Tolerogenic Artificial Antigen Presenting Cells for Selective Tolerance in Autoimmune Disease

Abstract

Abstract Autoimmune diseases like multiple sclerosis (MS) and type 1 diabetes develop when autoreactive immune cells attack healthy cells and tissues. Current treatments are non-curative and leave patients immunocompromised. As an alternative, therapies that expand regulatory T cells (Tregs) are being actively explored to establish antigen-specific tolerance. We recently showed that an IL-2 immunocytokine (IL-2_IC), a fusion of an antibody to IL-2, preferentially engages and expands Tregs over effector T cells. As a more targeted approach to tolerize the immune system towards a specific autoantigen, we explored the design and therapeutic efficacy of a microparticle bearing an IL-2_IC and an MHC II/peptide complex on its surface (TolAPC). Microparticles composed of a blend of PLGA and PBAE were loaded with rapamycin, and then chemically conjugated with IL-2_IC and MHC II I-A(b) tetramers loaded with a peptide derived from myelin oligodendrocyte glycoprotein (MOG). Characterized TolAPC were tested in a mouse model of MS, Experimental Autoimmune Encephalomyelitis (EAE). When administered prophylactically, TolAPC delayed EAE development and reduced severity compared to unconjugated controls, with 36.4% of mice remaining asymptomatic for the duration of the study. When administered therapeutically, TolAPC reversed symptomatic EAE. Clinical improvements correlated with a nearly two-fold increase in Tregs in the brain and spinal cord of TolAPC-treated mice compared to controls six days after treatment. Furthermore, administration of additional booster doses led to sustained amelioration of the disease. Overall, TolAPC can selectively expand Tregs and provide both protection and treatment in an autoimmune mouse model. Supported by grants from DoD (W81XWH-18-1-0735; W81XWH-21-1-0892), NIH (R01EB029455), and JDRF (1-INO-2020-923-A-N)