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J Autoimmun. 2015 Jan;56:66-80. doi: 10.1016/j.jaut.2014.10.002. Epub 2014 Oct 30.

Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

Author information

1
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 OXY, United Kingdom. Electronic address: charlie.bell@cimr.cam.ac.uk.
2
Former Roche Site of Pharmaceutical Research and Early Development, Discovery Inflammation, Nutley, NJ 07110, USA. Electronic address: yongliang.sun@pfizer.com.
3
Former Roche Site of Pharmaceutical Research and Early Development, Discovery Inflammation, Nutley, NJ 07110, USA. Electronic address: umn2001@med.cornell.edu.
4
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 OXY, United Kingdom. Electronic address: janclark@btinternet.com.
5
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 OXY, United Kingdom. Electronic address: sarah.howlett@cimr.cam.ac.uk.
6
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 OXY, United Kingdom. Electronic address: marcin.pekalski@cimr.cam.ac.uk.
7
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 OXY, United Kingdom. Electronic address: xin.yang@cimr.cam.ac.uk.
8
Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland. Electronic address: oliver.ast@roche.com.
9
Roche Pharmaceutical Research and Early Development, Oncology Discovery & Translational Area, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland. Electronic address: inja.waldhauer@roche.com.
10
Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland. Electronic address: anne.freimoser-grundschober@roche.com.
11
Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland. Electronic address: ekkehard.moessner@roche.com.
12
Roche Pharmaceutical Research and Early Development, Oncology Discovery & Translational Area, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland. Electronic address: pablo.umana@roche.com.
13
Roche Pharmaceutical Research and Early Development, Oncology Discovery & Translational Area, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland. Electronic address: christian.klein.ck1@roche.com.
14
Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Zurich, Wagistrasse 18, CH-8952 Schlieren, Switzerland. Electronic address: ralf.hosse@roche.com.
15
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 OXY, United Kingdom. Electronic address: linda.wicker@cimr.cam.ac.uk.
16
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 OXY, United Kingdom; Former Roche Site of Pharmaceutical Research and Early Development, Discovery Inflammation, Nutley, NJ 07110, USA. Electronic address: larry.peterson@cimr.cam.ac.uk.

Abstract

Regulatory T cells (Tregs) expressing FOXP3 are essential for the maintenance of self-tolerance and are deficient in many common autoimmune diseases. Immune tolerance is maintained in part by IL-2 and deficiencies in the IL-2 pathway cause reduced Treg function and an increased risk of autoimmunity. Recent studies expanding Tregs in vivo with low-dose IL-2 achieved major clinical successes highlighting the potential to optimize this pleiotropic cytokine for inflammatory and autoimmune disease indications. Here we compare the clinically approved IL-2 molecule, Proleukin, with two engineered IL-2 molecules with long half-lives owing to their fusion in monovalent and bivalent stoichiometry to a non-FcRγ binding human IgG1. Using nonhuman primates, we demonstrate that single ultra-low doses of IL-2 fusion proteins induce a prolonged state of in vivo activation that increases Tregs for an extended period of time similar to multiple-dose Proleukin. One of the common pleiotropic effects of high dose IL-2 treatment, eosinophilia, is eliminated at doses of the IL-2 fusion proteins that greatly expand Tregs. The long half-lives of the IL-2 fusion proteins facilitated a detailed characterization of an IL-2 dose response driving Treg expansion that correlates with increasingly sustained, suprathreshold pSTAT5a induction and subsequent sustained increases in the expression of CD25, FOXP3 and Ki-67 with retention of Treg-specific epigenetic signatures at FOXP3 and CTLA4.

KEYWORDS:

Autoimmunity; Cytokine therapy; Graft versus host disease; IL-2 fusion proteins; Regulatory T cells

PMID:
25457307
PMCID:
PMC4298360
DOI:
10.1016/j.jaut.2014.10.002
[Indexed for MEDLINE]
Free PMC Article

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