Prevention of Type 1 Diabetes via a Lipid Nanoparticle-Based Oral Immunotherapy that Targets Selective Lymphoid Tissues

Abstract

Abstract Type 1 diabetes (T1D) is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Antigen presenting cells (APCs) malfunctions and aberrant accumulation of type 1 interferons contribute to T1D, and the inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of the disease. However, maintenance of a therapeutic concentration of these drugs is challenging and their prolonged use leads to significant side effects. Our objective was to design a controlled and localized delivery of Tofa via lipid nanoparticles (LNp) and assess the impact of an oral short-term administration strategy on T1D development. We identified a LNp formulation with negligible toxicity, readily taken up by multiple immune cells, and with favorable Tofa encapsulation efficiency. Live animal imaging confirmed these particles have the unique property of accumulating in lymphoid tissues, particularly in pancreatic and mesenteric lymph nodes when administrated via oral gavage. Importantly, short-term administration (5 gavages once every other day) of Tofa-LNp early (3-week-old) or late (10-week-old) in disease prone NOD mice promoted a significant delay of T1D onset. Cell profiling and in vivo challenges indicated that this therapeutic effect is likely due to localized inhibition of APCs maturation and, surprisingly, promotion of anergy in diabetogenic T cells. Ex-vivo stimulation confirmed the hyporeactivity of these cells and adoptive transfer experiments confirmed their ability to act as reservoir of induced regulatory T cells. These results highlight the versatility of this novel LNp-based drug delivery strategy. This work was supported by grant 2-SRA-2016-310-S-B from the Juvenile Diabetes Research Foundation.