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Int. J. Mol. Sci. 2014, 15(10), 18574-18592;

Low-Dose Interleukin-2 Therapy: A Driver of an Imbalance between Immune Tolerance and Autoimmunity

Institute of Immunology and Experimental Therapy, Department of Experimental Therapy, Polish Academy of Sciences, 12 R. Weigla St., 53-114 Wroclaw, Poland
Received: 22 August 2014 / Revised: 22 September 2014 / Accepted: 8 October 2014 / Published: 15 October 2014
(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)
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For many years, the role of interleukin-2 (IL-2) in autoimmune responses was established as a cytokine possessing strong pro-inflammatory activity. Studies of the past few years have changed our knowledge on IL-2 in autoimmune chronic inflammation, suggesting its protective role, when administered at low-doses. The disrupted balance between regulatory and effector T cells (Tregs and Teffs, respectively) is a characteristic of autoimmune diseases, and is dependent on homeostatic cytokines, including IL-2. Actually, inherent defects in the IL-2 signaling pathway and/or levels leading to Treg compromised function and numbers as well as Th17 expansion have been attributed to autoimmune disorders. In this review, we discuss the role of IL-2 in the pathogenesis of autoimmune diseases. In particular, we highlight the impact of the dysregulated IL-2 pathway on disruption of the Treg/Th17 balance, reversal of which appears to be a possible mechanism of the low-dose IL-2 treatment. The negative effects of IL-2 on the differentiation of follicular helper T cells (Tfh) and pathogenic Th17 cells, both of which contribute to autoimmunity, is emphasized in the paper as well. We also compare the current IL-2-based therapies of animal and human subjects with immune-mediated diseases aimed at boosting the Treg population, which is the most IL-2-dependent cell subset desirable for sufficient control of autoimmunity. New perspectives of therapeutic approaches focused on selective delivery of IL-2 to inflamed tissues, thus allowing local activity of IL-2 to be combined with its reduced systemic and pleiotropic toxicity, are also proposed in this paper. View Full-Text
Keywords: interleukin-2; immunotherapy; immune-mediated disease; autoimmunity; immune tolerance; clinical trial interleukin-2; immunotherapy; immune-mediated disease; autoimmunity; immune tolerance; clinical trial
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kosmaczewska, A. Low-Dose Interleukin-2 Therapy: A Driver of an Imbalance between Immune Tolerance and Autoimmunity. Int. J. Mol. Sci. 2014, 15, 18574-18592.

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