title: Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients.
abstract: 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.
authors: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France.
authors: Michelle
authors: M
authors: Rosenzwajg
authors: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France.
authors: Guillaume
authors: G
authors: Churlaud
authors: Inserm, U1016, Institut Cochin, Immunology of Diabetes Team, DeAR Lab, F-75014, Paris, France; CNRS, UMR8104, F-75014, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75014, Paris, France; AP-HP, Hôpital Cochin-Port Royal, Diabetology Department, F-75014, Paris, France.
authors: Roberto
authors: R
authors: Mallone
authors: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France.
authors: Adrien
authors: A
authors: Six
authors: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France.
authors: Nicolas
authors: N
authors: Dérian
authors: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France.
authors: Wahiba
authors: W
authors: Chaara
authors: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France.
authors: Roberta
authors: R
authors: Lorenzon
authors: Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
authors: S Alice
authors: SA
authors: Long
authors: Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
authors: Jane H
authors: JH
authors: Buckner
authors: Inserm, U1016, Institut Cochin, Immunology of Diabetes Team, DeAR Lab, F-75014, Paris, France; CNRS, UMR8104, F-75014, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75014, Paris, France; AP-HP, Hôpital Cochin-Port Royal, Diabetology Department, F-75014, Paris, France.
authors: Georgia
authors: G
authors: Afonso
authors: ILTOO Pharma, iPEPS ICM, Hôpital Pitié Salpêtrière, 75013, Paris, France.
authors: Hang-Phuong
authors: HP
authors: Pham
authors: AP-HP, Hôpital Pitié-Salpêtrière, Diabetology, F-75651, Paris, France.
authors: Agnès
authors: A
authors: Hartemann
authors: The Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, University of Miami, Miami, FL, USA.
authors: Aixin
authors: A
authors: Yu
authors: The Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, University of Miami, Miami, FL, USA.
authors: Alberto
authors: A
authors: Pugliese
authors: The Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, University of Miami, Miami, FL, USA.
authors: Thomas R
authors: TR
authors: Malek
authors: AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (I2B), F-75651, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France; Inserm, UMRS 959, Immunology-Immunopathology-Immunotherapy (I3), F-75005, Paris, France. Electronic address: david.klatzmann@upmc.fr.
authors: David
authors: D
authors: Klatzmann
mesh_terms: D000293:Adolescent; D000328:Adult; D016827:CD8 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy / Q000379:methods*; D050417:Insulin-Secreting Cells / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D050799:STAT5 Transcription Factor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D059467:Transcriptome; D055815:Young Adult
chemical_list: D016827:CD8 Antigens; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D050799:STAT5 Transcription Factor; C491405:TNFRSF18 protein, human
keywords: Immunopathology; Immunotherapy; Inflammation; Pharmacokinetics; Tolerance
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