Journal
JOURNAL OF AUTOIMMUNITY
Volume 81, Issue -, Pages 44-55Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2017.03.005
Keywords
Autoimmunity; Heme oxygenase-1; T-lymphocyte; Migration; Diabetes; Auto-immune encephalomyelitis; Delayed type hypersensitivity; Tolerance; Monocyte-derived dendritic cells
Categories
Funding
- Fondation Progreffe
- JDRF [5-2010-640]
- IMBIO network
- Region Pays de la Loire
- IHU-Cesti project
- Investissements d'Avenir French Government
- Nantes Metropole and Region Pays de la Loire
- [ANR-10-IDEX-0001-02 PSL]
- [ANR-11-LABX-0043]
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Developing protocols aimed at inhibiting effector T cells would be key for the treatment of T cell dependent autoimmune diseases including type 1 autoimmune diabetes (T1D) and multiple sclerosis (MS). While heme oxygenase-1 (HO-1) inducers are clinically approved drugs for non-immune -related diseases, they do have immunosuppressive properties when administered systemically in rodents. Here we show that HO-1 inducers inhibit antigen-specific effector T cells when injected intradermally together with the T cell cognate antigens in mice. This phenomenon was observed in both a CD8(+) T cell-mediated model of T1D and in a CD4(+) T cell-dependent MS model. Intradermal injection of HO-1 inducers induced the recruitment of HO-1(+) monocyte-derived dendritic cell (MoDCs) exclusively to the lymph nodes (LN) draining the site of intradermal injection. After encountering HO-1(+)MoDCs, effector T-cells exhibited a lower velocity and a reduced ability to migrate towards chemokine gradients resulting in impaired accumulation to the inflamed organ. Intradermal co-injection of a clinically approved HO-1 inducer and a specific antigen to non-human primates also induced HO-1(+) MoDCs to accumulate in dermal draining LN and to suppress delayed-type hypersensitivity. Therefore, in both mice and non-human primates, HO-1 inducers delivered locally inhibited effector T-cells in an antigen-specific manner, paving the way for repositioning these drugs for the treatment of immune-mediated diseases. (C) 2017 Elsevier Ltd. All rights reserved.
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