Vascular Immunology Laboratory

Lab head: Professor Georges Grau
Location: K25 - Medical Foundation Building

This laboratory seeks to decipher the fine interactions between microvascular endothelial cells and circulating blood cells, by studying the biology and pathophysiology of microvascular endothelial cells. Diseases such as cerebral malaria, multiple sclerosis and viral encephalitis are being modelled using brain-derived endothelium, while lung-derived cell-lines are being used to study adult respiratory distress syndrome, asthma, and other pulmonary illnesses. In addition to functional studies, the latest imaging technology is being used to visualise the diverse players involved in inflammation. Using these integrated approaches, the cellular, molecular and genetic features of microvascular biology will be explored.

Improved understanding of pathophysiological mechanisms will lead not only to significant advances in fundamental knowledge of biology, but also will identify new targets for the development of drugs intended to treat the many diseases caused by inflammatory processes.

Defining the antigen presentation capacity of endothelial cells and their microparticles

Primary supervisor: Georges Grau

Cell arrest in brain microvessels and inflammation are the major fatal determinants of cerebral malaria (CM). There is good evidence in
inflammatory diseases that endothelial cells (EC) can behave as antigen presenting cells (APC) but this has not been investigated in CM. Here we will study this function of brain EC, as well as the immunomodulatory potential of their microparticles. We will use human and murine cells,
in order to exploit transgenic systems, with an approach encompassing immunology, advanced microscopy, proteomic analysis and electrophysiology.

Our central HYPOTHESIS is that brain EC can behave as APC and that this drives CM pathogenesis, via the triggering of vascular lesions.

Specifically our AIMS are to:
1. Compare the ability of brain microvascular EC and dendritic cells to acquire malaria antigens from infected red cells and present processed antigens to T lymphocytes. Among the tools to be used are transgenic mice whose T cells respond via class I or class II MHC molecules, and
transgenic parasites that express model T cell epitopes.
2. Define microparticle involvement in the immune response during malaria infection. Microparticles from brain EC will be phenotyped and their capacity to modify T cell activation established.
3. Determine how the antigen presentation capacity of EC in CM leads to EC damage. This likely occurs via the cytolytic effects of CD8+ cytotoxic lymphocytes. End points of endothelial integrity that parallel blood-brain barrier function will be measured, including trans-endothelial
electrical resistance.

1 – Establish a novel role for brain ECs as APCs in CM and compare this to professional APC.
2 – Demonstrate how microparticles modulate immune responses in CM.
3 – Identify new facets of EC biology: in the medium term, new mechanisms of pathogenic importance in CM and, in the long run, new
therapeutic avenues.

Discipline: Pathology
Co-supervisors: Valery Combes
Keywords: Immunology, Neuro immunology, Infection and immunity