Phosphatidylserine-Liposomes Promote Tolerogenic Features on Dendritic Cells in Human Type 1 Diabetes by Apoptotic Mimicry

Abstract

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.

Antigen-specific immunotherapy combined with a regenerative drug in the treatment of experimental type 1 diabetes

“…PSAB-liposomes prevented T1D in the NOD mice 8 , 9 by inducing tolerogenic DCs. Furthermore, this tolerogenic effect was also validated in human DCs from subjects with T1D 10 , 11 . With the aim to combine this immunotherapy with a regenerative strategy, we previously performed a Drug Repurposing analysis to search for already-existing compounds able to promote β-cell regeneration.…”

Reversal of Hyperglycemia and Suppression of Type 1 Diabetes in the NOD Mouse with Apoptotic DNA Immunotherapy™ (ADi™), ADi-100

“…In addition, ex vivo chemically-induced apoptosis of mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) [4] demonstrated efficacy in the autoimmune conditions of experimental autoimmune encephalomyelitis and T1D in mice and multiple sclerosis in human trials [40]. Others are using liposomes containing tolerogenic apoptosis mimicry substances such as phosphatidylserine to deliver autoantigen to tol-DCs from human T1D subjects [41].…”

All the small things: How virus‐like particles and liposomes modulate allergic immune responses

“…Similarly, critical contributions to binding and uptake of envelope proteins were also described for hepatitis C‐derived VNPs . For liposomes, enhanced PS‐mediated uptake has been proven in human and mouse models of tolerance induction in type I diabetes .…”