(396d) Engineering Lymph-Node Targeting Vaccines for Type 1 Diabetes

Vaccine approaches to restore antigen-specific immune tolerance to pancreatic beta-cell antigens without global immune suppression are potential therapeutic interventions for Type 1 diabetes (T1D). However, a method for realizing both efficacy and safety is yet to be developed. A major challenge in the development of effective vaccines is efficient delivery of vaccine components to antigen presenting cells (APCs) in lymphoid organs, where the orchestrations of immune cells are initiated.

We recently demonstrated that both the efficacy and safety of subunit vaccines can be dramatically enhanced by rational molecular design which target lymphoid organs via â??albumin-hitchhikingâ??, a mechanism by which structurally optimized molecular vaccines are engineered with a lipophilic albumin-binding tail and follow subcutaneous injection, exhibit dramatic increases in LN accumulation via in situ complexation and transport with endogenous albumin, leading to 30-fold augmentation in CD8+ T-cell priming while greatly reducing systemic toxicity. Here we translate these findings to deliver immune suppressive vaccines to LNs, where they can be efficiently filtered by resident phagocytes and accumulate, promoting antigen-specific tolerance. Treatment of NOD mice with albumin-hitchhiking peptide vaccines significantly delayed and reduced the incidence of diabetes. This is associated with significant suppression of antoreactive CD4 T cells and increased frequency of regulatory T cells, as well as increased suppressive cytokine productions. Our findings suggest antigen delivery to lymph nodes via albumin-hitchhiking might be broadly applicable to treat autoimmune diseases.