Preclinical evaluation of antigen-specific nanotherapy based on phosphatidylserine-liposomes for type 1 diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing cells. Due to the ability of apoptotic cells clearance to induce tolerance, we previously generated liposomes rich in phophatidylserine (PS)-a feature of apoptotic cells-loaded with insulin peptides to mimic apoptotic beta-cells. PS-liposomes arrested autoimmunity in experimental T1D through the induction of tolerance. The aim of this study was to investigate the potential of several peptides from different T1D autoantigens encapsulated in (PS)-liposomes for T1D prevention and to assess its safety. T1D autoantigens (Insulin, C-peptide, GAD65 and IA2) were encapsulated in PS-liposomes. Liposomes were administered to the 'gold-standard' model for the study of autoimmune T1D, the Non-Obese Diabetic mouse, that spontaneously develop the disease. Safety and toxicity of liposomes were also determined. Only PS-liposomes encapsulating insulin peptides decrease T1D incidence in the Non-Obese Diabetic mouse model. Disease prevention correlates with a decrease in the severity of the autoimmune islet destruction driven by leukocytes. PS-liposomes neither showed toxic effect nor secondary complications. Among the here referred autoantigens, insulin peptides are the best candidates to be encapsulated in liposomes, like an artificial apoptotic cell, for the arrest of autoimmunity in T1D in a safe manner.

GABA Administration Ameliorates Sjogren’s Syndrome in Two Different Mouse Models

“…Finally, in the T1D field, some experimental immunotherapies do not reduce the quantity of islet infiltrates, but rather shift their composition toward a “benign insulitis”. The benign insulitis is composed of more regulatory cells, such as Tregs, and fewer pro-inflammatory cells and is associated with long-term tolerance to the insulin-producing β-cells (e.g., [ 58 , 59 , 60 ]). In a similar fashion, GABA treatment may have led to a more “benign sialadenitis” in which pathogenic cells gave way to regulatory cells.…”

Tolerance induction by liposomes targeting a single CD8 epitope IGRP206–214 in a model of type 1 diabetes is impeded by co‐targeting a CD4+ islet epitope

“…However, the multiple‐epitope vaccine only induced marginal disease protection. Another study delivering a cocktail of islet epitopes in phosphatidylserine liposomes did not find improved disease protection 25 . However, tolerance has been induced by long‐peptide or whole‐protein vaccines, where it is not usually clear whether both CD4 and CD8 epitopes are efficiently presented by antigen‐presenting cells, and which epitopes contribute to tolerance induction 26,27 .…”

A Treg-Selective IL-2 Mutein Prevents the Formation of Factor VIII Inhibitors in Hemophilia Mice Treated With Factor VIII Gene Therapy

“…Previous experiments performed in this lab have shown similar effectiveness in preventing inhibitor formation using the IL-2/IL-2 antibody complex (20) and low-dose IL-2 using the same hydrodynamic gene therapy and mouse strain; a side-by-side comparison experiment could be performed to directly compare the effectiveness of these treatment methods. In addition, the use of half-life-extended IL-2 muteins and antigen therapy could also be applicable to other immune-related diseases that require the tolerance promoted by activated Tregs, such as organ transplant rejection (62,63) and autoimmune and allergic diseases where the antigens promoting the immune-mediated pathology are known (64)(65)(66)(67).…”