Publications by authors named "Sandra Hubert"

12 Publications

  • Page 1 of 1

Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19.

PLoS One 2021 22;16(7):e0254374. Epub 2021 Jul 22.

Servier, Research and Development, Suresnes Cedex, France.

While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1β, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254374PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297899PMC
August 2021

A new molecular classification to drive precision treatment strategies in primary Sjögren's syndrome.

Nat Commun 2021 06 10;12(1):3523. Epub 2021 Jun 10.

Institut de Recherches Internationales Servier, Departments of Translational Medicine and Immuno-Inflammatory Diseases Research and Development, Suresnes, France.

There is currently no approved treatment for primary Sjögren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials.
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http://dx.doi.org/10.1038/s41467-021-23472-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192578PMC
June 2021

Metformin Monotherapy Downregulates Diabetes-Associated Inflammatory Status and Impacts on Mortality.

Front Physiol 2019 21;10:572. Epub 2019 May 21.

Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.

Aging is the main risk factor for developing diabetes and other age-related diseases. One of the most common features of age-related comorbidities is the presence of low-grade chronic inflammation. This is also the case of metabolic syndrome and diabetes. At the subclinical level, a pro-inflammatory phenotype was shown to be associated with Type-2 diabetes mellitus (T2DM). This low to mid-grade inflammation is also present in elderly individuals and has been termed inflammaging. Whether inflammation is a component of aging or exclusively associated with age-related diseases in not entirely known. We used clinical data and biological readouts in a group of individuals stratified by age, diabetes status and comorbidities to investigate this aspect. While aging is the main predisposing factor for several diseases there is a concomitant increased level of pro-inflammatory cytokines. DM patients show an increased level of sTNFRll, sICAM-1, and TIMP-1 when compared to Healthy, Non-DM and Pre-DM individuals. These inflammatory molecules are also associated with insulin resistance and metabolic syndrome in Non-DM and pre-DM individuals. We also show that metformin monotherapy was associated with significantly lower levels of inflammatory molecules, like TNFα, sTNFRI, and sTNFRII, when compared to other monotherapies. Longitudinal follow up indicates a higher proportion of death occurs in individuals taking other monotherapies compared to metformin monotherapy. Together our finding shows that chronic inflammation is present in healthy elderly individuals and exacerbated with diabetes patients. Likewise, metformin could help target age-related chronic inflammation in general, and reduce the predisposition to comorbidities and mortality.
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http://dx.doi.org/10.3389/fphys.2019.00572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537753PMC
May 2019

A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGFα-Mediated Recruitment of Neutrophils.

Immunity 2019 04 27;50(4):1069-1083.e8. Epub 2019 Mar 27.

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Biopolis, Singapore 138648, Singapore; Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A(∗)STAR), 11 Mandalay Rd., Singapore 308232, Singapore. Electronic address:

Skin conventional dendritic cells (cDCs) exist as two distinct subsets, cDC1s and cDC2s, which maintain the balance of immunity to pathogens and tolerance to self and microbiota. Here, we examined the roles of dermal cDC1s and cDC2s during bacterial infection, notably Propionibacterium acnes (P. acnes). cDC1s, but not cDC2s, regulated the magnitude of the immune response to P. acnes in the murine dermis by controlling neutrophil recruitment to the inflamed site and survival and function therein. Single-cell mRNA sequencing revealed that this regulation relied on secretion of the cytokine vascular endothelial growth factor α (VEGF-α) by a minor subset of activated EpCAMCD59Ly-6D cDC1s. Neutrophil recruitment by dermal cDC1s was also observed during S. aureus, bacillus Calmette-Guérin (BCG), or E. coli infection, as well as in a model of bacterial insult in human skin. Thus, skin cDC1s are essential regulators of the innate response in cutaneous immunity and have roles beyond classical antigen presentation.
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http://dx.doi.org/10.1016/j.immuni.2019.03.001DOI Listing
April 2019

Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function.

Immunity 2017 07;47(1):183-198.e6

Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.

Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies.
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http://dx.doi.org/10.1016/j.immuni.2017.06.017DOI Listing
July 2017

Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2.

Nature 2017 06 14;546(7660):662-666. Epub 2017 Jun 14.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

During gestation the developing human fetus is exposed to a diverse range of potentially immune-stimulatory molecules including semi-allogeneic antigens from maternal cells, substances from ingested amniotic fluid, food antigens, and microbes. Yet the capacity of the fetal immune system, including antigen-presenting cells, to detect and respond to such stimuli remains unclear. In particular, dendritic cells, which are crucial for effective immunity and tolerance, remain poorly characterized in the developing fetus. Here we show that subsets of antigen-presenting cells can be identified in fetal tissues and are related to adult populations of antigen-presenting cells. Similar to adult dendritic cells, fetal dendritic cells migrate to lymph nodes and respond to toll-like receptor ligation; however, they differ markedly in their response to allogeneic antigens, strongly promoting regulatory T-cell induction and inhibiting T-cell tumour-necrosis factor-α production through arginase-2 activity. Our results reveal a previously unappreciated role of dendritic cells within the developing fetus and indicate that they mediate homeostatic immune-suppressive responses during gestation.
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http://dx.doi.org/10.1038/nature22795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588541PMC
June 2017

Melanoma-initiating cells exploit M2 macrophage TGFβ and arginase pathway for survival and proliferation.

Oncotarget 2014 Dec;5(23):12027-42

Singapore Immunology Network, BMSI, A-STAR, Singapore. Institut de Recherche Internationales Servier, 50 rue Carnot, Suresnes cedex, France.

M2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34- but not CD34+ tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34- TICs from chemotherapy in vitro. In vivo, while inhibition of CD115 suppressed the macrophage-dependent CD34- TIC population, chemotherapy accelerated its development. The ability of TICs to respond to TAMs was acquired during melanoma progression and immediately preceded a surge in metastatic outgrowth. TAM-derived transforming growth factor-β (TGFβ) and polyamines produced via the Arginase pathway were critical for stimulation of TICs and synergized to promote their growth.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322977PMC
http://dx.doi.org/10.18632/oncotarget.2482DOI Listing
December 2014

[The early steps of the metastatic process].

Med Sci (Paris) 2014 Apr 5;30(4):378-84. Epub 2014 May 5.

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, 8A biomedical grove, #04-06 Immunos, 138648 Singapour - Adresse actuelle : Institut de Recherches Internationales Servier, 53, rue Carnot, 92284 Suresnes, France.

Metastasis is the main cause of cancer-related death. While the development of clinically detectable metastases occurs only at late time points, recent data obtained in mice and humans indicate that cancer cell dissemination is an early event in the progression of several types of cancer. However, disseminated cancer cells can remain dormant for prolonged periods of time. Then, how do cancer cells acquire the ability to disseminate so early? What are the selective pressures driving their dissemination? What are the signals controlling dormancy and why do some cancer cells eventually escape these controls? The present review presents our current understanding on these questions and how this novel paradigm could be translated to the clinic.
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http://dx.doi.org/10.1051/medsci/20143004010DOI Listing
April 2014

Immune predictors of cancer progression.

Immunol Res 2012 Sep;53(1-3):229-34

Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #04-06 Immunos, Biopolis, Singapore.

The immune system has multiple, complex, and sometimes opposing roles during cancer progression. While immune-compromised individuals have a higher incidence of cancers, inflammation is also associated with increased risk of disease progression. It is becoming apparent that simple measures of immune responses in the blood are of limited use in cancer. Instead, the importance of the exact identity and functional characteristics of tumor-infiltrating immune cells is increasingly recognized. This realization has led to recent studies that have revealed a critical role for chemokine expression in the tumor microenvironment and suggested a therapeutic potential of manipulating intratumoral expression of chemokines to alter the local immune milieu.
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http://dx.doi.org/10.1007/s12026-012-8288-4DOI Listing
September 2012

Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.

J Exp Med 2010 Nov 25;207(12):2561-8. Epub 2010 Oct 25.

Institut National de la Santé et de la Recherche Medicale, U905, 76183 Rouen, France.

CD4(+)CD25(+)FoxP3(+) regulatory T cells (T reg cells) play a major role in the control of immune responses but the factors controlling their homeostasis and function remain poorly characterized. Nicotinamide adenine dinucleotide (NAD(+)) released during cell damage or inflammation results in ART2.2-mediated ADP-ribosylation of the cytolytic P2X7 receptor on T cells. We show that T reg cells express the ART2.2 enzyme and high levels of P2X7 and that T reg cells can be depleted by intravenous injection of NAD(+). Moreover, lower T reg cell numbers are found in mice deficient for the NAD-hydrolase CD38 than in wild-type, P2X7-deficient, or ART2-deficient mice, indicating a role for extracellular NAD(+) in T reg cell homeostasis. Even routine cell preparation leads to release of NAD(+) in sufficient quantities to profoundly affect T reg cell viability, phenotype, and function. We demonstrate that T reg cells can be protected from the deleterious effects of NAD(+) by an inhibitory ART2.2-specific single domain antibody. Furthermore, selective depletion of T reg cells by systemic administration of NAD(+) can be used to promote an antitumor response in several mouse tumor models. Collectively, our data demonstrate that NAD(+) influences survival, phenotype, and function of T reg cells and provide proof of principle that acting on the ART2-P2X7 pathway represents a new strategy to manipulate T reg cells in vivo.
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http://dx.doi.org/10.1084/jem.20091154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989765PMC
November 2010

NAD+ released during inflammation participates in T cell homeostasis by inducing ART2-mediated death of naive T cells in vivo.

J Immunol 2007 Jul;179(1):186-94

University Denis Diderot-Paris 7, EA 1556 Paris, France.

Mono ADP-ribosyltransferase 2 (ART2) is an ectoenzyme expressed on mouse T lymphocytes, which catalyze the transfer of ADP-ribose groups from NAD(+) onto several target proteins. In vitro, ADP-ribosylation by ART2 activates the P2X7 ATP receptor and is responsible for NAD(+)-induced T cell death (NICD). Yet, the origin of extracellular NAD(+) and the role of NICD in vivo remain elusive. In a model of acute inflammation induced by polyacrylamide beads, we demonstrate release of NAD(+) into exudates during the early phase of the inflammatory response. This leads to T cell depletion in the draining lymph nodes from wild-type and, more severely, from mice lacking the CD38 NAD(+) glycohydrolase, whereas no effect is observed in ART2-deficient animals. Intravenous injection of NAD(+) used to exacerbate NICD in vivo results in fast and dramatic ART2- and P2X7-dependent depletion of CD4+ and CD8+ T lymphocytes, which can affect up to 80% of peripheral T cells in CD38(-/-) mice. This affects mainly naive T cells as most cells surviving in vivo NAD+ treatment exhibit the phenotype of recently activated/memory cells. Consistently, treatment with NAD(+) abolishes primary Ab response to a T-dependent Ag in NICD-susceptible CD38(-/-) mice but has no effect on the secondary response when given several days after priming. Unexpectedly NAD+ treatment improves the response in their wild-type BALB/c counterparts. We propose that NAD(+) released during early inflammation facilitates the expansion of primed T cells, through ART2-driven death of resting cells, thus contributing to the dynamic regulation of T cell homeostasis.
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http://dx.doi.org/10.4049/jimmunol.179.1.186DOI Listing
July 2007
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