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. [1 ]
Sun, Yongliang
Nowak, Urszula M.
Clark, Jan [1 ]
Howlett, Sarah [1 ]
Pekalski, Marcin L. [1 ]
Yang, Xin [1 ]
Ast, Oliver [3 ]
Waldhauer, Inja [2 ]
Freimoser-Grundschober, Anne [3 ]
Moessner, Ekkehard [3 ]
Umana, Pablo [2 ]
Klein, Christian [2 ]
Hosse, Ralf J. [3 ]
Wicker, Linda S. [1 ]
Peterson, Laurence B. [1 ]
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.
引用
收藏
页码:66 / 80
页数:15
相关论文
共 47 条
[1]   Low-Dose IL-2 for In Vivo Expansion of CD4+ and CD8+ Regulatory T Cells in Nonhuman Primates [J].
Aoyama, A. ;
Klarin, D. ;
Yamada, Y. ;
Boskovic, S. ;
Nadazdin, O. ;
Kawai, K. ;
Schoenfeld, D. ;
Madsen, J. C. ;
Cosimi, A. B. ;
Benichou, G. ;
Kawai, T. .
AMERICAN JOURNAL OF TRANSPLANTATION, 2012, 12 (09) :2532-2537
[2]   DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells [J].
Baron, Udo ;
Floess, Stefan ;
Wieczorek, Georg ;
Baumann, Katrin ;
Gruetzkau, Andreas ;
Dong, Jun ;
Thiel, Andreas ;
Boeld, Tina J. ;
Hoffmann, Petra ;
Edinger, Matthias ;
Tuerbachova, Ivana ;
Hamann, Alf ;
Olek, Sven ;
Huehn, Jochen .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2007, 37 (09) :2378-2389
[3]   Bispecific human IgG by design [J].
Carter, P .
JOURNAL OF IMMUNOLOGICAL METHODS, 2001, 248 (1-2) :7-15
[4]   IL-2 Simultaneously Expands Foxp3+ T Regulatory and T Effector Cells and Confers Resistance to Severe Tuberculosis (TB): Implicative Treg-T Effector Cooperation in Immunity to TB [J].
Chen, Crystal Y. ;
Huang, Dan ;
Yao, Shuyu ;
Halliday, Lisa ;
Zeng, Gucheng ;
Wang, Richard C. ;
Chen, Zheng W. .
JOURNAL OF IMMUNOLOGY, 2012, 188 (09) :4278-4288
[5]   Resolving the identity myth: Key markers of functional CD4+FoxP3+ regulatory T cells [J].
Chen, Xin ;
Oppenheim, Joost J. .
INTERNATIONAL IMMUNOPHARMACOLOGY, 2011, 11 (10) :1489-1496
[6]   Further analysis of interleukin-2 receptor subunit expression on the different human peripheral blood mononuclear cell subsets [J].
David, D ;
Bani, L ;
Moreau, JL ;
Demaison, C ;
Sun, K ;
Salvucci, O ;
Nakarai, T ;
de Montalembert, M ;
Chouaïb, S ;
Joussemet, M ;
Ritz, J ;
Thèze, J .
BLOOD, 1998, 91 (01) :165-172
[7]   Interleukin-2 is essential for CD4+CD25+ regulatory T cell function [J].
de la Rosa, M ;
Rutz, S ;
Dorninger, H ;
Scheffold, A .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2004, 34 (09) :2480-2488
[8]   Type 1 Diabetes-Associated IL2RA Variation Lowers IL-2 Signaling and Contributes to Diminished CD4+CD25+ Regulatory T Cell Function [J].
Garg, Garima ;
Tyler, Jennifer R. ;
Yang, Jennie H. M. ;
Cutler, Antony J. ;
Downes, Kate ;
Pekalski, Marcin ;
Bell, Gwynneth L. ;
Nutland, Sarah ;
Peakman, Mark ;
Todd, John A. ;
Wicker, Linda S. ;
Tree, Timothy I. M. .
JOURNAL OF IMMUNOLOGY, 2012, 188 (09) :4644-4653
[9]   Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial [J].
Hartemann, Agnes ;
Bensimon, Gilbert ;
Payan, Christine A. ;
Jacqueminet, Sophie ;
Bourron, Olivier ;
Nicolas, Nathalie ;
Fonfrede, Michele ;
Rosenzwajg, Michelle ;
Bernard, Claude ;
Klatzmann, David .
LANCET DIABETES & ENDOCRINOLOGY, 2013, 1 (04) :295-305
[10]   An engineered human IgG1 antibody with longer serum half-life [J].
Hinton, PR ;
Xiong, JM ;
Johlfs, MG ;
Tang, MT ;
Keller, S ;
Tsurushita, N .
JOURNAL OF IMMUNOLOGY, 2006, 176 (01) :346-356