共 47 条
Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells
被引:69
作者:

Bell, Charles J. M.
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机构:
Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Sun, Yongliang
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h-index: 0
机构: Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Nowak, Urszula M.
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h-index: 0
机构: Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Clark, Jan
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h-index: 0
机构:
Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Howlett, Sarah
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h-index: 0
机构:
Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Pekalski, Marcin L.
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h-index: 0
机构:
Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Yang, Xin
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h-index: 0
机构:
Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Ast, Oliver
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h-index: 0
机构:
Roche Innovat Ctr Zurich, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Waldhauer, Inja
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h-index: 0
机构:
Roche Innovat Ctr Zurich, Oncol Discovery & Translat Area, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Freimoser-Grundschober, Anne
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机构:
Roche Innovat Ctr Zurich, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Moessner, Ekkehard
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机构:
Roche Innovat Ctr Zurich, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Umana, Pablo
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机构:
Roche Innovat Ctr Zurich, Oncol Discovery & Translat Area, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Klein, Christian
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机构:
Roche Innovat Ctr Zurich, Oncol Discovery & Translat Area, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Hosse, Ralf J.
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h-index: 0
机构:
Roche Innovat Ctr Zurich, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Wicker, Linda S.
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England

Peterson, Laurence B.
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England
机构:
[1] Univ Cambridge, NIHR Cambridge Biomed Res Ctr, JDRF Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge CB2 OXY, England
[2] Roche Innovat Ctr Zurich, Oncol Discovery & Translat Area, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland
[3] Roche Innovat Ctr Zurich, Roche Pharmaceut Res & Early Dev, CH-8952 Schlieren, Switzerland
基金:
英国惠康基金;
英国医学研究理事会;
关键词:
Cytokine therapy;
Autoimmunity;
Graft versus host disease;
IL-2 fusion proteins;
Regulatory T cells;
LOW-DOSE INTERLEUKIN-2;
RECOMBINANT INTERLEUKIN-2;
NONHUMAN-PRIMATES;
FOXP3;
EXPRESSION;
EXPANSION;
IMMUNITY;
THERAPY;
PHARMACOKINETICS;
IMMUNODEFICIENCY;
D O I:
10.1016/j.jaut.2014.10.002
中图分类号:
R392 [医学免疫学];
Q939.91 [免疫学];
学科分类号:
100102 ;
摘要:
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-FcR gamma 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. (C) 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license.
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页码:66 / 80
页数:15
相关论文
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Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Cambridge CB2 0XY, England Kings Coll London, Sch Med, Dept Immunobiol, London SE1 9RT, England

Wicker, Linda S.
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Cambridge CB2 0XY, England Kings Coll London, Sch Med, Dept Immunobiol, London SE1 9RT, England

Tree, Timothy I. M.
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h-index: 0
机构:
Kings Coll London, Sch Med, Dept Immunobiol, London SE1 9RT, England
Guys & St Thomas Natl Hlth Serv Fdn Trust, Biomed Res Ctr, Natl Inst Hlth Res, London SE1 7EH, England
Kings Coll London, London SE1 7EH, England Kings Coll London, Sch Med, Dept Immunobiol, London SE1 9RT, England
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Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

Bensimon, Gilbert
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h-index: 0
机构:
Hop La Pitie Salpetriere, AP HP, Dept Clin Pharmacol, Paris, France
Univ Paris 06, UPMC, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

Payan, Christine A.
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h-index: 0
机构:
Hop La Pitie Salpetriere, AP HP, Dept Clin Pharmacol, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

Jacqueminet, Sophie
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h-index: 0
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Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

Bourron, Olivier
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h-index: 0
机构:
Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

Nicolas, Nathalie
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h-index: 0
机构:
Hop La Pitie Salpetriere, AP HP, Clin Invest Ctr Paris Est CIC 9304, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

Fonfrede, Michele
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h-index: 0
机构:
Hop La Pitie Salpetriere, AP HP, Dept Biochem, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

Rosenzwajg, Michelle
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h-index: 0
机构:
Hop La Pitie Salpetriere, Biotherapy Dept, Clin Invest Ctr Biotherapies & Inflammat Immu, F-75013 Paris, France
Univ Paris 06, UPMC, Paris, France
INSERM, UMR S 959, Paris, France
CNRS, UMR 7211, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

Bernard, Claude
论文数: 0 引用数: 0
h-index: 0
机构:
Hop La Pitie Salpetriere, Biotherapy Dept, Clin Invest Ctr Biotherapies & Inflammat Immu, F-75013 Paris, France
Univ Paris 06, UPMC, Paris, France
INSERM, UMR S 959, Paris, France
CNRS, UMR 7211, Paris, France Hop La Pitie Salpetriere, AP HP, Dept Diabetol, Paris, France

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Hinton, PR
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Prot Design Labs, Fremont, CA 94555 USA Prot Design Labs, Fremont, CA 94555 USA

Xiong, JM
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h-index: 0
机构:
Prot Design Labs, Fremont, CA 94555 USA Prot Design Labs, Fremont, CA 94555 USA

Johlfs, MG
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h-index: 0
机构:
Prot Design Labs, Fremont, CA 94555 USA Prot Design Labs, Fremont, CA 94555 USA

Tang, MT
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机构:
Prot Design Labs, Fremont, CA 94555 USA Prot Design Labs, Fremont, CA 94555 USA

Keller, S
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h-index: 0
机构:
Prot Design Labs, Fremont, CA 94555 USA Prot Design Labs, Fremont, CA 94555 USA

Tsurushita, N
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h-index: 0
机构:
Prot Design Labs, Fremont, CA 94555 USA Prot Design Labs, Fremont, CA 94555 USA