sepsis affects more patients than breast, lung, and estimate the risk for infections for each patient, and prostate cancer combined, and is responsible for up to half of US hospital mortalities. Treatment of sepsis is the single largest expenditure in US during sepsis can lead to tissue damage, organ hospitals, but is misdiagnosed in one third of cases. dysfunction, and death. Enterotoxins such as S. Early diagnosis of sepsis is crucial, with mortality aureus enterotoxin A (SEA) are thought to play rates increasing by 10% for every 6 hours that major causative roles in the mechanism of injury. treatment is delayed. Current diagnostic approaches SEA directly crosslinks MHC II and specific T cell are complicated by clinical overlap with systemic receptor Vβ chains, triggering oligoclonal T cell inflammatory
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