Phosphatidylserine-liposomes Promote Tolerogenic Features on Dendritic cells in human Type 1 Diabetes by apoptotic Mimicry

dc.contributor.authorRodríguez Fernández, Silvia
dc.contributor.authorPujol Autonell, Irma
dc.contributor.authorBriansó Castilla, Ferran
dc.contributor.authorPerna Barrull, David
dc.contributor.authorCano Sarabia, Antonia María
dc.contributor.authorGarcía Jimeno, Sonia
dc.contributor.authorVillalba, Adrian
dc.contributor.authorSánchez (Sànchez Pla), Álex
dc.contributor.authorAguilera, Eva
dc.contributor.authorVázquez San Miguel, Federico
dc.contributor.authorVerdaguer Autonell, Joan
dc.contributor.authorMaspoch, Daniel
dc.contributor.authorVives Pi, Marta
dc.description.abstractType 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.ca_ES
dc.description.sponsorshipThis work has been funded by a grant from the Spanish Government (FIS PI15/00198) co-financed with the European Regional Development funds (FEDER), by Fundació La Marató de TV3 (28/201632-10), by Catalan AGAUR (project 2014 SGR1365) and by CERCA Program/Generalitat de Catalunya. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III. ICN2 acknowledges the support of the Spanish MINECO through the Severo Ochoa Centers of Excellence Program, under grant SEV-2013-0295. This work has been supported by positive discussion through A FACTT network (Cost Action BM1305: 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.ca_ES
dc.publisherFrontiers Mediaca_ES
dc.relation.isformatofReproducció del document publicat a
dc.relation.ispartofFrontiers in Immunology, 2018, vol. 9, a253ca_ES
dc.rightscc-by (c) Silvia Rodríguez Fernández et al., 2018ca_ES
dc.subjectHuman type 1 diabetesca_ES
dc.subjectDendritic cellsca_ES
dc.titlePhosphatidylserine-liposomes Promote Tolerogenic Features on Dendritic cells in human Type 1 Diabetes by apoptotic Mimicryca_ES
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