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Title:
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Treatment of T1D via optimized expansion of antigen-specific Tregs induced by IL-2/anti-IL-2 monoclonal antibody complexes and peptide/MHC tetramers
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Author:
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Izquierdo, Cristina; Zarama Ortiz, Angela; Presa, Maximiliano; Malo, Sara; Montoya, Anna; Garabatos, Nahir; Mora Giral, Concepció; Verdaguer Autonell, Joan; Stratmann, Thomas
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Notes:
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Type 1 diabetes can be overcome by regulatory T cells (Treg) in NOD mice yet an efficient method to generate and maintain antigen-specific Treg is difficult to come by. Here, we devised a combination therapy of peptide/MHC tetramers and IL-2/anti-IL-2 monoclonal antibody complexes to generate antigen-specific Treg and maintain them over extended time periods. We first optimized treatment protocols conceived to obtain an improved islet-specific Treg/effector T cell ratio that led to the in vivo expansion and activation of these Treg as well as to an improved suppressor function. Optimized protocols were applied to treatment for testing diabetes prevention in NOD mice as well as in an accelerated T cell transfer model of T1D. The combined treatment led to robust protection against diabetes, and in the NOD model, to a close to complete prevention of insulitis. Treatment was accompanied with increased secretion of IL-10, detectable in total splenocytes and in Foxp3− CD4 T cells. Our data suggest that a dual protection mechanism takes place by the collaboration of Foxp3+ and Foxp3− regulatory cells. We conclude that antigen-specific Treg are an important target to improve current clinical interventions against this disease.
This work was supported by grants from the Spanish Ministry of Economy, Industry, the Juvenile Diabetes Research Foundation, and Competition and European Regional Development Funds (FEDER; SAF2010-18548 and SAF2011-29319 to T.S.; SAF2016-77227-R and SAF2013-45140-R to J.V. and T.S., SAF2008-02536 and SAF2014-55077-R to C.M.). Research of J.V. was also supported by CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) that is an initiative from the Instituto de Salud Carlos III (Spain). C.I. received a FPU fellowship. C.M., J.V. and T.S. are Serra Húnter Fellows. |
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Rights:
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cc-by (c) Izquierdo et al., 2018
http://creativecommons.org/licenses/by/4.0/
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Document type:
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Article
Article - Published version |
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Published by:
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Nature Publishing Group
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