CV Science

Antonino Nicoletti PhD Immunobiology - Professor of Immunology

Course and current status

Scientific summary

Cardiovascular diseases and atherosclerosis

Cardiovascular diseases are the leading cause of death in industrialized countries. The common characteristic of these diseases is damage to the arteries of large and medium size which leads to the formation of atherosclerotic plaques. These plaques consist in an accumulation of lipids and blood cell that progresses slowly with age and risk factors. Sometimes these arterial lesions are "complicated" in that a blood clot may suddenly compromise the integrity of the arterial lumen. Tissues irrigated by the artery will not receive blood supply anymore. This can lead to irreversible damage to the organ. If the affected organ is the brain (stroke) or heart (myocardial infarction), this damage can be fatal. Another complication is a pathological arterial dilation. This "aneurysmal" dilation, when extreme, can lead to unpredictable rupture of the artery. Often, this complication relates to the aorta. The outcome in this case is always fatal. It is therefore essential to understand the mechanisms that control the occurrence of these "complications".

Atherosclerosis and inflammation

The formation of atherosclerotic plaques depends on the activity of inflammatory cells such as macrophages or lymphocytes. In fact, we now consider that paques result from an inflammatory reaction. This type of reaction is a response to the organism intended to eliminate a noxious agent while trying to maintain tissue integrity. Resolution of inflammation should be accompanied by a healing and a return to a normal state. However, under certain circumstances, the local inflammatory reaction persists and changes in nature. It is then characterized by the presence of an organized immune cell infiltrate which gradually destroy the tissue that hosts it. It is precisely this scenario that we recently described in the context of atherosclerosis.

The local immune response, a new target for treatments

We believe that the local organization of immune cells contributes to the destruction of atheromatous arteries. Our project aims at understanding the cellular and molecular mechanisms of this organization in humans. This knowledge will allow us to interfere with their formation and open new therapeutic avenues potentially transferable to other pathologies. Indeed, these inflammatory organized structures have recently been described in autoimmune diseases, diabetes or certain cancers.

Our team

Our INSERM team was created in January 2009. Our activities are focused on two main research themes:

• The first theme concerns CD31, an immunoregulatory molecule expressed on blood-vessel interface. We found that CD31 could be cleaved from the surface of lymphocytes in atherothrombotic patients. This has opened two lines of research. The first seeks to determine whether CD31 cleavage may be a prognostic marker of plaque complications (patent and industrial partnership with Becton Dickinson). The second line of research is based on the observation that the cleavage of CD31 is partial, leaving on the cell surface a portion of the molecule. We have patented peptides capable of binding to this residual fragment and that are able to restore signaling downstream of CD31. We have demonstrated that this can restore the physiological role of immunoregulatory CD31. These peptides could define a new class of immunoregulatory tools.

• The second theme concerns the adventitial lymphoid neogenesis. This process sheds new light on the immunobiology of atherothrombosis. Because our understanding of the pathophysiology of atherothrombosis is thereby transformed, new therapeutic possibilities open to us.

These two main research programs share a common overall strategy and similar objectives: understanding the immunobiology of atherothrombosis in order to draw future strategies for diagnosis, prognosis, and therapeutics.

Team expertise

Our team has the knowledge and know-how to complete these projects. We have developed collaborations with clinical departments of the hospital Bichat allowing us to conduct research on human tissues. We explore our hypotheses using in vivo experimental models and in vitro (Technology Keywords: multiplexed and high-speed flow cytometry; cytometric beads; fluorescence microscopy; experimental transplantation; implantation of scaffold in vivo; cell culture; in vivo experimental model of cardiovascular disease).