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Elucidating the impact of inflammation on lymphatic vessel function and on the induction of adaptive immunity

English title Elucidating the impact of inflammation on lymphatic vessel function and on the induction of adaptive immunity
Applicant Halin Cornelia
Number 138330
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Immunology, Immunopathology
Start/End 01.11.2011 - 31.10.2014
Approved amount 421'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Cardiovascular Research

Keywords (6)

Inflammation; Lymphatic vessels; Lymphatic function; Adaptive immunity; VEGF-A; ALCAM

Lay Summary (English)

Lead
Lay summary

Chronic inflammation is accompanied by profound changes in lymphatic vessels, such as the upregulation of adhesion molecules and chemokines and the formation and expansion of new lymphatic vessels (lymphangiogenesis). The significance of  these inflammation-induced changes is presently not well understood. In particular, it is unclear how chronic inflammation affects lymphatic vessel function, most importantly, the migration of antigen-presenting dendritic cells and the transport of free antigen to draining lymph nodes. Since the induction of adaptive immunity in draining lymph nodes is tightly linked to the functionality of the lymphatic system, it is also largely unknown how chronic inflammation affects immune function in draining lymph nodes and thereby impacts the course of the inflammatory and/or autoimmune response.

In this project we plan to make use of two different mouse models to study how acute and chronic skin inflammation affect lymphatic vessel function and, as a consequence, the induction of adaptive T cell immunity. A specific aim of our research is to investigate, whether vascular endothelial growth factor-A (VEGF-A), which is up-regulated in inflamed skin and skin-draining lymph nodes, affects the induction of adaptive T cell immunity in inflammation. Furthermore we plan to study the involvement of a selected, inflammation-induced adhesion molecule, namely ALCAM (CD166), in inflammation-induced lymphangiogenesis and in dendritic cell migration to draining lymph nodes.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Oxazolone-induced contact hypersensitivity reduces lymphatic drainage but enhances the induction of adaptive immunity.
Aebischer David, Willrodt Ann-Helen, Halin Cornelia (2014), Oxazolone-induced contact hypersensitivity reduces lymphatic drainage but enhances the induction of adaptive immunity., in PloS one, 9(6), 99297-99297.
The inflammatory response of lymphatic endothelium.
Aebischer David, Iolyeva Maria, Halin Cornelia (2014), The inflammatory response of lymphatic endothelium., in Angiogenesis, 17(2), 383-93.
Dendritic cell interactions with lymphatic endothelium.
Russo Erica, Nitschké Maximilian, Halin Cornelia (2013), Dendritic cell interactions with lymphatic endothelium., in Lymphatic research and biology, 11(3), 172-82.
Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage.
Iolyeva Maria, Aebischer David, Proulx Steven T, Willrodt Ann-Helen, Ecoiffier Tatiana, Häner Simone, Bouchaud Grégory, Krieg Carsten, Onder Lucas, Ludewig Burkhard, Santambrogio Laura, Boyman Onur, Chen Lu, Finke Daniela, Halin Cornelia (2013), Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage., in Blood, 122(13), 2271-81.
Novel role for ALCAM in lymphatic network formation and function.
Iolyeva Maria, Karaman Sinem, Willrodt Ann-Helen, Weingartner Stephanie, Vigl Benjamin, Halin Cornelia (2013), Novel role for ALCAM in lymphatic network formation and function., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 27(3), 978-90.
Lymphatic vessels in inflammation
Vranova Martina, Halin Cornelia, Lymphatic vessels in inflammation, in Immunology.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
MMI, Imaging the immune system Poster CCL21 guides intralymphatic dendritic cell migration in downstream direction of the draining lymph node 23.10.2014 Milan, Italy Russo Erica;
European Conference on Mathematical and Theoretical Biology (ECMTB) Talk given at a conference Inflammatory lymphangiogenesis and identification of new lymphangiogenic mediators 19.06.2014 Göteborg, Sweden Halin Cornelia;
Gordon Research Conference Poster Investigating the role of CCL21 in dendritic cell migration through lymphatic vessels 09.03.2014 Lucca, Italy Russo Erica;
2nd joint meeting of the German Society of Microcirculation and Vascular Research and SSMVR Poster Investigating the role of CCL21 in dendritic cell migration within lymphatic vessels 28.09.2013 Dresden, Germany Russo Erica;
Seminar at University of Southern California (USC) Poster New insights into the immune and drainage functions of lymphatic vessels 15.07.2013 Los Angeles, United States of America Halin Cornelia;
Seminar at Albert Einstein College of Medicine Individual talk New insights into the immune and drainage functions of lymphatic vessels 01.07.2013 New York, United States of America Halin Cornelia;
Annual Meeting of the Federation of Clinical Immunology Societies (FOCIS) Talk given at a conference Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage 29.06.2013 Boston, United States of America Halin Cornelia;
Seminar at EPFL Individual talk New Insights into Lymphatic Vessel Immune and Drainage Function 24.06.2013 Lausanne, Switzerland Halin Cornelia;
Schweizerische Gesellschaft für Allergologie und Immunologie SGAI Poster Investigating the role of CCL21 in dendritic cell migration through lymphatic vessels 17.04.2013 Bern, Switzerland Russo Erica;
Annual Congress of the Union of Vascular Societies of Switzerland (USGG) Talk given at a conference Lymphatic vessels and inflammation 21.11.2012 Bern, Switzerland Halin Cornelia;
Seminar at the German Cancer Research Center (DKFZ) Individual talk New Insights into Lymphatic Vessel Biology and Function 29.09.2012 Heidelberg, Germany Halin Cornelia;
3rd European Congress of Immunology (ECI 2012) Talk given at a conference Chronic skin inflammation facilitates immune priming by dendritic cells 07.09.2012 Glasgow, Great Britain and Northern Ireland Aebischer David;
Seminar at the Institute of Clinical Chemistry Individual talk Lymphatic vessels in inflammation and immunity 05.08.2012 Zurich, Switzerland Halin Cornelia;
Gordon Research Conference on Molecular Mechanisms of Lymphatic Function and Diseases Poster Lymphatic vessels draining sites of chronic inflammation are functional and correlate with an increased induction of adaptive immunity 04.03.2012 Ventura, CA, United States of America Aebischer David;
International Vascular Biology Meeting - IVBM 2012 Poster Role of ALCAM in lymphatic endothelial cell biology 02.02.2012 Wiesbaden, Germany Willrodt Ann-Helen;
Keystone Symposium on Chemokines and Leukocyte Trafficking in Homeostasis and Inflammation Poster Lymphatic vessels draining sites of chronic inflammation are functional and correlate with an increased induction of adaptive immunity 09.01.2012 Breckenridge, CO, United States of America Russo Erica;


Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) New function for a messenger molecule eth Life International 2013

Abstract

Background:Chronic inflammation is accompanied by profound changes in lymphatic vessels, such as the upregulation of adhesion molecules and chemokines, the onset of lymphangiogenesis and the induction of lymphatic vessel remodeling. The significance of most of these inflammation-induced changes is presently not well understood. In particular, it is unclear how chronic inflammation affects lymphatic vessel function, most importantly, the migration of dendritic cells (DCs) and the transport of tissue fluids to draining lymph nodes (dLNs). Since the induction of adaptive immunity in dLNs is tightly linked to the functionality of the lymphatic system, it is also largely unknown how chronic inflammation affects immune function in dLNs and thereby impacts the course of the inflammatory and/or autoimmune response. Specific Aims:With the proposed research we seek to study how acute and chronic skin inflammation affect the induction of adaptive T cell immunity in dLNs. In specific, we plan to address what impact psoriasis-like skin inflammation has on lymphatic vessel function, namely on DC migration and fluid / inflammatory mediator transport to dLNs. Furthermore, we seek to study how chronic inflammation affects T cell activation and T helper cell differentiation in dLNs. In this context, a further aim of our research is to investigate, whether VEGF-A, which is upregulated in inflamed skin and skin-draining LNs, affects T cell priming and T helper cell differentiation. Finally, we plan to study the involvement of a selected, inflammation-induced adhesion molecule, namely ALCAM (CD166), in inflammation-induced lymphangiogenesis and in DC migration to dLNs. Experimental Design and Methods:We will make use of two mouse models of the inflammatory skin disease psoriasis, namely, contact hypersensitivity-induced skin inflammation in K14-VEGF-A tg mice and skin inflammation induced in wild-type mice by repeated topical application of imiquimod. These models will be used to study the effects of inflammation on DC migration, fluid drainage and on the induction of adaptive T cell immunity. Inflammation-induced changes in the lymphatic vasculature, in leukocyte composition and cytokine levels in the skin and dLNs will be analyzed by FACS, whole-mount immunofluorescence, ELISA or gene expression profiling of ex vivo isolated cells. Furthermore, T cell receptor transgenic mice will be used to study the effect of inflammation and of inflammation-induced VEGF-A on T cell activation and polarization in vivo and in vitro (in combination with VEGF-A / VEGFR blocking antibodies or VEGFR tyrosine kinase inhibitors). Furthermore, in vitro and in vivo assays involving blocking antibodies and knockout mice will be used to study the involvement of ALCAM in inflammation-induced lymphangiogenesis and in DC migration. Expected Value of the Proposed Project:The project will shed light on the functional significance of inflammation-induced changes in the lymphatic vessel network, namely, on their impact on DC migration, antigen drainage and on the initiation of adaptive T cell immunity in dLNs. Our experiments will also help to better understand how chronic skin inflammation affects T helper cell activation and differentiation and thereby shapes the course of the immune response. Furthermore, the proposed experiments will help to expand our mechanistic understanding of the importance of VEGF-A and VEGFR signaling in immunity and inflammation. Given that VEGF-A and VEGFRs are emerging as new targets for anti-inflammatory therapies, such knowledge may be valuable for anticipating the therapeutic benefit as well as potential side effects of such treatments.
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