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Identification of leukocyte trafficking mechanisms in autoimmune diseases
Universita degli Studi di Verona
Department of Medicine, Section of General Pathology
Prof. Oliviero Olivieri
Prof. Gabriela Constantin, MD, PhD E-mail: firstname.lastname@example.org
Type of Research Project
- Basic science
What is the background of the project?
Autoimmune diseases are characterised by chronic inflammation mediated by immune system cells against own body tissues. Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases of the central nervous system (CNS) induced auto reactive immune cells agains CNS antigens. Leukocyte trafficking from the blood vessels into the central nervous system (CNS) represents a key process in the induction of MS and EAE. In this project we will investigate the molecular mechanisms controlling neutrophil and T cell tethering, rolling, arrest and intravascular crawling in spinal cord (SC) venules by performing epifluorescence intravital microscopy in mice with EAE. Invading leukocytes accumulate in the CNS during EAE in both the perivascular space and the parenchyma, potentially having an impact on glial cell activation and neuronal loss. In this project we will also use two-photon laser scanning microscopy (TPLSM) to characterize the molecular mechanisms controlling leukocyte intraparenchymal dynamics including the role of chemotactic factors and damage-associated molecular patterns (DAMPs). Finally, we will study the potential therapeutic effect of the blockade of trafficking mechanisms on EAE.
What is the aim of the project?
The final goal of this project will be to identify more specific disease pathways and potentially new therapeutic strategies in autoimmune diseases.
What techniques and methods are used?
We will use epifluorescence intravital microscopy and two-photon microscopy to study leukocyte trafficking mechanisms in EAE. The therapeutic effect of migration blockade will be studied by using monoclonal antibodies and pharmacological inhibitors as suggested by our promising preliminary data showing that intravenous or intrathecal treatment with antibodies interfering with leukocyte trafficking after disease onset significantly improves disease course in EAE mice.
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student will acquire basic knowledge on inflammatory diseases and will learn about imaging methods to study the molecular mechanisms controlling leukocyte trafficking under pathological conditions. He/she will actively participate to lab meetings and seminars and will interact with people from Constantin’s group (18 members) and learn about their research projects, including projects funded by the EU and US agencies.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
High motivation for research activity.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system
- Constantin G; Laudanna C. Transmigration of effector T lymphocytes: changing the rules. Nat Immunol. 2011 Dec 16;13(1):15-6.
- Regulatory T Cells Suppress the Late Phase of the Immune Response in Lymph Nodes through P-Selectin Glycoprotein Ligand-1. Angiari S; Rossi B; Piccio L; Zinselmeyer BH; Budui S; Zenaro E; Della Bianca V; Bach SD; Scarpini E; Bolomini-Vittori M; Piacentino G; Dusi S; Laudanna C; Cross AH; Miller MJ; Constantin G. J Immunol. 2013 Dec 1;191(11):5489-500.
- Angiari S; Donnarumma T; Rossi B; Dusi S Pietronigro E; Zenaro E; Della Bianca V; Toffali L; Piacentino G; Budui S; Rennert P; Xiao S; Laudanna C; Casasnovas JM; Kuchroo VK; Constantin G. TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity. Immunity. 2014; April 17; 40:1-12.
- Angiari S; Constantin G. Regulation of T cell trafficking by the T cell immunoglobulin and mucin domain 1 glycoprotein. Trends Mol Med. 2014 Oct 31;20(12):675-684.
- Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Zenaro E; Pietronigro E; Della Bianca V; Piacentino G; Marongiu L; Budui S; Turano E; Rossi B; Angiari S; Dusi S; Montresor A; Carlucci T; Nanì S; Tosadori G; Calciano L; Catalucci D; Berton G; Bonetti B; Constantin G. Nat Med. 2015 Aug;21(8):880-6. doi: 10.1038/nm.3913. Epub 2015 Jul 27.
- Rossi B; Constantin G. Live Imaging of Immune Responses in Experimental Models of Multiple Sclerosis. Front Immunol. 2016 Nov 21;7:506.
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