Prevention of Type 1 Diabetes via a Lipid Nanoparticle-Based JAK inhibitor Treatment that Involves Anergy Formation

Abstract Type 1 diabetes is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. The inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of this disease. To improve on drug bioavailability and reduce deleterious systemic exposure, we identified a lipid nanoparticle (LNp) formulation with favorable Tofa encapsulation efficiency and negligible cellular toxicity. Live animal imaging indicated these particles have the unique property of accumulating in lymphoid tissues, particularly in pancreatic and mesenteric lymph nodes when administrated via oral gavage. Spectral flow analysis revealed that multiple immune cells, like dendritic cells, T cells, and B cells, uptake the particles in these tissues. 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 disease onset. Importantly, the therapeutic effect was associated with a profound increase in anergic CD4 T cells in the draining sites of LNp. Anergic cells have been known to form following stimulation in absence of co-stimulation, however, additional in vitro stimulation assays suggest a distinctive path of anergy induction promoted by blocking cytokine signaling. Overall, our results suggest an unexpected and novel immunomodulatory effect of JAK inhibition that warrants further investigation for the development of an effective treatment of type 1 diabetes.