Interleukin 2 in the Pathogenesis and Therapy of Type 1 Diabetes
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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.
KeywordsTolerance Immunotherapy Autoimmune disease Inflammation Pharmacokinetics
This work was supported by our academic institution (AP-HP, UPMC, INSERM), by the Inflammation-Immunopathology-Biotherapy Department (DHU i2B; http://www.dhu-i2b.fr), by French state funds managed by the ANR within the “Investissements d’Avenir” program under reference ANR-11-IDEX-0004-02, and by DIABIL-2, part of the Seventh Framework Program collaborative project for type 1 diabetes under the grant agreement #305380 (http://www.diabil-2.eu).
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Conflict of Interest
Michelle Rosenzwajg is a shareholder of ILTOO Pharma and is an inventor on a patent application related to the therapeutic use of low-dose IL-2, which belongs to her academic institution and has been licensed to ILTOO Pharma. Guillaume Churlaud is a shareholder of ILTOO Pharma. Agnès Hartemann declares that she has no conflict of interest. David Klatzmann is a shareholder of ILTOO Pharma and is an inventor on a patent application related to the therapeutic use of low-dose IL-2, which belongs to his academic institution and has been licensed to ILTOO Pharma.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 19.Herold KC, Gitelman SE, Ehlers MR, Gottlieb PA, Greenbaum CJ, Hagopian W, et al. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes. 2013;62:3766.PubMedCentralPubMedCrossRefGoogle Scholar
- 20.•Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, et al. Administration of CD4+CD25highCD127-regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care. 2012;35:1817. Proof of concept for using ex vivo expanded Treg in human T1D.PubMedCentralPubMedCrossRefGoogle Scholar
- 47.•Churlaud G, Jimenez V, Ruberte J, Amadoudji Zin M, Fourcade G, Gottrand G, et al. Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer. Clin Immunol. 2014;151:114–26. This study reports the safety and preservation of antiviral and antitumor immune responses upon long term low dose IL-2 delivery in mice.PubMedCrossRefGoogle Scholar
- 49.Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J cancer J. 2010;127:759.Google Scholar
- 54.Landau DA, Rosenzwajg M, Saadoun D, Trebeden-Negre H, Klatzmann D, Cacoub P. Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus-induced mixed cryoglobulinemia vasculitis. Arthritis Rheum. 2008;58:2897.PubMedCrossRefGoogle Scholar
- 66.••Hartemann A, Bensimon G, Payan C, Jacqueminet S, Bourron O, Nicolas N, et al. Low-dose interleukin-2 in patients with type-1 diabetes: a phase 1/2 randomized, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2013;1:295–305. Double-blind placebo controlled evaluation of dose-dependent safety and biological efficacy of low doses of IL-2 in human T1D.PubMedCrossRefGoogle Scholar
- 73.Klatzmann D. Immunoregulation without immunosuppression: the promise of low dose. 2014. FOCIS meeting Chicago.Google Scholar
- 74.S. E. Von Spee-Mayer C, Rose A, Humrich J, Riemekasten G. Low-dose interleukin-2 therapy caused selective expansion of Tregs together with rapid reduction of disease activity in a patient with severe refractory SLE. 2014. EULAR meeting Paris.Google Scholar
- 75.Yu D. Low-dose interleukin-2 in active systemic lupus erythematosus. 2014. FOCIS meeting Chicago.Google Scholar