Use of Autoantigen-Loaded Phosphatidylserine-Liposomes to Arrest Autoimmunity in Type 1 Diabetes

Abstract

IntroductionThe development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes.ObjectiveTo generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes.MethodsA central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides.ResultsWe have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion.ConclusionsWe conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for autoimmune diseases.

Liposome-Based Immunotherapy Against Autoimmune Diseases: Therapeutic Effect on Multiple Sclerosis

“…This conceptual innovation allows us to consider this strategy as a potential platform for the reestablishment of immunological tolerance. In vitro experiments demonstrate that liposomes are phagocytosed by DCs from another experimental model (EAE) inducing the same phenotypic and functional changes in DCs than in the T1D model [8].…”

“…In this sense, several approaches have been developed [7,20,24]. We have recently shown that apoptotic mimicry by means of liposomes -rich in PS and encapsulating autoantigens -arrest autoimmunity in T1D [8]. Therefore, we hypothesized that by replacing the encapsulated autoantigen, PS-liposomes would show therapeutic effect for other autoimmune diseases.…”

“…We recently developed a liposome-based immunotherapy -inspired by the features of apoptotic cells [7] -to re-establish tolerance to self and avoid autoimmune diseases [8]. These liposomes are rich in phosphatidylserine (PS), a phospholipid membrane component that is exposed in apoptotic cells and modulates immune responses [9], and are loaded with self-peptides -named autoantigens -as the selective molecule for tolerance induction.…”

“…Therefore, antigen-specific, simple and safe approaches to recover self-tolerance are required to arrest autoimmunity and to allow target tissue regeneration. In our previous study, an innovative liposome-based immunotherapy -mimicking apoptotic β cells to induce self-tolerance -arrested autoimmunity in Type 1 diabetes (T1D) [8]. Considering the potential of liposomes as immunomodulators, we aimed to develop PS-liposomes for another autoimmune disease, multiple sclerosis (MS), to validate their tolerogenic power.…”

Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 and PD-1 Antibodies in Melanoma

“…When intratumoral dendritic cells bind and ingest PS-expressing cells, they maintain an immature phenotype that prevents the expression of costimulatory molecules required for functional antigen presentation (26,38). Moreover, PS externalized on tumor-derived microvesicles suppresses activation of T-cell responses (39), and administration of PS-expressing liposomes containing insulin restores tolerance in a murine model of autoimmune diabetes (40). Lastly, although chemotherapy induces tumor cell apoptosis, the concomitant expression of PS on these cells (41,42) further suppresses potential immune-associated antitumor responses (43).…”