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

Abstract

Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. To revert type 1 diabetes, the suppression of the autoimmune attack should be combined with a β-cell replacement strategy. It has been previously demonstrated that liraglutide, a glucagon-like peptide-1 receptor agonist, restores β-cell mass in type 1 diabetes, via α-cell transdifferentiation and neogenesis. We report here that treatment with liraglutide does not prevent type 1 diabetes in the spontaneous non-obese diabetic (NOD) mouse model, but it tends to reduce leukocytic islet infiltration. However, in combination with an immunotherapy based on tolerogenic liposomes, it is effective in ameliorating hyperglycaemia in diabetic NOD mice. Importantly, liraglutide is not detrimental for the tolerogenic effect that liposomes exert on dendritic cells from patients with type 1 diabetes in terms of membrane expression of molecules involved in antigen presentation, immunoregulation and activation. Moreover, the in vivo effect of the combined therapy was tested in mice humanised with peripheral blood mononuclear cells from patients with type 1 diabetes, showing no adverse effects in leukocyte subsets. In conclusion, the combination therapy with liraglutide and a liposome-based immunotherapy is a promising candidate strategy for type 1 diabetes.

Delivery Route Considerations for Designing Antigen‐Specific Biomaterial Strategies to Combat Autoimmunity

“…[103] Various preclinical studies using biomaterials focus on S.C. delivery. [99][100][101][102][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120] These therapies combine antigen with immunomodulatory cues (i.e., cytokines, toll-like receptor antagonists, immunosuppressants, etc.) through loading or coupling with NPs and MPs to enable combinatory presentation to relevant immune cells.…”

Novel delivery mechanisms for antigen-specific immunotherapy

“…Several groups have used these particulate systems as treatment for autoimmunity generally and for T1D in particular [32]. Particlesin this section can be divided into three categories: encapsulating liposomes/lipoplexes [28,[33][34][35] and encapsulating nonliposomes [36][37][38][39], decorated metal particles [21,40,41,42,43 Copyright © 2021 Wolters Kluwer Health, Inc. rights reserved. Regarding liposomes/lipoplexes, all three examples encapsulate biological molecules and are meant to target APCs.…”

“…Regarding liposomes/lipoplexes, all three examples encapsulate biological molecules and are meant to target APCs. Both Akimoto et al [33] and Villalba et al [34,35] used liposomes to encapsulate insulin peptides. The former incorporated the lipid a-galactosylceramide (a-GalCer), a ligand for iNKT cells, and encapsulated insulin B chain 9-23 (InsB 9-23 ), resulting in a synergistic augmentation of tolerance, including transferrable prevention of T1D in young NOD mice, reduction of insulitis, and increase of pancreatic FoxP3þ Tregs.…”

“…A single injection in NOD mice at 8 weeks of age (WOA) lowered disease incidence, decreased insulitis, and was safe and well-tolerated [34]. A second study [35] determined that liposomes combined with the b cell regenerating agent liraglutide maintained low blood glucose for longer than either therapy alone and that there are early signs this may be effective in humans. Another study discussed above [28] used lipoplexes to encapsulate mRNA and protect it from degradation, comparing the product to electroporated DCs.…”

“…Several groups have used these particulate systems as treatment for autoimmunity generally and for T1D in particular [32]. Particles in this section can be divided into three categories: encapsulating liposomes/lipoplexes [28,33–35] and encapsulating nonliposomes [36–39], decorated metal particles [21,40,41,42,43,44 ▪▪ ,45 ▪▪ ], and negatively charged PLG nanoparticles [46,47,48,49,50 ▪ –52 ▪ ]. Here, we only highlight recent, novel antigen delivery micro/nanoparticles (summarized in Fig.…”