Immune system and neuroinflammation

Guillaume Dorothée
Team Leader : Guillaume Dorothée
Administrative contact : Maryse Nana

Hôpital Saint-Antoine – Bâtiment Kourilsky – 3ème étage
34 rue Crozatier – 75571 PARIS cedex 12

Accumulating evidence support a key instrumental involvement of brain innate neuroinflammation and peripheral immunity in neurodegenerative diseases and other neurological disorders. Our studies aim at addressing the role of recently emerging aspects of innate and adaptive neuroimmune interactions in the pathophysiology of Alzheimer’s disease (AD) and Tauopathies, as well as other neuroinflammatory and/or neurovascular conditions (cerebral amyloid angiopathy (CAA), stroke, epilepsy). Our research strategy is based on a translational approach combining a) pre-clinical studies in transgenic mouse models, b) joint clinical studies with the Neurology department of Memory and Language Disorders (Pr. Marie Sarazin, Hôpital Sainte-Anne, Paris), Service Hospitalier Frédéric Jolio (Dr Michel Bottlaender, CEA, Orsay), and the department of Neurology and Neurovascular Emergencies (Pr. Sonia Alamowitch, Hôpital Saint-Antoine, Paris).

Our research program is composed of four work packages: i) WP1 aims at deciphering the interplay of T-cell immunity and innate neuroinflammation in the pathophysiology ofAD and other Tauopathies, and developing T-cell-targeting immunotherapy approaches and related biomarkers; ii) WP2 focuses on studying the impact of early neuroinflammatory processes on neuronal function in AD; iii) WP3 addresses the role and biomarker value of polymorphonuclear neutrophils (PMNs) in the pathophysiology of AD, stroke and epilepsy; iv) WP4 aims at defining and validating candidate serological biomarkers in CAA, using innovative multiparametric analyses.

Overall, our studies aim at better understanding the role of neuroimmune interactions in the pathophysiology of neurodegeneration and other neuroinflammatory disorders, with the goal of developing and evaluating innovative disease-modifying immunotherapy approaches, as well as diagnostic and/or prognostic blood-based immune biomarkers.

Keywords:

Neuroinflammation; neurodegeneration; 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 showed that regulatory T cells (Tregs) critically control Aβ-specific CD4+ T cell responses in both physiological settings and in the context of amyloid pathology (Toly-Ndour et al, J Immunol, 2011). More recently, we further evidenced the beneficial role of Tregs in the pathophysiology of AD-like amyloid pathology. Our study showed that peripheral modulation of Tregs impact on the rate of disease progression, at least partially by restraining the development of detrimental innate neuroinflammatory responses associated with amyloid deposition. Our work was the first to show the therapeutic potential in AD-like pathology of Treg-targeting immunomodulatory approach based on low-dose IL-2 treatment (Dansokho et al, Brain, 2016). Our collaborative studies addressing the role of T cells in the context of Tau pathology, carried out with David Blum and Luc Buée (INSERM UMR 1172, Lille), further suggested that Tau pathology may drive T-cell-mediated detrimental processes, which contribute to promote Tau-related cognitive deficits and detrimental innate neuroinflammatory responses in a vicious amplification cycle (Laurent et al, Brain, 2017). Furthermore, we contributed to clinical studies that provide evidence of early and beneficial neuroinflammation in the brain of patients with AD (Hamelin et al, Brain, 2016), as well as distinct dynamic profiles of microglial activation that correlate with the rate of cognitive decline in AD patients (Hamelin et al, Brain, 2018).

Altogether, these findings highlight that peripheral modulation of T cell responses is a promising approach for rebalancing innate neuroinflammatory responses towards beneficial neuroinflammation in AD and potentially other neurodegenerative disorders. Among such strategies, amplification of Tregs throughlow-dose IL-2 treatment was shown to be clinically well tolerated in several human pathological settings, which underlines its high potential for rapid translation to clinical trials in neurodegeneration. Of note, our studies suggest that such approaches may translate into beneficial effects on cognitive functions without significantly impacting on pathological protein deposition. Thus, T-cell targeting immunomodulatory approaches appear as an innovative third generation immunotherapy strategy in AD and neurodegeneration, non-redundant with current approaches aimed at neutralizing and/or promoting clearance of pathological protein species.

- Our clinical studies on PMNs in neurodegeneration evidenced a shift in their inflammatory properties and an altered homeostasis of circulating PMNs in AD patients, which is associated with the rate of cognitive decline. These data underline the crucial need for better understanding the role of this previously overlooked innate immune population in AD, for fully deciphering the complex neuroimmune interactions and inflammatory processes that contribute to the pathophysiology of AD. Importantly, our study suggests that peripheral PMNs phenotype may constitute an innovative prognostic blood biomarker in AD patients (Dong et al, Annals Neurol, 2018).

- We evidenced that during acute ischemic strokes, the inflammatory properties of circulating PMNs rise, in association with the expansion of harmful PMNs subsets. These changes in PMNs homeostasis, associated with disease severity, may play an instrumental role by contributing to systemic inflammation and to the breakdown of blood-brain barrier. These findings open new perspectives in the development of innovative immunotherapy strategies in acute ischemic strokes, based on modulation of PMNs (Weisenburger et al, Neurol Neuroimmunol Neuroinflamm, in press).

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

Saint-Antoine
Research Center
UMR_S 938

Hôpital St-Antoine

Contact

Phone : +(33) 1 49 28 46 00