Strategies capable of specifically abrogating autoimmune responses in an antigen-specific manner would revolutionize the treatment of autoimmune diseases. The liver is continuously exposed to non-pathogenic food, self, and microbial antigens and thus has acquired specialized mechanisms that induce immune tolerance to antigens. In the liver, antigens taken up by hepatic antigen presenting cells (HAPCs), are presented to T cells in the presences of anti-inflammatory mediators, which induces T cell deletion and anergy. For this reason, we hypothesized that a biomaterial-based strategy that targets antigens to HAPCs would induce antigen-specific tolerance. In order to target antigens to HAPCs, we identified receptors for N-acetylgalactosamine, which are enriched on HAPCs, as suitable targets for antigen delivery. Here, we present a synthetic N-acetylgalactosamine glycol-polymer, termed pGal, that when conjugated to protein antigens targets these antigens to HAPCs and thus induces antigen-specific tolerance. Conjugates of pGal and the fluorescent protein phycoerythrin (PE) were synthesized and administered to mice via tail vein injection. Flow cytometry analysis of the liver cells revealed that liver sinusoidal endothelial cells, hepatocytes, and stellate cells from mice treated with pGal-PE had a multi-fold increase in the percentage of PE+ cells as compared to mice treated with free PE. To demonstrate the ability of pGal-antigen conjugates to prevent the development of autoimmunity, we treated nonobese diabetic (NOD) mice with pGal-insulin conjugates via weekly tail vein injection. After 30 weeks, only 45% of the animals treated with pGal-insulin developed diabetes, whereas 93% of the mice treated with appropriate controls developed diabetes (Figure 1). Given the ability to tether pGal to virtually any protein antigen, we anticipate that pGal conjugates can be used to treat and prevent a variety of autoimmune disorders as well as host versus graph diseases.

Poly(n-acetylgalactosamine)-antigen conjugates induce antigen-specific tolerance

249th National Meeting (2015)

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