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1. Treatment of COVID-19-associated ARDS with umbilical cord-derived mesenchymal stromal cells in the STROMA-CoV-2 multicenter randomized double-blind trial: long-term safety, respiratory function, and quality of life

Author

Alexandre Sitbon, Caroline Hauw-Berlemont, Miryam Mebarki, Nicholas Heming, Julien Mayaux, Jean-Luc Diehl, Alexandre Demoule, Djillali Annane, Clémence Marois, Sophie Demeret, Emmanuel Weiss, Guillaume Voiriot, Muriel Fartoukh, Jean‐Michel Constantin, Bruno Mégarbane, Gaëtan Plantefève, Hélène Boucher-Pillet, Guillaume Churlaud, Audrey Cras, Camille Maheux, Chloé Pezzana, Mamadou Hassimiou Diallo, Said Lebbah, Jacques Ropers, Joe-Elie Salem, Christian Straus, Philippe Menasché, Jérôme Larghero, Antoine Monsel, and APHP STROMA–CoV‐2 Collaborative Research Group

Subjects
Severe acute respiratory syndrome coronavirus‐2, Acute respiratory distress syndrome, Umbilical cord‐ derived mesenchymal stromal cells, Long-term outcomes, Follow-up Studies, Quality of Life at six and twelve months after hospital discharge, Medicine (General), R5-920, Biochemistry, QD415-436
Abstract

Abstract Background The STROMA-CoV-2 study was a French phase 2b, multicenter, double-blind, randomized, placebo-controlled clinical trial that did not identify a significant efficacy of umbilical cord-derived mesenchymal stromal cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome. Safety on day 28 was found to be good. The aim of our extended study was to assess the 6- and 12-month safety of UC-MSCs administration in the STROMA-CoV-2 cohort. Methods A detailed multi-domain assessment was conducted at 6 and 12 months following hospital discharge focusing on adverse events, lung computed tomography-scan, pulmonary and muscular functional status, and quality of life in the STROMA-CoV-2 cohort including SARS–CoV-2-related early (

Published
2024
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2. Endothelial CD34 expression and regulation of immune cell response in-vitro

Author

Lousineh Arakelian, Julien Lion, Guillaume Churlaud, Rezlene Bargui, Briac Thierry, Evelyne Mutabazi, Patrick Bruneval, Antonio José Alberdi, Christelle Doliger, Maëva Veyssiere, Jérôme Larghero, and Nuala Mooney

Subjects
Medicine, Science
Abstract

Abstract Endothelial cells cover the lining of different blood vessels and lymph nodes, and have major functions including the transport of blood, vessel homeostasis, inflammatory responses, control of transendothelial migration of circulating cells into the tissues, and formation of new blood vessels. Therefore, understanding these cells is of major interest. The morphological features, phenotype and function of endothelial cells varies according to the vascular bed examined. The sialomucin, CD34, is widely used as an endothelial marker. However, CD34 is differentially expressed on endothelial cells in different organs and in pathological conditions. Little is known about regulation of endothelial CD34 expression or function. Expression of CD34 is also strongly regulated in-vitro in endothelial cell models, including human umbilical vein endothelial cells (HUVEC) and endothelial colony forming cells (ECFC). We have therefore analysed the expression and function of CD34 by comparing CD34high and CD34low endothelial cell subpopulations. Transcriptomic analysis showed that CD34 gene and protein expressions are highly correlated, that CD34high cells proliferate less but express higher levels of IL-33 and Angiopoietin 2, compared with CD34low cells. Higher secretion levels of IL-33 and Angiopoietin 2 by CD34high HUVECs was confirmed by ELISA. Finally, when endothelial cells were allowed to interact with peripheral blood mononuclear cells, CD34high endothelial cells activated stronger proliferation of regulatory T lymphocytes (Tregs) compared to CD34low cells whereas expansion of other CD4+-T cell subsets was equivalent. These results suggest that CD34 expression by endothelial cells in-vitro associates with their ability to proliferate and with an immunogenic ability that favours the tolerogenic response.

Published
2023
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3. Therapeutic potential of extracellular vesicles derived from cardiac progenitor cells in rodent models of chemotherapy-induced cardiomyopathy

Author

Manon Desgres, Bruna Lima Correa, Lorena Petrusca, Gwennhael Autret, Chloé Pezzana, Céline Marigny, Chloé Guillas, Valérie Bellamy, José Vilar, Marie-Cécile Perier, Florent Dingli, Damarys Loew, Camille Humbert, Jérôme Larghero, Guillaume Churlaud, Nisa Renault, Pierre Croisille, Albert Hagège, Jean-Sébastien Silvestre, and Philippe Menasché

Subjects
cardiovascular progenitor, extracellular vesicles, chemotherapy-induced cardiomyopathy, cardiac strain, cardio-oncology, regenerative medicine, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundCurrent treatments of chemotherapy-induced cardiomyopathy (CCM) are of limited efficacy. We assessed whether repeated intravenous injections of human extracellular vesicles from cardiac progenitor cells (EV-CPC) could represent a new therapeutic option and whether EV manufacturing according to a Good Manufacturing Practices (GMP)-compatible process did not impair their bioactivity.MethodsImmuno-competent mice received intra-peritoneal injections (IP) of doxorubicin (DOX) (4 mg/kg each; cumulative dose: 12 mg/kg) and were then intravenously (IV) injected three times with EV-CPC (total dose: 30 billion). Cardiac function was assessed 9–11 weeks later by cardiac magnetic resonance imaging (CMR) using strain as the primary end point. Then, immuno-competent rats received 5 IP injections of DOX (3 mg/kg each; cumulative dose 15 mg/kg) followed by 3 equal IV injections of GMP-EV (total dose: 100 billion). Cardiac function was assessed by two dimensional-echocardiography.ResultsIn the chronic mouse model of CCM, DOX + placebo-injected hearts incurred a significant decline in basal (global, epi- and endocardial) circumferential strain compared with sham DOX-untreated mice (p = 0.043, p = 0.042, p = 0.048 respectively) while EV-CPC preserved these indices. Global longitudinal strain followed a similar pattern. In the rat model, IV injections of GMP-EV also preserved left ventricular end-systolic and end-diastolic volumes compared with untreated controls.ConclusionsIntravenously-injected extracellular vesicles derived from CPC have cardio-protective effects which may make them an attractive user-friendly option for the treatment of CCM.

Published
2023
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4. Treatment of COVID-19-associated ARDS with mesenchymal stromal cells: a multicenter randomized double-blind trial

Author

Antoine Monsel, Caroline Hauw-Berlemont, Miryam Mebarki, Nicholas Heming, Julien Mayaux, Otriv Nguekap Tchoumba, Jean-Luc Diehl, Alexandre Demoule, Djillali Annane, Clémence Marois, Sophie Demeret, Emmanuel Weiss, Guillaume Voiriot, Muriel Fartoukh, Jean-Michel Constantin, Bruno Mégarbane, Gaëtan Plantefève, Stéphanie Malard-Castagnet, Sonia Burrel, Michelle Rosenzwajg, Nicolas Tchitchek, Hélène Boucher-Pillet, Guillaume Churlaud, Audrey Cras, Camille Maheux, Chloé Pezzana, Mamadou Hassimiou Diallo, Jacques Ropers, Philippe Menasché, Jérôme Larghero, and APHP STROMA–CoV-2 Collaborative Research Group

Subjects
Severe acute respiratory syndrome coronavirus-2, Acute respiratory distress syndrome, Umbilical cord-derived mesenchymal stromal cells, Good-manufacturing practice, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS–CoV-2-induced ARDS. Methods This multicentre, double-blind, randomized, placebo-controlled trial (STROMA–CoV-2) recruited adults (≥ 18 years) with SARS–CoV-2-induced early (

Published
2022
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5. Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases

Author

Miryam Mebarki, Nathan Iglicki, Céline Marigny, Camille Abadie, Claire Nicolet, Guillaume Churlaud, Camille Maheux, Hélène Boucher, Antoine Monsel, Philippe Menasché, Jérôme Larghero, Lionel Faivre, and Audrey Cras

Subjects
Human umbilical cord, Mesenchymal stromal cells, Immunomodulation, Inflammation, Advanced therapy medicinal product, Good manufacturing practice, Medicine (General), R5-920, Biochemistry, QD415-436
Abstract

Abstract Background Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) revealed their key role in immune regulation, offering promising therapeutic perspectives for immune and inflammatory diseases. We aimed to develop a production process of an UC-MSC-based product and then to characterize UC-MSC properties and immunomodulatory activities in vitro, related to their clinical use and finally, to transfer this technology to a good manufacturing practice (GMP) compliant facility, to manufacture an advanced therapy medicinal product (ATMP). Methods Fifteen human umbilical cords (UCs) were collected to develop the production process. Three batches of UC-MSCs from a single donor were characterized at basal state and after in vitro pro-inflammatory stimulation by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Proliferation, immunophenotype, activation markers’ expression and the inhibition of T cell proliferation were assessed. Finally, this technology was transferred to a GMP-compliant facility to manufacture an UC-MSC-based ATMP, from a single donor, using the explant method followed by the establishment of master and work cell stocks. Results Twelve UCs were processed successfully allowing to isolate UC-MSCs with doubling time and population doubling remaining stable until passage 4. CD90, CD105, CD73, CD44, CD29, CD166 expression was positive; CD14, CD45, CD31, HLA-DR, CD40, CD80 and CD86 expression was negative, while CD146 and HLA-ABC expression was heterogeneous. Cell morphology, proliferation and immunophenotype were not modified by inflammatory treatment. Indoleamine 2,3-dioxygenase (IDO) expression was significantly induced by IFNγ and IFNγ + TNFα versus non-treated cells. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression was induced significantly after priming. T cell proliferation was significantly decreased in the presence of UC-MSCs in a dose-dependent manner. This inhibitory effect was improved by IFNγ or IFNγ + TNFα, at UC-MSCs:PBMC ratio 1:10 and 1:30, whereas only IFNγ allowed to decrease significantly T cell proliferation at ratio 1:100. The manufacturing process of the UC-MSC-based ATMP was qualified and authorized by the French regulatory agency for clinical use (NCT04333368). Conclusion This work allowed to develop an investigational UC-MSC-based ATMP authorized for clinical use. Our results showed that an inflammatory environment preserves the biological properties of UC-MSCs with an improvement of their immunomodulatory functions.

Published
2021
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6. Low-dose IL-2 shapes a tolerogenic gut microbiota that improves autoimmunity and gut inflammation

Author

Nicolas Tchitchek, Otriv Nguekap Tchoumba, Gabriel Pires, Sarah Dandou, Julien Campagne, Guillaume Churlaud, Gwladys Fourcade, Thomas W. Hoffmann, Francesco Strozzi, Camille Gaal, Christophe Bonny, Emmanuelle Le Chatelier, Stanislav Dusko Erlich, Harry Sokol, and David Klatzmann

Subjects
Autoimmunity, Therapeutics, Medicine
Abstract

Gut microbiota dysbiosis is associated with inflammatory bowel diseases and with cardiometabolic, neurological, and autoimmune diseases. Gut microbiota composition has a direct effect on the immune system, and vice versa, and it has a particular effect on Treg homeostasis. Low-dose IL-2 (IL-2LD) stimulates Tregs and is a promising treatment for autoimmune and inflammatory diseases. We aimed to evaluate the impact of IL-2LD on gut microbiota and correlatively on the immune system. We used 16S ribosomal RNA profiling and metagenomics to characterize gut microbiota of mice and humans treated or not with IL-2LD. We performed fecal microbiota transplantation (FMT) from IL-2LD–treated to naive recipient mice and evaluated its effects in models of gut inflammation and diabetes. IL-2LD markedly affected gut microbiota composition in mice and humans. Transfer of an IL-2–tuned microbiota by FMT protected C57BL/6J mice from dextran sulfate sodium–induced colitis and prevented diabetes in NOD mice. Metagenomic analyses highlighted a role for several species affected by IL-2LD and for microbial pathways involved in the biosynthesis of amino acids, short-chain fatty acids, and L-arginine. Our results demonstrate that IL-2LD induced changes in gut microbiota that are involved in the immunoregulatory effects of IL-2LD and suggest a crosstalk between Tregs and gut microbiota. These results provide potentially novel insight for understanding the mode of action of Treg-directed therapies.

Published
2022
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7. Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice

Author

Berglind Bergmann, Ying Fei, Pernilla Jirholt, Zhicheng Hu, Maria Bergquist, Abukar Ali, Catharina Lindholm, Olov Ekwall, Guillaume Churlaud, David Klatzmann, Tao Jin, and Inger Gjertsson

Subjects
T regulatory cells, Tregs, IL2, S. aureus, Arthritis, Mice, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis. Methods C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. Results Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host’s ability to clear the infection. Conclusions Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.

Published
2020
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8. Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells.

Author

Michel Lecendreux, Guillaume Churlaud, Fabien Pitoiset, Armelle Regnault, Tu Anh Tran, Roland Liblau, David Klatzmann, and Michelle Rosenzwajg

Subjects
Medicine, Science
Abstract

Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (

Published
2017
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9. Treatment of COVID-19-associated ARDS with mesenchymal stromal cells: a multicenter randomized double-blind trial

Author

Antoine, Monsel, Caroline, Hauw-Berlemont, Miryam, Mebarki, Nicholas, Heming, Julien, Mayaux, Otriv, Nguekap Tchoumba, Jean-Luc, Diehl, Alexandre, Demoule, Djillali, Annane, Clémence, Marois, Sophie, Demeret, Emmanuel, Weiss, Guillaume, Voiriot, Muriel, Fartoukh, Jean-Michel, Constantin, Bruno, Mégarbane, Gaëtan, Plantefève, Stéphanie, Malard-Castagnet, Sonia, Burrel, Michelle, Rosenzwajg, Nicolas, Tchitchek, Hélène, Boucher-Pillet, Guillaume, Churlaud, Audrey, Cras, Camille, Maheux, Chloé, Pezzana, Mamadou Hassimiou, Diallo, Jacques, Ropers, Philippe, Menasché, Jérôme, Larghero, Corinne, Vezinet, HAL UVSQ, Équipe, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Raymond Poincaré [AP-HP], Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aigüE [CHU Pitié-Salpêtrière] (GRC RESPIRE), Hôpital Beaujon [AP-HP], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Tenon [AP-HP], Sorbonne Université (SU), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Centre Hospitalier Victor Dupouy, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Innovations thérapeutiques en hémostase (IThEM - U1140), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and APHP STROMA–CoV-2 Collaborative Research Group: Déborah Benchetrit, Harold Bonvallot, Fanny Charbonnier-Beaupel, Meriem Dhib-Charfi, Pierre Romain Delmotte, Assitan Kone, Marine Le Corre, Anne-Geneviève Marcelin, Carole Metz, Louis Puybasset, Joe-Elie Salem, Corinne Vezinet

Subjects
Respiratory Distress Syndrome, Acute respiratory distress syndrome, SARS-CoV-2, [SDV]Life Sciences [q-bio], COVID-19, Mesenchymal Stem Cells, Good-manufacturing practice, Critical Care and Intensive Care Medicine, Severe acute respiratory syndrome coronavirus-2, [SDV] Life Sciences [q-bio], Treatment Outcome, Double-Blind Method, Humans, Umbilical cord-derived mesenchymal stromal cells
Abstract

Background Severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS–CoV-2-induced ARDS. Methods This multicentre, double-blind, randomized, placebo-controlled trial (STROMA–CoV-2) recruited adults (≥ 18 years) with SARS–CoV-2-induced early (6 UC-MSCs/kg or placebo (0.9% NaCl) over 5 days after recruitment. For the modified intention-to-treat population, the primary endpoint was the partial pressure of oxygen to fractional inspired oxygen (PaO2/FiO2)-ratio change between baseline (day (D) 0) and D7. Results Among the 107 patients screened for eligibility from April 6, 2020, to October 29, 2020, 45 were enrolled, randomized and analyzed. PaO2/FiO2 changes between D0 and D7 did not differ significantly between the UC-MSCs and placebo groups (medians [IQR] 54.3 [− 15.5 to 93.3] vs 25.3 [− 33.3 to 104.6], respectively; ANCOVA estimated treatment effect 7.4, 95% CI − 44.7 to 59.7; P = 0.77). Six (28.6%) of the 21 UC-MSCs recipients and six of 24 (25%) placebo-group patients experienced serious adverse events, none of which were related to UC-MSCs treatment. Conclusions D0-to-D7 PaO2/FiO2 changes for intravenous UC-MSCs-versus placebo-treated adults with SARS–CoV-2-induced ARDS did not differ significantly. Repeated UC-MSCs infusions were not associated with any serious adverse events during treatment or thereafter (until D28). Larger trials enrolling patients earlier during the course of their ARDS are needed to further assess UC-MSCs efficacy in this context. Trial registration: NCT04333368. Registered 01 April 2020, https://clinicaltrials.gov/ct2/history/NCT04333368.

Published
2021
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10. Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice

Author

Pierre Barennes, Paul-Gydeon Ritvo, Hang P. Pham, Vanessa Mhanna, Valentin Quiniou, Encarnita Mariotti-Ferrandiz, Guillaume Churlaud, Bruno Gouritin, Faustine Brimaud, Gwladys Fourcade, Adrien Six, David Klatzmann, Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Gestionnaire, Hal Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP]

Subjects
0301 basic medicine, Male, Regulatory T cell, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Receptors, Antigen, T-Cell, 030209 endocrinology & metabolism, Nod, Biology, T-Lymphocytes, Regulatory, 03 medical and health sciences, Mice, 0302 clinical medicine, Antigen, Mice, Inbred NOD, Internal Medicine, medicine, Animals, Receptor, NOD mice, Autoimmune disease, Effector, T-cell receptor, medicine.disease, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Diabetes Mellitus, Type 1, Immunology, Interleukin-2, Female
Abstract

Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic b cells by auto-reactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in non‑obese diabetic (NOD) mice. We investigated the contribution to diabetes of the TCR repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. IL-2 administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2 expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.

Published
2021
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11. Regulatory T cell/Th17 balance in the pathogenesis of paediatric Behçet disease

Author

Pierre Corbeau, Isabelle Koné-Paut, Michelle Rosenzwajg, Renaud Cezar, Alexia Letierce, Anne Filleron, Audrey Hubert, Tu Anh Tran, David Saadoun, and Guillaume Churlaud

Subjects
0301 basic medicine, Male, Adolescent, Regulatory T cell, T cell, chemical and pharmacologic phenomena, T-Lymphocytes, Regulatory, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Antigen, Interferon, Medicine, Humans, Pharmacology (medical), Child, 030203 arthritis & rheumatology, business.industry, Behcet Syndrome, Interleukin, hemic and immune systems, CD4 Lymphocyte Count, 030104 developmental biology, medicine.anatomical_structure, T cell differentiation, Case-Control Studies, Child, Preschool, Immunology, Th17 Cells, Female, business, CD8, medicine.drug
Abstract

Objectives Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown aetiology. The aim of this study was to determine the orientation of T cell subpopulations in paediatric BD and more precisely to look for a regulatory T lymphocyte (Treg)/Th17 imbalance. Methods T cell subpopulations were analysed by flow cytometry in the peripheral blood of paediatric patients with acute BD (aBD; n = 24), remitting BD (rBD; n = 12) and in healthy controls (HCs; n = 24). Tregs (CD4+CD25hiCD127−/loFoxp3+), activated Tregs (GITR, LAP, CTLA-4 and HLA-DR expression), CD4+ and CD8+ T cells producing IFN-γ (Th1 and Tc1) or IL-17 (Th17 and Tc17) under polyclonal (OKT3/IL-2) or antigenic (Streptococcus sanguis KTH-1 peptides and heat shock protein 60) stimulation were enumerated. Results Th17 (1.9- and 5.1-fold) and Tc17 (4.0- and 2.0-fold) frequency under mitogenic stimulation was significantly increased in aBD and rBD patients as compared with HCs. Th17 frequency under antigenic stimulation was also higher in patients than in HCs. The percentage and number of Tregs and activated Tregs in patients and in HCs were similar. However, when Tregs were removed, antigen-driven differentiation into Th1 and Th17 was significantly boosted in BD but not in HC CD4+ T cells. Conclusion There is a bias towards Th17 polarization in aBD and rBD in children. Although we did not observe an increase in the number of Tregs in these patients, their Tregs limit CD4+ T cell differentiation into Th1 and Th17 cells. Thus, in paediatric BD, Tregs seem to incompletely counterbalance a Th17 orientation of the Th cell response.

Published
2021

12. Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice

Author

David Klatzmann, Encarnita Mariotti-Ferrandiz, Adrien Six, Guillaume Churlaud, Bruno Gouritin, Faustine Brimaud, Paul-Gydeon Ritvo, Hang P. Pham, Valentin Quiniou, Pierre Barennes, Gwladys Fourcade, Vanessa Mhanna, and Ada Admin

Abstract

Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic b cells by auto-reactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in non‑obese diabetic (NOD) mice. We investigated the contribution to diabetes of the TCR repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. IL-2 administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2 expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.

Published
2021
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13. Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice

Author

Maria Bergquist, Olov Ekwall, Ying Fei, Abukar Ali, Inger Gjertsson, Tao Jin, David Klatzmann, Pernilla Jirholt, Berglind Bergmann, Zhicheng Hu, Guillaume Churlaud, Catharina Lindholm, Sahlgrenska Academy at University of Gothenburg [Göteborg], Guizhou Medical University (贵州医科大学), Centre d’Investigation Clinique intégré en Biothérapies et immunologie [AP-HP pitié-salpêtrière, Paris] (CIC-BTi), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], This work was supported by grants from Göteborg Medical Society, Swedish Science Research Council, Reumatikerförbundet (The Swedish Rheumatism Association), King Gustav V Stiftelse, IngaBritt och Arne Lundbergs Stiftelse, Lundgrens Stiftelse, Amlövs Stiftelse, Swedish Medical Society and National Natural Science Foundation of China (grant 81460334 to Y. Fei). Open access funding provided by University of Gothenburg., Biotherapy [Paris] (CIC-BTi), CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapie (I3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Bodescot, Myriam, Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP]

Subjects
Male, 0301 basic medicine, Genetic enhancement, Arthritis, medicine.disease_cause, T-Lymphocytes, Regulatory, Mice, 0302 clinical medicine, Medicine, 030212 general & internal medicine, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, biology, Antibodies, Monoclonal, hemic and immune systems, Dependovirus, Recombinant Proteins, 3. Good health, Infectious Diseases, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Staphylococcus aureus, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, Research Article, medicine.drug, Interleukin 2, [SDV.IMM] Life Sciences [q-bio]/Immunology, T regulatory cells, Genetic Vectors, chemical and pharmacologic phenomena, Tregs, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Immune system, Animals, lcsh:RC109-216, Arthritis, Infectious, IL2, business.industry, Weight change, Interleukin-2 Receptor alpha Subunit, Genetic Therapy, medicine.disease, S. aureus, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Immunology, biology.protein, Interleukin-2, Septic arthritis, business
Abstract

Background Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis. Methods C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. Results Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host’s ability to clear the infection. Conclusions Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.

Published
2020
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14. IL-2 antibodies in type 1 diabetes and during IL-2 therapy

Author

David Saadoun, Michelle Rosenzwajg, Dominique Valteau-Couanet, Patrice Cacoub, Guillaume Churlaud, Nathalie Chaput, David Klatzmann, and Alberto Pugliese

Subjects
0301 basic medicine, Time Factors, Endocrinology, Diabetes and Metabolism, Autoimmunity, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Internal Medicine, medicine, Immune Tolerance, Humans, Autoantibodies, Autoimmune disease, Type 1 diabetes, Il-2 therapy, biology, business.industry, Autoantibody, Human physiology, medicine.disease, Hepatitis C, Healthy Volunteers, 030104 developmental biology, Diabetes Mellitus, Type 1, Immunology, biology.protein, Interleukin-2, Antibody, business, 030217 neurology & neurosurgery
Published
2018

15. Reply: Beneficial effect of interleukin-2-based immunomodulation in Alzheimer-like pathology

Author

David Klatzmann, Sandro Alves, Nathalie Cartier, Guillaume Churlaud, Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), KLATZMANN, DAVID, Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biothérapies [CHU Pitié-Salpétrière], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Interleukin 2, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Amyloidosis, 3. Good health, Immunomodulation, Mice, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Alzheimer Disease, Memory, Immunology, Animals, Interleukin-2, Medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

International audience; No abstract available

Published
2017
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16. Lymphodepletion followed by infusion of suicide gene-transduced donor lymphocytes to safely enhance their antitumor effect: a phase I/II study

Author

Felipe Suarez, Gregoire L, Rabah Redjoul, Boyer O, Catherine Cordonnier, Sébastien Maury, Nabih Azar, José Cohen, David Klatzmann, Jean-Louis Beaumont, Cabanne L, Gérard Socié, Claude C.A. Bernard, Debbache K, Aliénor Xhaard, Ambroise Marçais, Françoise Roudot-Thoraval, François M. Lemoine, Michelle Rosenzwajg, Guillaume Churlaud, and Mustapha Cherai

Subjects
Cancer Research, business.industry, medicine.medical_treatment, Treatment outcome, Lymphocyte depletion, Neoplasms therapy, Hematology, Immunotherapy, Pharmacology, Suicide gene, Donor Lymphocytes, Genetic therapy, Phase i ii, Oncology, Immunology, medicine, business
Abstract

Lymphodepletion followed by infusion of suicide gene-transduced donor lymphocytes to safely enhance their antitumor effect: a phase I/II study

Published
2014
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17. Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer

Author

Bertrand Bellier, Martin Amadoudji Zin, Fatima Bosch, David Klatzmann, Gwladys Fourcade, Veronica Jimenez, Estefania Casana, Eliane Piaggio, Guillaume Churlaud, Jesús Ruberte, Gaelle Gottrand, and Bénédicte Lambrecht

Subjects
Male, musculoskeletal diseases, Interleukin 2, Time Factors, medicine.medical_treatment, Immunology, Autoimmunity, chemical and pharmacologic phenomena, Inflammation, Biology, Infections, Lymphocyte Activation, medicine.disease_cause, T-Lymphocytes, Regulatory, Viral vector, Mice, Immune system, Mice, Inbred NOD, immune system diseases, Neoplasms, medicine, Animals, Humans, Immunology and Allergy, NOD mice, Mice, Inbred BALB C, Vaccination, Gene Transfer Techniques, hemic and immune systems, Mice, Inbred C57BL, stomatognathic diseases, HEK293 Cells, Cytokine, Gene Expression Regulation, Interleukin-2, Female, medicine.symptom, medicine.drug
Abstract

Interleukin 2 (IL2) is the key cytokine supporting survival and function of regulatory T cells (Tregs). We recently reported that low-dose IL2 safely expands/stimulates Tregs and improves autoimmune conditions in humans. Further development of IL2 in autoimmune diseases will require chronic IL2 administration, which could affect beneficial effector immune responses regulated by Tregs. We used recombinant adeno-associated viral vector (rAAV)-mediated gene transfer to continuously release IL2 in mice and assessed its long-term effects on immune responses. A single rAAV-IL2 injection enabled sustained stimulation and expansion of Tregs without inducing Teff activation and prevented diabetes in NOD mice. After several weeks of IL2 production, mice responded normally to a viral challenge and to vaccination, and had pregnancies with offspring that developed normally. They showed no change in the occurrence and growth of chemically-induced tumors. Altogether, chronic low-dose IL2 treatment does not affect beneficial effector immune responses at doses that prevent autoimmune diabetes.

Published
2014
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18. Self-Specific Memory Regulatory T Cells Protect Embryos at Implantation in Mice

Author

Tristan Courau, Guillaume Churlaud, Gérard Chaouat, Jack L. Strominger, Anne-Sophie Bergot, David Klatzmann, Maria Grazia Ruocco, Guillaume Darrasse-Jèze, Karina Valdivia, and Ting Chen

Subjects
Male, Adoptive cell transfer, Immunology, chemical and pharmacologic phenomena, Stimulation, T-Lymphocytes, Regulatory, Article, Immune tolerance, Flow cytometry, Mice, Pregnancy, Immune Tolerance, medicine, Animals, Humans, Immunology and Allergy, Embryo Implantation, Mice, Inbred BALB C, Fetus, medicine.diagnostic_test, biology, Reverse Transcriptase Polymerase Chain Reaction, CD44, hemic and immune systems, Embryo, Neoplasms, Experimental, Embryo, Mammalian, Flow Cytometry, Adoptive Transfer, Mice, Inbred C57BL, Immunosurveillance, biology.protein, Female, Immunologic Memory
Abstract

Regulatory T cells (Tregs) play crucial roles in both fetal and tumor development. We recently showed that immunosurveillance by pre-existing CD44highCD62Llow activated/memory Tregs (amTregs) specific for self-Ags protects emergent tumor cells in mice. This Treg response of a memory type is more rapid than and dominates the antitumor response of tumor-specific effector T cells. In this study, we report striking similarities between the early Treg responses to embryo and tumor implantation. Tregs are rapidly recruited to uterus-draining lymph nodes and activated in the first days after embryo implantation in both syngeneic and allogeneic matings; express the markers of the amTreg subset; and are at least in part self-Ag specific, as seen in tumor emergence. Unlike in the tumor emergence setting, however, for which preimmunization against tumor Ags is sufficient for complete tumor eradication even in the presence of Tregs, Treg depletion is additionally required for high frequencies of fetus loss after preimmunization against paternal tissue Ags. Thus, amTregs play a major role in protecting embryos in both naive and preimmune settings. This role and the ensuing therapeutic potential are further highlighted by showing that Treg stimulation, directly by low-dose IL-2 or indirectly by Fms-related tyrosine kinase 3 ligand, led to normal pregnancy rates in a spontaneous abortion-prone model.

Published
2013
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19. Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

Author

Faustine Brimaud, Fabien Pitoiset, Thomas Vazquez, David Klatzmann, Guillaume Churlaud, Bertrand Bellier, James Vigneron, Benjamin Bonnet, Béatrice Levacher, Immunologie - Immunopathologie - Immunothérapeutique (I3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Immunologie - Immunopathologie - Immunothérapie (I3), Service de biothérapies [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], KLATZMANN, DAVID, Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
0301 basic medicine, Allergy, Arachis, Regulatory T cell, Ovalbumin, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, chemical and pharmacologic phenomena, T-Lymphocytes, Regulatory, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Food allergy, medicine, Immunology and Allergy, Animals, Humans, Mast Cells, Th1-Th2 Balance, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Mice, Inbred BALB C, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Immunosuppression, Allergens, medicine.disease, Mast cell, 3. Good health, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Self Tolerance, Interleukin-2, Female, Immunotherapy, business, Food Hypersensitivity, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

Regulatory T cells (Tregs) are pivotal for maintenance of immune self-tolerance and also regulate immune responses to exogenous Ags, including allergens. Both decreased Treg number and function have been reported in allergic patients, offering new therapeutic perspectives. We previously demonstrated that Tregs can be selectively expanded and activated by low doses of IL-2 (ld-IL-2) inducing immunoregulation without immunosuppression and established its protective effect in autoimmune diseases. In this study, we evaluated the ability of ld-IL-2 to control allergy in an experimental model of food allergy. Ld-IL-2 induced Treg expansion and activation that elicited protection against clinical manifestations of food allergy in two mouse models with OVA and peanut. This clinical effect was lost in Treg-depleted mice, demonstrating the major contribution of Tregs in ld-IL-2 efficacy. Mechanistic studies further indicated that protection from allergy could be explained by a Treg-dependent local modification of the Th1/Th2 balance and an inhibition of mast cell recruitment and activation. Preventive and therapeutic effects of ld-IL-2 were observed over a 7-mo-period, highlighting its long-term efficacy. This study demonstrated that ld-IL-2 is efficient to prevent and to treat allergic immune responses, and thus represents a promising therapeutic strategy for managing allergic diseases.

Published
2016
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20. Pharmacodynamics of regulatory T cells in mice and humans treated with low-dose IL-2

Author

Roberta Lorenzon, Guillaume Churlaud, Paul-Gydeon Ritvo, David Klatzmann, Bertrand Diquet, Michelle Rosenzwajg, Pierre-Axel Vinot, Chadi Abbara, Gwladys Fourcade, Service de biothérapies [CHU Pitié-Salpétrière], Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers - Faculté de médecine (UA UFR Médecine), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Immunologie - Immunopathologie - Immunothérapie (I3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
0301 basic medicine, business.industry, [SDV]Life Sciences [q-bio], Immunology, Low dose, Pharmacology, 3. Good health, law.invention, Clinical trial, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Randomized controlled trial, law, Pharmacodynamics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, Medicine, business, ComputingMilieux_MISCELLANEOUS, 030215 immunology
Abstract

International audience

Published
2018
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21. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice

Author

Romain Fol, Kristin Michaelsen-Preusse, Martin Korte, Nathalie Cartier, Jérôme Braudeau, Sandro Alves, Guillaume Churlaud, David Klatzmann, Mickael Audrain, Benoit Souchet, Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Zoological Institute, Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig], Helmholtz Centre for Infection Research (HZI), Université Paris-Sud - Paris 11 (UP11) - Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - Institut National de la Santé et de la Recherche Médicale (INSERM), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Université Pierre et Marie Curie - Paris 6 (UPMC) - CHU Pitié-Salpêtrière [APHP], Technische Universität Braunschweig [Braunschweig], Helmholtz - Centre for Infection Research, HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany., and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Male, 0301 basic medicine, Pathology, Hippocampus, Morris water navigation task, Plaque, Amyloid, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Aldesleukin, Aged, 80 and over, Neurons, Neuronal Plasticity, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Neurodegeneration, AAV, 3. Good health, Female, Alzheimer's disease, Psychology, Antipsychotic Agents, medicine.medical_specialty, Dendritic Spines, Mice, Transgenic, Presenilin, Immunomodulation, 03 medical and health sciences, Gene therapy, Alzheimer Disease, Presenilin-1, medicine, Animals, Humans, Neuroinflammation, Aged, Memory Disorders, Excitatory Postsynaptic Potentials, medicine.disease, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, Astrocytes, Synapses, Synaptic plasticity, Interleukin-2, Neurology (clinical), Therapy, Neuroscience, 030217 neurology & neurosurgery, Immunosuppression, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Neurological diseases
Abstract

International audience; Interleukin-2 (IL-2)-deficient mice have cytoarchitectural hippocampal modifications and impaired learning and memory ability reminiscent of Alzheimer’s disease. IL-2 stimulates regulatory T cells whose role is to control inflammation. As neuroinflammation contributes to neurodegeneration, we investigated IL-2 in Alzheimer’s disease. Therefore, we investigated IL-2 levels in hippocampal biopsies of patients with Alzheimer’s disease relative to age-matched control individuals. We then treated APP/PS1ΔE9 mice having established Alzheimer’s disease with IL-2 for 5 months using single administration of an AAV-IL-2 vector. We first found decreased IL-2 levels in hippocampal biopsies of patients with Alzheimer’s disease. In mice, IL-2-induced systemic and brain regulatory T cells expansion and activation. In the hippocampus, IL-2 induced astrocytic activation and recruitment of astrocytes around amyloid plaques, decreased amyloid-β42/40 ratio and amyloid plaque load, improved synaptic plasticity and significantly rescued spine density. Of note, this tissue remodelling was associated with recovery of memory deficits, as assessed in the Morris water maze task. Altogether, our data strongly suggest that IL-2 can alleviate Alzheimer’s disease hallmarks in APP/PS1ΔE9 mice with established pathology. Therefore, this should prompt the investigation of low-dose IL-2 in Alzheimer’s disease and other neuroinflammatory/neurodegenerative disorders.

Published
2016
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22. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients

Author

Aixin Yu, Alberto Pugliese, Georgia Afonso, Wahiba Chaara, Roberto Mallone, Guillaume Churlaud, Agnès Hartemann, Nicolas Dérian, Michelle Rosenzwajg, Roberta Lorenzon, S. Alice Long, David Klatzmann, Adrien Six, Thomas R. Malek, Hang-Phuong Pham, Jane H. Buckner, Service de biothérapies [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Immunologie - Immunopathologie - Immunothérapeutique ( I3 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de diabétologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Translational Research Program, Benaroya Research Institute, Virginia Mason-Virginia Mason, ILTOO Pharma, CHU Pitié-Salpêtrière [APHP], Service de Diabétologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], The Diabetes Research Institute, University of Miami, University of Miami [Coral Gables]-University of Miami [Coral Gables], Department of Microbiology and Immunology, Department of Medicine, Miller School of Medicine, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapeutique (I3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Miami Leonard M. Miller School of Medicine (UMMSM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de diabétologie [CHU Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Diabétologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Administateur, HAL Sorbonne Université

Subjects
Male, medicine.medical_treatment, Lymphocyte Activation, T-Lymphocytes, Regulatory, T-Lymphocyte Subsets, Insulin-Secreting Cells, STAT5 Transcription Factor, Immunology and Allergy, Drug Dosage Calculations, IL-2 receptor, Cells, Cultured, FOXP3, Forkhead Transcription Factors, hemic and immune systems, Middle Aged, 3. Good health, medicine.anatomical_structure, Cytokines, Female, Immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.drug, Adult, Interleukin 2, Adolescent, Regulatory T cell, CD8 Antigens, Immunology, chemical and pharmacologic phenomena, [ SDV.IMM.IMM ] Life Sciences [q-bio]/Immunology/Immunotherapy, Immunopathology, Biology, Article, Young Adult, Immune system, Antigen, Glucocorticoid-Induced TNFR-Related Protein, medicine, Humans, Pharmacokinetics, Immunosuppression Therapy, Inflammation, Dose-Response Relationship, Drug, Interleukin-2 Receptor alpha Subunit, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Diabetes Mellitus, Type 1, Interleukin-2, Transcriptome, Tolerance, CD8
Abstract

International audience; Most autoimmune diseases (AID) are linked to an imbalance between autoreactive effector T cells (Teffs) and regulatory T cells (Tregs). While blocking Teffs with immunosuppression has long been the only therapeutic option, activating/expanding Tregs may achieve the same objective without the toxicity of immunosuppression. We showed that low-dose interleukin-2 (ld-IL-2) safely expands/activates Tregs in patients with AID, such HCV-induced vasculitis and Type 1 Diabetes (T1D). Here we analyzed the kinetics and dose-relationship of IL-2 effects on immune responses in T1D patients. Ld-IL-2 therapy induced a dose-dependent increase in CD4+Foxp3+ and CD8+Foxp3+ Treg numbers and proportions, the duration of which was markedly dose-dependent. Tregs expressed enhanced levels of activation markers, including CD25, GITR, CTLA-4 and basal pSTAT5, and retained a 20-fold higher sensitivity to IL-2 than Teff and NK cells. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and Th17 inflammatory cells were mostly unchanged. Global transcriptome analyses showed a dose-dependent decrease in immune response signatures. At the highest dose, Teff responses against beta-cell antigens were suppressed in all 4 patients tested. These results inform of broader changes induced by ld-IL-2 beyond direct effects on Tregs, and relevant for further development of ld-IL-2 for therapy and prevention of T1D, and other autoimmune and inflammatory diseases.

Published
2015
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23. Human and Mouse CD8(+)CD25(+)FOXP3(+) Regulatory T Cells at Steady State and during Interleukin-2 Therapy

Author

Guillaume, Churlaud, Fabien, Pitoiset, Fadi, Jebbawi, Roberta, Lorenzon, Bertrand, Bellier, Michelle, Rosenzwajg, and David, Klatzmann

Subjects
T cell biology, Immunology, autoimmunity, chemical and pharmacologic phenomena, hemic and immune systems, immunotherapy, immunological tolerance, immune response, Original Research
Abstract

In addition to CD4(+) regulatory T cells (Tregs), CD8(+) suppressor T cells are emerging as an important subset of regulatory T cells. Diverse populations of CD8(+) T cells with suppressive activities have been described. Among them, a small population of CD8(+)CD25(+)FOXP3(+) T cells is found both in mice and humans. In contrast to thymic-derived CD4(+)CD25(+)FOXP3(+) Tregs, their origin and their role in the pathophysiology of autoimmune diseases (AIDs) are less understood. We report here the number, phenotype, and function of CD8(+) Tregs cells in mice and humans, at the steady state and in response to low-dose interleukin-2 (IL-2). CD8(+) Tregs represent approximately 0.4 and 0.1% of peripheral blood T cells in healthy humans and mice, respectively. In mice, their frequencies are quite similar in lymph nodes (LNs) and the spleen, but two to threefold higher in Peyer patches and mesenteric LNs. CD8(+) Tregs express low levels of CD127. CD8(+) Tregs express more activation or proliferation markers such as CTLA-4, ICOS, and Ki-67 than other CD8(+) T cells. In vitro, they suppress effector T cell proliferation as well as or even better than CD4(+) Tregs. Owing to constitutive expression of CD25, CD8(+) Tregs are 20- to 40-fold more sensitive to in vitro IL-2 stimulation than CD8(+) effector T cells, but 2-4 times less than CD4(+) Tregs. Nevertheless, low-dose IL-2 dramatically expands and activates CD8(+) Tregs even more than CD4(+) Tregs, in mice and humans. Further studies are warranted to fully appreciate the clinical relevance of CD8(+) Tregs in AIDs and the efficacy of IL-2 treatment.

Published
2014

24. Interleukin 2 in the pathogenesis and therapy of type 1 diabetes

Author

Michelle Rosenzwajg, David Klatzmann, Agnès Hartemann, and Guillaume Churlaud

Subjects
Autoimmune disease, Interleukin 2, Type 1 diabetes, Clinical Trials as Topic, Effector, business.industry, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Dose-Response Relationship, Immunologic, Immunosuppression, Inflammation, Immunotherapy, medicine.disease, T-Lymphocytes, Regulatory, Diabetes Mellitus, Type 1, Diabetes mellitus, Immunology, Internal Medicine, medicine, Humans, Interleukin-2, medicine.symptom, business, medicine.drug
Abstract

Regulatory T cells (Tregs) play a major role in controlling effector T cells (Teffs) responding to self-antigens, which cause autoimmune diseases. An improper Treg/Teff balance contributes to most autoimmune diseases, including type 1 diabetes (T1D). To restore a proper balance, blocking Teffs with immunosuppressants has been the only option, which was partly effective and too toxic. It now appears that expanding/activating Tregs with low-dose interleukin-2 (IL-2) could provide immunoregulation without immunosuppression. This is particularly interesting in T1D as Tregs from T1D patients are reported as dysfunctional and a relative deficiency in IL-2 production and/or IL-2-mediated signaling could contribute to this phenotype. A clinical study of low-dose IL-2 showed a very good safety profile and good Treg expansion/activation in T1D patients. This opens the way for efficacy trials to test low-dose IL-2 in prevention and treatment of T1D and to establish in which condition restoration of a proper Treg/Teff balance would be beneficial in the field of autoimmune and inflammatory diseases.

Published
2014

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