Biodegradable polymeric microparticles comprised of acetalated dextran induce immune tolerance

ABSTRACT The clinical treatment of autoimmune diseases traditionally uses immunosuppression to curtail the pathogenesis of the autoimmune disease. An alternative for general immune suppression, is antigen specific tolerance. However, there is currently no antigen specific tolerance therapy in the clinics. We have recently discovered serendipitously that degradable microparticles comprised of the biopolymer acetalated dextran (Ace-DEX) can specifically bind to the surface of B cells both in vitro and in vivo. The binding of this biomaterial microparticle to B cells is due to the protein corona that is uniquely generated by Ace-DEX. The binding of this specific biomaterial to the B cell surface results in the generation of the tolerogenic cytokine IL-10. Uniquely this phenomenon is not observed when the microparticles are fabricated through emulsion, but only when they are fabricated through a spray drying technique. In comparison to other biomaterials, such as poly lactic-co-glycolic acid (PLGA) the observed phenomenon is significantly less compared to Ace-DEX. We observed less binding to B cells and diminished production of IL-10, indicating that our observed effect is biomaterial specific. Further, in the treatment of an animal model of MS, Experimental Autoimmune Encephalomyelitis (EAE), we show that administration of Ace-DEX MPs encapsulating Myelin Oligodendrocyte Glycoprotein (MOG) bound to B cells can drastically decrease the clinical score of EAE. The degree of reduction of clinical score for our treatment in the EAE model was greater than observed in other published antigen specific EAE treatments that used biomaterial particle systems. Further it is significantly improved in comparison to microparticles of other biomaterials (i.e. PLGA). At peak disease we show a drastic decrease in the symptoms of mice with EAE. In this grant we propose three specific aims. In aim one we will focus on biomaterial particle synthesis and characterize the protein corona on the surface of the microparticle to determine the protein(s) responsible for Ace-DEX MPs binding to B cells. We will additionally fully characterize the phenotype of the B cells most influenced by our Ace-DEX biomaterial MPs by using RNA-seq. In the second aim of our proposal, we will optimize our proposed therapy. This includes exploring the route of administration, B cell dose, MP dose, route, and other pharmaceutic parameters. Additionally, we will explore the biodistribution of our adoptively transferred B cells and the attached MPs. Also, we will look at general toxicity of our therapy, as well as the general immune suppression of our proposed therapy. Finally, in the third aim, we will attempt to elucidate the mechanism of action of our proposed therapy. This includes using in vitro methods exploring the interaction of B cells with other cells from the immune system. Additionally, we propose in vivo various knockout mice to explore the mechanism of our novel immunotherapy. Overall, the goal of our proposal is to elucidate the interaction between microparticles comprised of the biomaterial Ace-DEX and B cells.