Phosphatidylserine-liposomes promote tolerogenic features on dendritic cells in human type 1 diabetes by apoptotic mimicry
Rodriguez Fernandez, Silvia (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Pujol-Autonell, Irma (Institut Germans Trias i Pujol)
Brianso, Ferran (Universitat de Barcelona. Departament de Genètica, Microbiologia i Estadística)
Perna-Barrull, David (Institut Germans Trias i Pujol)
Cano-Sarabia, Mary (Institut Català de Nanociència i Nanotecnologia)
García Jimeno, Sonia (Institut Català de Nanociència i Nanotecnologia)
Villalba Felipe, Adrián (Institut Germans Trias i Pujol)
Sánchez, Alex (Universitat de Barcelona. Departament de Genètica, Microbiologia i Estadística)
Aguilera, Eva (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Vázquez, Federico (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Verdaguer, Joan (Universitat de Lleida. Departament de Medicina Experimental)
Maspoch Comamala, Daniel (Institució Catalana de Recerca i Estudis Avançats)
Vives Pi, Marta (Institut Germans Trias i Pujol)

Data:	2018
Resum:	Type 1 diabetes (T1D) is a metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. With its incidence increasing worldwide, to find a safe approach to permanently cease autoimmunity and allow β-cell recovery has become vital. Relying on the inherent ability of apoptotic cells to induce immunological tolerance, we demonstrated that liposomes mimicking apoptotic β-cells arrested autoimmunity to β-cells and prevented experimental T1D through tolerogenic dendritic cell (DC) generation. These liposomes contained phosphatidylserine (PS)-the main signal of the apoptotic cell membrane-and β-cell autoantigens. To move toward a clinical application, PS-liposomes with optimum size and composition for phagocytosis were loaded with human insulin peptides and tested on DCs from patients with T1D and control age-related subjects. PS accelerated phagocytosis of liposomes with a dynamic typical of apoptotic cell clearance, preserving DCs viability. After PS-liposomes phagocytosis, the expression pattern of molecules involved in efferocytosis, antigen presentation, immunoregulation, and activation in DCs concurred with a tolerogenic functionality, both in patients and control subjects. Furthermore, DCs exposed to PS-liposomes displayed decreased ability to stimulate autologous T cell proliferation. Moreover, transcriptional changes in DCs from patients with T1D after PS-liposomes phagocytosis pointed to an immunoregulatory prolife. Bioinformatics analysis showed 233 differentially expressed genes. Genes involved in antigen presentation were downregulated, whereas genes pertaining to tolerogenic/anti-inflammatory pathways were mostly upregulated. In conclusion, PS-liposomes phagocytosis mimics efferocytosis and leads to phenotypic and functional changes in human DCs, which are accountable for tolerance induction. The herein reported results reinforce the potential of this novel immunotherapy to re-establish immunological tolerance, opening the door to new therapeutic approaches in the field of autoimmunity.
Ajuts:	Ministerio de Economía y Competitividad FIS/PI15/00198 Ministerio de Economía y Competitividad SEV-2013-0295 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014-SGR-1365
Nota:	Altres ajuts: This work has been supported by positive discussion through A FACTT network (Cost Action BM1305: www.afactt.eu). COST is supported by the EU Framework Program Horizon 2020. SR-F is supported by the Agency for Management of University and Research Grants (AGAUR) of the Generalitat de Catalunya.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Immunotherapy ; Autoimmunity ; Human type 1 diabetes ; Liposomes ; Tolerance ; Dendritic cells
Publicat a:	Frontiers in immunology, Vol. 9 (Feb. 2018) , art. 253, ISSN 1664-3224

DOI: 10.3389/fimmu.2018.00253
PMID: 29491866

17 p, 2.4 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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