Immune system and neuroinflammation

Guillaume Dorothée
Team leader(s) : Guillaume Dorothée
Administrative contact : Maryse Nana

Saint-Antoine Hospital– Kourilsky Building – 3rd floor
34 rue Crozatier - 75571 Paris cedex 12 - France

Professors, Lecturers, Researchers, Clinicians
Post-docs, Contract researchers, Emeritus, Volunteering
Engineers, Technicians
PhD candidates, MSc students

Increasing evidence points to a crucial involvement of innate neuroinflammatory responses and peripheral immunity in neurodegenerative diseases and other neurological pathologies. Our studies seek to examine the role of emerging aspects of innate and adaptive neuro-immune interactions in the pathophysiology of Alzheimer's disease (AD) and Tauopathies, as well as other neuro-inflammatory and/or neurovascular conditions (cerebral amyloid angiopathy (CAA), stroke, epilepsy). Our research strategy relies on a translational approach combining a) preclinical studies in transgenic mouse models, b) joint clinical studies with the Memory and Language Neurology Service (Pr. Marie Sarazin, Hôpital Sainte-Anne, Paris), the Frédéric Jolio Hospital Service (Dr. Michel Bottlaender, CEA, Orsay), and the Neurology and Neurovascular Emergencies Service (Pr. Sonia Alamowitch, Hôpital Saint-Antoine, Paris, France)
Our research program consists of four areas of research : (i) WP1 aims to decipher the interactions between T cell responses and innate neuroinflammation in the pathophysiology of AD and other Tauopathies, and to develop immunotherapy approaches by targeting T cells as well as associated biomarkers; (ii) WP2 consists in studying the impact of early neuroinflammatory processes on neuronal function in AD; iii) WP3 focuses on the role of polymorphonuclear neutrophils (PMNs), and their potential interest as biomarkers, in the pathophysiology of AD, stroke, and epilepsy; iv) WP4 intends to define and validate candidate serological biomarkers in CAA, using innovative multiparametric analyses.
Our overall goal is to better understand the role of neuro-immune interactions in the pathophysiology of neurodegenerative diseases and other neuroinflammatory pathologies, to develop and assess innovative disease-modifying immunotherapy approaches, as well as blood-based immune biomarkers with diagnostic and/or prognostic value.

Key words:
Neuroinflammation; neurodegenerative diseases; Alzheimer's disease; Tauopathies; cerebral amyloid angiopathy; stroke; epilepsy; adaptive immunity; regulatory T cells; neutrophils; anti-Ab antibodies; immune biomarkers; immunotherapy; immunomodulation.

Recent highlights:
• Our previous studies have shown that regulatory T cells (Treg) critically control anti-Aβ CD4+ T cell responses, both in physiological conditions and in the context of amyloid pathology (Toly-Ndour et al, J Immunol, 2011). More recently, we have uncovered the beneficial role of Treg in a mouse model of Alzheimer's-like amyloid pathology. Our study revealed that peripheral modulation of Tregs impacted how rapidly the disease progressed, at least partly by limiting the development of deleterious innate neuroinflammatory responses associated with amyloid pathology. Our work was the first to highlight the therapeutic potential, in a mouse model of AD, of a Treg-targeted immunomodulation approach based on low-dose IL-2 treatment (Dansokho et al, Brain, 2016). Additionally, our collaborative studies on the role of T cells in the context of Tau pathology, performed with David Blum and Luc Buée (INSERM UMR 1172, Lille) suggested that Tau pathology may lead to the development of deleterious T cell-mediated processes, which contribute to promoting the deleterious cognitive deficits and innate neuroinflammatory responses associated with Tau pathology, in a detrimental cycle of amplification (Laurent et al, Brain, 2017). Moreover, we have contributed to a series of clinical studies that provide evidence of early and beneficial neuroinflammation in the brains of AD patients (Hamelin et al, Brain, 2016), as well as different patterns of microglial activation dynamics, correlating with a rapid progression of cognitive decline in AD patients (Hamelin et al, Brain, 2018).
Overall, these results show that peripheral modulation of T cell responses is a promising approach for rebalancing innate neuroinflammatory responses towards beneficial neuroinflammation in AD and possibly other neurodegenerative disorders. Among these strategies, Tregs amplification with low-dose IL-2 therapy is well-tolerated clinically in multiple disease settings, emphasizing its high potential for a rapid transition to clinical trials in neurodegenerative diseases. Furthermore, our studies suggest that such approaches may yield beneficial effects on cognitive function, without a major impact on pathogenic protein deposition. This is why immunomodulation approaches targeting T cells appear to be an innovative third-generation immunotherapy strategy in AD and neurodegenerative diseases, non-redundant with current approaches designed to neutralize and/or promote the removal of pathogenic protein species.

• Our clinical studies on the role of PMNs in AD have demonstrated a shift in their inflammatory properties and altered homeostasis of circulating PMNs in AD patients, both of which are associated with rapid progression of cognitive decline. These data emphasize that a better understanding of the role played by this still-neglected innate immune population in AD is crucial to fully decipher the complex neuroimmune interactions and inflammatory processes that contribute to the pathophysiology of the disease. Our findings strongly suggest that peripheral PMNs phenotype could be a novel blood-based prognostic biomarker in AD patients (Dong et al, Annals Neurol, 2018).

• Our recent studies indicate that during acute ischemic stroke, the inflammatory properties of circulating PMNs increase, in combination with the expansion of detrimental PMN subpopulations. These changes in PMN homeostasis, associated with disease severity, may play a critical role by contributing to systemic inflammation and blood-brain barrier damage. These results offer new prospects for the development of innovative immunotherapy strategies for acute ischemic stroke based on PMN modulation. (Weisenburger et al, Neurol Neuroimmunol Neuroinflamm, in press).

•We have recently developed a multiparametric serological test defining anti-Ab antibodies as potential diagnostic biomarkers for inflammatory and hemorrhagic forms of CAA (Chantra et al, Annals Neurol, in review). This breakthrough is of major clinical interest, as no such biomarkers for complications of CAA are currently available.

St. Antoine Hospital

Kourilsky Building
34 rue Crozatier - 75012 Paris

Sorbonne Université Medicine
Saint-Antoine Site
27 rue Chaligny - 75012 Paris

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